A novel degradable metal drug-loading method

Abstract

The application relates to the technical field of medical materials, in particular to a novel degradable metal drug loading method. 6 Pa to 3.0x10 7 Pa pressure conditions to press into an ellipsoidal metal block, then the metal block is secondarily pressed under the condition of 5-20 GPa pressure, then pressure is kept for 5-20 hours, finally the pressure is released to normal pressure, and the target drug-loaded metal sample is obtained. The novel degradable metal drug loading method uniformly loads and slowly releases drugs in the degradable metal through a pure physical method for the first time, and solves the problems of small drug loading dose, short release time, drug burst release and the need to introduce a drug carrier in the traditional drug loading method.

Description

Technical Field

[0001] The present invention relates to the technical field of medical materials, and in particular to a novel degradable metal drug loading method. Background Art

[0002] Metal implants, with their advantages of high strength, high toughness, high biocompatibility, and high machinability, play an irreplaceable role in orthopedic surgery. For a long time, people have tried various methods to functionalize metal implants, hoping to give them anti-infection, osteogenesis, and other functions. Drug delivery is the most effective, widest-ranging, and most widely used method. However, traditional drug delivery technologies based on carriers and coatings perform better in porous metals, but are prone to drug release and coating shedding in non-porous metals, making them unsuitable for implants such as nails, plates, and rods that are more widely used in clinical practice. Therefore, there is an urgent need to develop a more universal drug delivery method for non-porous metals. Traditional titanium alloy implants cannot be absorbed by the human body and require secondary removal or lifelong maintenance. Secondary surgery increases the patient's financial burden and surgical risks, and lifelong maintenance may lead to complications such as foreign body reactions and loosening and fracture of internal fixation. To address the above problems, people have designed biodegradable and biofunctionalized metal implants. On the one hand, by allowing metals to degrade, foreign body reactions can be avoided; on the other hand, by giving metals anti-infection and anti-tumor functions, recurrence of primary diseases can be prevented. This is also the future development direction of metal implants.

[0003] Numerous clinical trials have demonstrated the potential of zinc and magnesium alloys as implants for orthopedic surgery. Their biodegradable properties avoid the many drawbacks of secondary removal or lifelong wear, making them promising candidates for next-generation metal implant substrates. Furthermore, the biodegradable nature of zinc and magnesium alloys also opens up the possibility of drug loading. If drugs can be directly mixed with liquid metal and then cooled to a solid state, the metal will be encapsulated within the metal and slowly released as the metal degrades, achieving uniform, slow drug release. However, high temperatures, necessary for metal melting, also render most drugs ineffective. Therefore, ensuring drug activity while uniformly loading them into biodegradable metals presents a pressing technical challenge. High-pressure science studies the changes in the physical and chemical properties of materials under high pressure. The application of extremely high pressures can significantly alter the structure, electronic state, and phase transitions of materials, providing a crucial tool for exploring new materials and discovering novel principles. In the aviation industry, it has long been recognized that extreme environments (such as high pressure and vacuum) can cause atoms on the surface of titanium alloys to form a tight bond without melting at high temperatures, creating a phenomenon known as "cold welding," resulting in a tight connection. In clinical practice, locking screws and titanium plates that are in close contact for a long time will also experience "cold welding", making it difficult to separate the two.

[0004] The current drug-loading method often involves coating a drug layer on the surface of the implant, which continuously releases the drug within a period of time after implantation to exert its corresponding effect. There are two main methods for preparing drug coatings for implants. One is the immersion method, in which the implant is immersed in a solution and then solidified. The other is the ultrasonic spraying method. The process of this process mainly involves preparing a solution of the active drug and a controlled-release carrier (or a single active drug). The solution is then evenly coated on the surface of the implant through an ultrasonic spraying device. After post-processing steps such as drying and curing, the desired drug coating sample is prepared. However, drug coatings have obvious disadvantages, such as the difficulty in accurately controlling the release rate and time of the drug. At the same time, the coating may fall off, causing the risk of local thrombosis. In addition, the modification technology for the coating is often technically complex and costly, making it difficult to achieve clinical transformation.

[0005] Existing medical biodegradable metals are synthesized using techniques such as sintering, casting, and additive manufacturing. However, these inevitably require high temperatures, which can damage the structure and efficacy of the drug, making them theoretically unfeasible. This issue must be avoided if biodegradable metals are to be used for drug delivery. However, traditional methods of combining metals and drug delivery have numerous drawbacks, making it difficult to achieve uniform drug release.

[0006] Based on this, the present invention provides a novel method for drug-loaded degradable metals, which adopts GPa-level pressure to avoid sintering, uses high-pressure theory to synthesize the target product, and realizes the construction of drug-loaded degradable metal implants by room-temperature high-pressure die-casting. Summary of the Invention

[0007] In view of the shortcomings of the above-mentioned prior art, the purpose of the present invention is to provide a new method for drug loading on degradable metals, which realizes non-coating drug loading on degradable metals through room temperature and high pressure technology, and achieves uniform loading and slow release of drugs in degradable metals, solving the problems faced by traditional drug loading methods such as small drug loading dose, short release time, burst drug release, and the need to introduce drug carriers.

[0008] The present invention provides a novel degradable metal drug loading method, comprising the following steps: mixing and dispersing alloy powder and antibiotic powder in a weight ratio of (90-99.9): (0.1-10) to obtain a sample; 6 Pa to 3.0×10 7 Pa pressure conditions to form an ellipsoidal metal block, which is then pressed for a second time under 5-20 GPa pressure conditions, followed by maintaining the pressure for 5-20 hours, and finally releasing the pressure to normal pressure to obtain the target drug-loaded metal sample.

[0009] Furthermore, the particle size of the alloy powder is 20-70 μm.

[0010] Furthermore, the alloy powder includes any one of zinc alloy, zinc-magnesium alloy, magnesium-yttrium-rare earth element alloy or magnesium-yttrium-rare earth element-zirconium alloy.

[0011] Furthermore, the weight percentage of magnesium in the zinc-magnesium alloy is 1%, and the balance is zinc.

[0012] Furthermore, in the magnesium-yttrium-rare earth element alloy, the weight percentage of yttrium is 3.7-4.3%, the weight percentage of rare earth elements is 2.4-4.4%, and the rare earth elements are Nd and / or Gd.

[0013] Furthermore, in the magnesium-yttrium-rare earth element-zirconium alloy, the weight percentage of yttrium is 3.7-4.3%, the weight percentage of rare earth element is 2.4-4.4%, the rare earth element is Nd and / or Gd, and the weight percentage of zirconium is 0.3-1.0%.

[0014] Furthermore, the antibiotics include at least one of penicillins, cephalosporins, novel β-lactams, aminoglycosides, macrolides, lincomycins and quinolones.

[0015] Furthermore, the penicillin antibiotics include any one of penicillin G, ampicillin and amoxicillin.

[0016] Furthermore, the cephalosporin antibiotics include cefazolin and / or cephradine.

[0017] Furthermore, the novel β-lactam antibiotics include meropenem.

[0018] Furthermore, the aminoglycoside antibiotic includes any one of gentamicin, tobramycin and netilmicin.

[0019] Furthermore, the macrolide antibiotics include any one of erythromycin, roxithromycin, and azithromycin.

[0020] Furthermore, the lincomycin antibiotics include lincomycin and / or clindamycin.

[0021] Furthermore, the quinolone antibiotics include any one of norfloxacin, ciprofloxacin, ofloxacin, and levofloxacin.

[0022] Furthermore, the antibiotics include cefuroxime and / or vancomycin.

[0023] Furthermore, the sample is pressed into an ellipsoidal metal block at a pressure of 1 GPa to 20 GPa for a period of 1 to 24 hours.

[0024] Furthermore, the secondary pressing step includes: increasing the pressure to 1-6 GPa at a rate of 0.01-0.1 GPa / min, increasing the pressure to 4-8 GPa at a rate of 0.01-0.1 GPa / min, increasing the pressure to 6-10 GPa at a rate of 0.01-0.1 GPa / min, and increasing the pressure to 8 GPa-20 GPa at a rate of 0.01-0.1 GPa / min.

[0025] Furthermore, the secondary pressing step includes: increasing the pressure to 4 GPa at a rate of 0.06 GPa / min, increasing the pressure to 6 GPa at a rate of 0.04 GPa / min, increasing the pressure to 8 GPa at a rate of 0.02 GPa / min, and increasing the pressure to 10 GPa at a rate of 0.01 GPa / min. 。

[0026] Furthermore, the time for increasing the pressure of the metal block to 8GPa-20GPa is 1-24 hours, and the rate of decompression is 0.01-0.1GPa / min.

[0027] The beneficial effects of the present invention are:

[0028] This invention proposes an innovative method that utilizes high-pressure technology to achieve non-coating drug delivery on biodegradable metals, opening up a new path for drug delivery to biodegradable metals. The core of this method lies in using high pressure to bring metal particles into close contact, shortening the distance between metal atoms to form metallic bonds, and ultimately fusing small metal particles into a large metal bulk. This "cold welding" effect between the metal particles occurs at room temperature, eliminating the need for high-temperature treatment.

[0029] This invention adopts a purely physical method for the first time, using high-pressure die-casting technology at room temperature to evenly load multiple drugs into biodegradable metals, achieving stable loading and slow release of drugs, solving the problems of small drug dosage, short release time and burst release in traditional drug loading methods, and avoiding the need to introduce additional drug carriers.

[0030] The technology of the present invention is not only suitable for loading antibacterial drugs, but also has the potential to load a variety of drugs or biological molecules such as anti-tumor drugs, osteogenic materials, and bioactive substances (such as proteins and nucleic acids), providing a new idea and feasible solution for the functionalization of degradable metal implants.

[0031] The room-temperature, high-pressure technology employed in this invention maintains the structural integrity and bioactivity of the drug while ensuring uniform mixing of the drug with the degradable metal component. As the metal degrades, the drug is stably released, achieving the desired therapeutic effect. Furthermore, since this invention does not require a drug coating, it avoids biocompatibility issues and the risk of coating shedding, thereby improving the overall stability and safety of the material. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 This is a schematic diagram of a non-drug-loaded pressed Zn alloy product in Example 1 of the present invention;

[0033] Figure 2 This is a surface scan of the un-drug-loaded pressed Zn alloy product in Example 1 of the present invention;

[0034] Figure 3 This is a scan of the interior of the un-drug-loaded pressed Zn alloy product in Example 1 of the present invention;

[0035] Figure 4 This is a schematic diagram of the drug-loaded compressed Zn alloy product in Example 1 of the present invention;

[0036] Figure 5 This is a surface scan of the drug-loaded compressed Zn alloy product in Example 1 of the present invention;

[0037] Figure 6 This is a scan of the interior of the drug-loaded compressed Zn alloy product in Example 1 of the present invention;

[0038] Figure 7 This is a load comparison diagram of the unloaded compressed Zn alloy product, the loaded compressed Zn alloy product, and the unloaded compressed Zn alloy product and the loaded compressed Zn alloy product after immersion;

[0039] Figure 8 This is a comparison chart of the elastic modulus of the unloaded compressed Zn alloy product, the loaded compressed Zn alloy product, and the unloaded compressed Zn alloy product and the loaded compressed Zn alloy product after immersion;

[0040] Figure 9 This is a comparison chart of the maximum loads of the unloaded compressed Zn alloy product, the loaded compressed Zn alloy product, and the unloaded compressed Zn alloy product and the loaded compressed Zn alloy product after immersion;

[0041] Figure 10 This is a comparison chart of the antibiotic concentrations released by the unloaded compressed Zn alloy product of the present invention after 15 days and 28 days, and the antibiotic concentrations released by the drug-loaded compressed Zn alloy product after immersion for 15 days and 28 days;

[0042] Figure 11 The unloaded Mg alloy of the present invention (Mg alloy loaded with drug product made under 10 GPa pressure) and the Mg alloy product pressed by a hand press (0 GPa, pressure of 1×10 7 Pa, load comparison diagram of magnesium alloy products made under pressure;

[0043] Figure 12The unloaded Mg alloy of the present invention (Mg alloy loaded with drug product made under 10 GPa pressure) and the Mg alloy product pressed by a hand press (0 GPa, pressure of 1×10 7 Pa, elastic modulus comparison chart of magnesium alloy products made under pressure;

[0044] Figure 13 The unloaded Mg alloy of the present invention (Mg alloy loaded with drug product made under 10 GPa pressure) and the Mg alloy product pressed by a hand press (0 GPa, pressure of 1×10 7 Pa, maximum load comparison chart of magnesium alloy products made under pressure. DETAILED DESCRIPTION

[0045] The following is a clear and complete description of the technical solution of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0046] It should be noted that the zinc alloy and magnesium alloy in the present invention are both from Nanoval, a manufacturer in Germany.

[0047] It should also be noted that in the novel degradable metal drug-loading method provided by the present invention, the weight ratio of the alloy powder to the antibiotic powder is any value in the range of (90-99.9): (0.1-10).

[0048] The present invention will be further described below with specific examples.

[0049] Example 1

[0050] This embodiment provides a novel method for drug loading with degradable metals, wherein metal powder and drug powder are pressed into shape using a Paris-Edinburgh press, and the steps include:

[0051] (1) At room temperature, 1% by weight of the antibiotic cefuroxime was added to Zn alloy powder having a particle size of 40±20 μm and uniformly dispersed to obtain a 580 mg sample;

[0052] The Zn alloy powder in this embodiment is of the type Zn1Mg, i.e., a zinc alloy containing one percent magnesium;

[0053] (2) The sample was placed in a 6 mm diameter mold and pressed with a hand press at a pressure of 1 × 10 7 Pa conditions to form an ellipsoidal metal block, which is then covered with a stainless steel washer for support during pressurization;

[0054] (3) The metal block was rapidly pressurized to 2 GPa within 7 min using a Paris-Edinburgh press equipped with a single-ring sintered diamond anvil;

[0055] (4) Increase the pressure to 4 GPa at a rate of 0.06 GPa / min, increase the pressure to 6 GPa at a rate of 0.04 GPa / min, increase the pressure to 8 GPa at a rate of 0.02 GPa / min, and increase the pressure to 10 GPa at a rate of 0.01 GPa / min;

[0056] (5) After maintaining the pressure for 10 h, the pressure was reduced to normal pressure at a rate of 0.04 GPa / min. Finally, the stainless steel gasket around S3 was removed using a cutting machine to obtain the drug-loaded pressed Zn alloy product.

[0057] It should be further explained that common high-pressure experimental devices include large volume press (LVP) and diamond anvil cell (DAC). The Paris-Edinburgh press is a press between LVP and DAC. It is suitable for large sample volumes (tens of mm2). 3 The system features a convenient operation (concave tungsten carbide or polycrystalline diamond, boron nitride anvils, and prefabricated metal gaskets), and moderate pressure (25 GPa). The system consists of an oil pump and a press. Depending on the required pressure, the anvil materials used are primarily cubic boron nitride, tungsten carbide, and sintered diamond.

[0058] Among them, the structure of the Paris-Edinburgh press is divided into two parts: the oil pump and the press. During the pressurization process, the oil pump will pump oil into the oil cylinder at the bottom of the press at a certain rate, thereby squeezing the pads and anvils on the upper part of the oil cylinder to pressurize the sample. When the pressure is transmitted to the sample, the force-bearing area becomes very small, only on the order of a few square millimeters, so the pressure at the sample position becomes very large, reaching the GPa level. Depending on the sample size, the anvils are mainly divided into single-ring anvils and double-ring anvils. The sample volume of the single-ring anvil is usually 87.1mm 3 , while the sample size of the double ring anvil is usually 31.1mm 3 During the pressurization process, T304 stainless steel is typically used as a sample seal. During the pressurization process, the oil pump pumps oil into the cylinder at the bottom of the press at a certain rate, thereby squeezing the pad and anvil at the top of the cylinder to pressurize the sample.

[0059] Test Example 1: Material Characterization

[0060] The macroscopic morphology of the surface of the target sample in Example 1 was photographed and observed using a precision image measuring instrument, and the microscopic morphology was observed using a scanning electron microscope (SEM, S4800, Hitachi). For comparison, the alloy material was pressed into shape without adding the antibiotic cefuroxime according to the method of Example 1. The results are shown in FIG. Figure 1-6 shown.

[0061] Macroscopic corrosion morphology reveals that the drug-loaded zinc alloy metal is darker, with a rough, granular surface, while the unloaded zinc alloy surface is smoother. Microscopic SEM observations reveal a distinct white antibiotic component within the zinc-drug-loaded sample, uniformly mixed with the metal components, demonstrating that this high-pressure die-casting method successfully constructed the desired biodegradable metal-drug delivery system.

[0062] Test Example 2: Mechanical Test

[0063] The compression test was carried out using a universal tensile testing machine (Instron 5969, USA). The compression rate was set to 2×10 - 4 mm / s. The test was conducted at room temperature, with three parallel samples of each material tested. Mechanical tests were performed on both immersed and unimmersed samples. Immersion refers to the complete immersion of the sample in a 0.85% NaCl solution at room temperature. Referring to GB / T 7314-2017, the maximum load and elastic modulus of the material were obtained through compression testing. GraphPad was used to draw a bar graph and displacement-load curve, as shown in the figure below. Figure 7-9 shown.

[0064] Typically, the elastic modulus of titanium alloy is 110 GPa, the elastic modulus of ordinary zinc alloy is 80-110 GPa, the elastic modulus of cortical bone is 10-30 GPa, and the elastic modulus of die-cast zinc alloy is 1.0-1.5 GPa.

[0065] Normally, the maximum load of titanium alloy is 1200N, and the maximum load of ordinary zinc alloy is generally less than <800N. This product does not reduce the maximum load after drug loading, and its mechanical properties can meet the requirements for implants.

[0066] In orthopedic implants, a large elastic modulus is prone to produce a stress shielding effect, affecting bone growth and healing. The results show that the maximum load of the zinc alloy produced by high-pressure die-casting in the present invention is close to that of traditional zinc alloys, and it has excellent mechanical properties. In fact, due to its porous internal structure, its elastic modulus is even smaller. A smaller elastic modulus has a positive effect on the growth and healing of bone tissue and can effectively reduce the stress shielding effect.

[0067] Test Example 3: Antibacterial Test

[0068] The antibacterial effect test refers to WS / T 650-2019 "Methods for Evaluation of Antibacterial and Antibacterial Effects", 5.1.1 Suspension Quantitative Antibacterial Test, and the test bacteria is Staphylococcus aureus ATCC 6538. The specific steps are as follows:

[0069] (1) Antibacterial experiments were conducted using the WS / T6505.1.1 standard. Samples were soaked in physiological saline. Two samples were added to 50 ml of saline and soaked at room temperature. The soaking solution was used for testing. Three parallel groups were set up for each group.

[0070] (2) Take out 5 ml of the sample every 1, 3, 7, 14, and 28 days for a 4-hour contact time test with Staphylococcus aureus. Immediately after the immersion solution is taken out, fill up the volume with an equal amount of sterile saline. The test ends at day 28.

[0071] The test results are shown in the following table:

[0072]

[0073]

[0074] The table shows the data of antibacterial experiments 1 and 3 days, among which sample 1 is zinc alloy and sample 2 is zinc alloy-cefuroxime complex, that is, drug-loaded compressed Zn alloy product.

[0075] The results showed that there was a significant statistical difference in the antibacterial rates of the two at 1 and 3 days, and the antibacterial rate of the drug-loaded zinc alloy was higher, proving that the high-pressure die-cast drug-loaded zinc alloy had significantly better antibacterial properties than the non-drug-loaded zinc alloy.

[0076] Test Example 4: Concentration Release Curve Test

[0077] The concentration of cefuroxime was detected by liquid chromatography-mass spectrometry (LC-MS). The antibiotics in the sample were separated by liquid chromatography (LC) system and detected by mass spectrometry (MS). The concentration of antibiotics released from the sample at 15 days and 28 days was quantitatively tested by external standard method and a bar graph was drawn as shown in the figure. Figure 10 As shown in the figure, the results show that the drug-loaded zinc alloy has excellent drug release function.

[0078] Example 2

[0079] In a further embodiment, the zinc alloy in Example 1 can be replaced by a magnesium-yttrium-rare earth element-zirconium alloy with the designation WE43, wherein the weight percentage of yttrium is 4%, the weight percentage of rare earth elements is 3.3%, the rare earth elements are Nd and Gd, the weight percentage of zirconium is 0.5%, and the particle size is 20-70um.

[0080] The drug-loaded Mg alloy product was prepared by referring to the method in Example 1 and named Mg-10GPa. The product was prepared by hand pressing at a pressure of 1×10 7 The ellipsoidal metal block magnesium alloy drug-loaded product made of Pa is named Mg-0GPa.

[0081] The mechanical properties of the samples were tested by using a universal tensile testing machine (Instron 5969, USA) for compression testing. The compression rate was set at 2×10 -4 The test was carried out at room temperature, and 3 parallel samples were tested for each material. The maximum load and elastic modulus of the material were obtained through compression test, and the bar graph and displacement-load curve were drawn using GraphPad. Figure 11-13 shown.

[0082] Normally, the elastic modulus of ordinary magnesium alloy is 41-45GPa. The results show that the elastic modulus of high-pressure die-cast magnesium alloy is 0.6-0.8GPa, and the maximum load of high-pressure die-cast magnesium alloy is significantly increased. It has good mechanical properties and can be used as a bone substitute for cancellous bone.

[0083] Finally, it should be noted that the above embodiments are only used to illustrate the present invention and are not intended to limit the technical solutions described in the present invention. Those skilled in the art should understand that the present invention can still be modified or replaced by equivalents. All technical solutions and improvements that do not depart from the spirit and scope of the present invention should be included in the scope of the claims of the present invention.

Claims

1. A novel degradable metal drug loading method, characterized in that the steps include: The alloy powder and antibiotic powder were mixed and dispersed in a weight ratio of (90-99.9): (0.1-10) to obtain a sample. The sample was placed in a 1.5×10 6 Pa to 3.0×10 7 Pa pressure conditions to form an ellipsoidal metal block, the metal block is rapidly pressurized to 2 GPa within 7 minutes; then a secondary pressing is performed under a pressure condition of 8-20 GPa, and the pressurization step includes increasing the pressure to 4 GPa at a rate of 0.01-0.1 GPa / min, increasing the pressure to 4-8 GPa at a rate of 0.01-0.1 GPa / min, increasing the pressure to 6-10 GPa at a rate of 0.01-0.1 GPa / min, and increasing the pressure to 8GPa-20 GPa at a rate of 0.01-0.1 GPa / min, then maintaining the pressure for 5-20 hours, and finally releasing the pressure to normal pressure to obtain the target drug-loaded metal sample; The alloy powder includes any one of zinc-magnesium alloy, magnesium-yttrium-rare earth element alloy or magnesium-yttrium-rare earth element-zirconium alloy; the antibiotics include at least one of penicillins, cephalosporins, meropenem, aminoglycosides, macrolides, lincomycins and quinolones.

2. A novel degradable metal drug loading method according to claim 1, characterized in that: The particle size of the alloy powder is 20-70 μm.

3. A novel degradable metal drug loading method according to claim 1, characterized in that: The weight percentage of magnesium in the zinc-magnesium alloy is 1%, and the balance is zinc.

4. A novel degradable metal drug loading method according to claim 1, characterized in that: The weight percentage of yttrium in the magnesium-yttrium-rare earth element alloy is 3.7-4.3%, the weight percentage of the rare earth element is 2.4-4.4%, and the rare earth element is Nd and / or Gd.

5. A novel degradable metal drug loading method according to claim 1, characterized in that: The weight percentage of yttrium in the magnesium-yttrium-rare earth element-zirconium alloy is 3.7-4.3%, the weight percentage of the rare earth element is 2.4-4.4%, the rare earth element is Nd and / or Gd, and the weight percentage of zirconium is 0.3-1.0%.

6. A novel degradable metal drug loading method according to claim 1, characterized in that: The time for increasing the pressure of the metal block to 8 GPa-20 GPa is 1-24 hours, and the rate of decompression is 0.01-0.1 GPa / min.

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