A low-humidity ethylene oxide sterilization method for absorbable medical devices and its application

Abstract

This application provides a sterilization method for an absorbable medical device, comprising: S1, placing the absorbable medical device in a sterilization device and performing 1 to 5 nitrogen replacement cycles under conditions of 30-45°C and 10-20% RH; each nitrogen replacement cycle includes evacuating to -75 kPa to -50 kPa and then injecting dry nitrogen to -15 kPa to -5 kPa; S2, injecting ethylene oxide to a concentration of 300-450 mg / L and performing ethylene oxide exposure for 60 min to 180 min; S3, performing 40 to 50 nitrogen purging cycles; each nitrogen purging cycle includes evacuating to -75 kPa to -50 kPa and then injecting dry nitrogen to -15 kPa to -5 kPa; S4, performing 40 to 50 drying cycles; each drying cycle includes evacuating to -75 kPa to -50 kPa and then injecting dry nitrogen to -15 kPa to -5 kPa. The sterilization method employs a completely non-humidified process and multiple rounds of nitrogen drying, ensuring that the moisture content, EO residue, molecular weight, and mechanical properties of the sterilized absorbable medical devices all meet the standards. Furthermore, the sterilization and analysis process is integrated, shortening the production cycle.

Description

Technical Field

[0001] This invention belongs to the field of medical device sterilization, specifically relating to an integrated method for sterilization, drying, and desorption of absorbable medical devices. Background Technology

[0002] Absorbable medical devices are typically made from biodegradable absorbable materials. After implantation, they can perform their intended clinical therapeutic functions while gradually degrading within a predetermined period through biochemical reactions such as hydrolysis and enzymatic hydrolysis. They are then absorbed by the body through metabolism or harmlessly excreted, eliminating the need for secondary surgery. Commonly used materials include synthetic biodegradable polyesters such as poly(p-dioxanone) (PPDO), polylactic-co-glycolic acid copolymer (PLGA), polyglycolic acid-caprolactone copolymer (PGA-PCL), polyglycolic acid (PGA), and polycaprolactone (PCL), and can also be combined with natural biodegradable polymers such as collagen, chitosan, and gelatin. Through material composition and structural design, the degradation cycle, mechanical properties, and biocompatibility of the device can be controlled to meet different clinical application needs. However, absorbable materials are generally sensitive to temperature, humidity, and irradiation conditions. During sterilization, they are prone to hydrolysis, thermal degradation, or molecular chain breakage, leading to a decrease in molecular weight, deterioration of mechanical properties, and uncontrolled degradation cycles. Therefore, how to maintain material performance stability while achieving sterility assurance levels has become a key technical issue in the fabrication of absorbable medical devices.

[0003] Traditional terminal sterilization methods for medical devices mainly include moist heat sterilization, dry heat sterilization, irradiation sterilization, and ethylene oxide (EO) sterilization. Moist heat sterilization and dry heat sterilization, due to their high-temperature conditions, are not suitable for absorbable medical devices. While irradiation sterilization can be used for some absorbable products, it requires prior verification of the material's irradiation stability and is costly. Ethylene oxide sterilization is suitable for most medical devices that are not resistant to high temperatures and humidity, and its cost is significantly lower than irradiation sterilization.

[0004] Currently, sterilization methods used to ensure aseptic performance of absorbable medical devices mainly include irradiation sterilization and ethylene oxide sterilization. Patent document US20110209442A1 discloses a method for sterilizing biodegradable scaffolds using an electron beam, requiring an irradiation dose not exceeding 15 kGy. While this method reduces the impact on the product by lowering the irradiation dose, it still significantly affects the molecular weight of the absorbable material. Conventional ethylene oxide sterilization processes typically use parameters of 45–55°C, 30%–80% RH, and a concentration of 400–1000 mg / L. After sterilization, the device is transferred to a vacuum desorption chamber for forced desorption, with the desorption temperature generally set above 45°C. Sterilizing absorbable medical devices under these conditions leads to severely substandard product performance; therefore, the industry has widely explored low-temperature and low-humidity methods for sterilizing absorbable products. However, if the ethylene oxide sterilization parameters are not properly selected, degradation of the absorbable material can still occur. Patent document CN103656701A discloses a low-temperature sterilization method suitable for biodegradable scaffolds, which sets the EO sterilization parameters as follows: temperature 20-40℃, relative humidity 20-60%, concentration 500-800 mg / L, sterilization time 4-8 hours, followed by desorption under vacuum at 20-45℃ for more than 24 hours. WO2013043429A1 discloses a method for sterilizing biodegradable polymer scaffolds using cold ethylene oxide gas, with sterilization parameters also being low temperature and low humidity: temperature 15-40℃, humidity approximately 30% RH, and concentration 400-1000 mg / L. However, although these methods employ low temperature and low humidity, water vapor is still introduced during the sterilization process to control the humidity inside the chamber. Synthetic biodegradable polyesters such as PPDO, PLGA, PGA-PCL, PGA, and PCL are highly susceptible to hydrolysis upon contact with water vapor. Furthermore, the aforementioned methods do not detail how to perform residual analysis while maintaining the absorbable material's performance without significant loss, nor do they address changes in product moisture content after sterilization. Moisture content is a key indicator affecting the performance of biodegradable polyester products and directly impacts their degradation cycle. In areas with high relative humidity, the product's moisture content is already high after production, and it will further absorb moisture during transportation, accelerating ester bond degradation. In addition, the methods do not disclose how to specifically transport and store absorbable products before and after sterilization. Especially in high-humidity areas such as coastal regions, without special treatment, the product will absorb a large amount of moisture during transportation, accelerating material degradation.

[0005] Therefore, how to avoid introducing water vapor during sterilization, reduce the moisture content of the product, minimize the impact of sterilization and desorption processes on the molecular weight and mechanical properties of the material, and simultaneously achieve EO residue compliance and long-term stable product preservation has become an urgent technical problem to be solved in the field of sterilization of absorbable medical devices. Summary of the Invention

[0006] The purpose of this application is to provide an easy-to-operate and low-cost sterilization method for absorbable medical devices, which overcomes the problems of existing low-temperature and low-humidity ethylene oxide sterilization methods that still require the introduction of water vapor to regulate humidity, resulting in high moisture content of the product after sterilization and thus affecting its performance, as well as the lack of detailed analytical methods for absorbable products and transportation and storage schemes in high-humidity environments.

[0007] To address the above problems, this application provides the following technical solution: A sterilization method for an absorbable medical device includes the following steps: S1. Place the absorbable medical device in a sterilization device and perform 1 to 5 nitrogen replacement cycles under the conditions of temperature 30-45℃ and humidity 10-20% RH. Each nitrogen replacement cycle includes: evacuating to -75 kPa to -50 kPa, and then injecting dry nitrogen to -15 kPa to -5 kPa. S2. Inject ethylene oxide to a concentration of 300-450 mg / L and expose the product to ethylene oxide for 60 to 180 minutes. S3. Perform 40 to 50 nitrogen cleaning cycles; each nitrogen cleaning cycle includes: evacuating to -75 kPa to -50 kPa, then injecting dry nitrogen to charge to -15 kPa to -5 kPa; S4. Perform 40 to 50 drying cycles; each drying cycle includes: evacuating to -75 kPa to -50 kPa, and then injecting dry nitrogen to -15 kPa to -5 kPa.

[0008] This application also provides the following technical solutions: The aforementioned sterilization method is applied in the production of absorbable medical devices.

[0009] The technical solution provided in this application has the following beneficial effects: (1) The sterilization method provided by this invention eliminates the introduction of moisture at the source by designing low-temperature ethylene oxide sterilization parameters that are not humidified throughout the entire process. This fundamentally avoids the risk of pre-hydrolysis of materials caused by contact between water vapor and absorbable materials (such as synthetic polyesters like PPDO, PLGA, and PGA-PCL). Through the synergistic effect of low temperature and dry environment, the integrity of the material molecular chain is maximized, reducing the loss of material molecular weight during the sterilization process. Furthermore, the sterilization effect is compensated by appropriately increasing the ethylene oxide concentration and sterilization temperature during the sterilization exposure stage, ensuring that the product can still achieve the sterility assurance level (SAL=10) even without contact with water vapor. -6 ).

[0010] (2) The sterilization method provided by this invention replaces the air cleaning and ventilation steps at the end of the conventional sterilization process with multiple rounds of nitrogen cleaning and drying cycles. High-purity dry nitrogen (99.99% purity) is used to clean the product, which effectively reduces the residual ethylene oxide content in the product and actively removes existing moisture. Using the method provided by this invention, regardless of whether the moisture content of the product exceeds the standard before sterilization, its moisture content after sterilization will meet the qualified standard.

[0011] (3) The sterilization method provided by the present invention integrates sterilization and analysis into a continuous process, which is completed in the same sterilization device. There is no need to transfer to a separate analysis room after sterilization, which fundamentally avoids the secondary impact of the external environment (such as temperature, humidity and light) on product performance during the transfer process, realizes the efficient process of "sterilization is completed", and significantly shortens the production cycle.

[0012] (4) The sterilization method provided by the present invention can be further matched with a special transportation and storage scheme for the product: before and after sterilization, the product is vacuum stored in a vacuum barrel to isolate moisture in the air, and aluminum foil bags can be used to isolate the potential impact of ultraviolet light and other light on the product performance, thereby ensuring the stability of the product's performance throughout the entire process from production to clinical use.

[0013] (5) The sterilization method provided by this invention has wide applicability. It can ensure the sterility level of absorbable medical devices after terminal sterilization, and also ensure that the key indicators of the sterilized products, such as moisture content, ethylene oxide residue, molecular weight retention rate, intrinsic viscosity, and mechanical properties (e.g., pressure resistance and tensile strength), meet the standards. It has important practical value and promotion significance. Applicable products include, but are not limited to, PPDO absorbable hemostatic clips, PPDO absorbable sutures, PGA-PCL partially absorbable hernia repair patches, and β-tricalcium phosphate blended glycolide-lactide copolymer resin (PLGA / β-TCP) absorbable suture anchors, etc. Invention Details 1. Terminology Explanation All patents and other publications cited herein are incorporated herein in their entirety. In the event of any conflict between any description of terminology herein and any document incorporated herein by reference, this document shall prevail.

[0015] Numerical ranges can be represented by a hyphen "-" or a tilde "~". Unless otherwise stated, the range should be understood to encompass both the endpoint values ​​and any values ​​in between. There are no particular restrictions on the type of numeric values ​​within the range, including but not limited to integers, decimals, fractions, percentages, etc., unless explicitly excluded by the context or a particular numeric type is technically unavailable. The type of numeric values ​​within the range is not limited by the specific representation of the endpoints.

[0016] The terms “including,” “containing,” and similar expressions have a non-restrictive meaning.

[0017] "Optional" is used to indicate that a certain feature (including but not limited to components, steps, parameters or structures) may be present in some embodiments, but may not appear in other embodiments, thereby providing technical flexibility for different implementations without departing from the core concept of the present invention.

[0018] "Any combination" of the enumeration items means any two or more of the enumeration items that coexist or are used together, including but not limited to any two combinations, any three combinations, any more items, and combinations of all the enumeration items, unless the context explicitly excludes it or a particular combination is technically impossible.

[0019] The use of labels such as a), b), i), ii), 1), 2), S1, S2, etc. to number the steps of a method is only for the convenience of description and reading, and does not mean that the corresponding steps must be performed in the order of the numbers, unless the text explicitly states or the information in the text can be clearly inferred that there is a logical or temporal relationship between specific steps.

[0020] The term "medical device" as used herein refers to an instrument, device, material, or combination thereof used for disease prevention, diagnosis, treatment, monitoring, relief, compensatory function, anatomical or physiological structural support, or for medical purposes such as implantation, intervention, fixation, closure, and repair. A medical device can be a single device, a component, part, semi-finished product, a sterile medical device product, or a finished product ready for clinical use. Medical devices include single-use devices as well as implantable, interventional, or other devices requiring sterilization. Medical devices can act on tissues or organs within the human body, such as subcutaneous tissue, muscles, blood vessels, bone tissue, or organs such as the heart, liver, spleen, lungs, and kidneys, or their lesions. "Absorbable medical device" refers to a medical device made of absorbable materials.

[0021] The term "absorbable" as used herein refers to the characteristic that a material or device, within the physiological environment of the human body, can be gradually degraded, absorbed, metabolized, or harmlessly excreted over a certain period of time through hydrolysis, enzymatic hydrolysis, oxidation, or other biochemical processes, thus eliminating the need for surgical removal after the intended medical function has been achieved. The physiological environment within the human body includes the internal environment of normal physiological tissues and diseased physiological tissues (e.g., tumors, inflamed tissues). This degradation can occur through metabolic processes (e.g., enzymatic reactions, redox reactions), under specific microenvironmental stimuli (e.g., acidic or alkaline pH), or induced by stimuli applied during clinical treatment (e.g., light, heat, low temperature). Absorbable materials can be either fully absorbable or partially absorbable. The absorbable material comprises at least one biodegradable polymer as a matrix component, and optionally also includes one or more other matrix components (e.g., non-biodegradable polymers; specifically, PP), fillers (e.g., bioactive ceramics; specifically, tricalcium β-phosphate), or modifying components (e.g., auxiliary components to improve the material's processing performance, appearance, or biocompatibility; specifically, dyes, plasticizers, surface modifiers, etc.). Unless otherwise specified, the other matrix components, fillers, and modifying components do not undergo substantial degradation or performance deterioration under the sterilization method provided in this application, nor do they substantially affect the effectiveness of the sterilization method. The biodegradable polymer can be a synthetic or natural biodegradable polymer, examples of which include, but are not limited to: poly(p-dioxanone) (PPDO), polylactic-co-glycolic acid copolymer (PLGA), polyglycolic acid-caprolactone copolymer (PGA-PCL), polyglycolic acid (PGA), polycaprolactone (PCL), collagen, chitosan, gelatin, and any combination thereof. PPDO is an aliphatic polyester with excellent flexibility, biocompatibility, and a degradation cycle of approximately 6-8 months. It is widely used in products such as absorbable ligature clips and absorbable sutures. These products are typically required to maintain their initial mechanical strength (such as clamping force and tensile strength) and degrade according to a predetermined period during wound closure and tissue support. PGA-PCL is a biocompatible aliphatic polyester whose physicochemical properties and degradation cycle can be controlled by adjusting the PGA / PCL monomer ratio. PGA-PCL molecules contain hydrophilic ester groups, which are prone to ester bond hydrolysis and chain breakage under high humidity conditions. Furthermore, its thermal stability is poor; at high temperatures, the terminal groups of the molecular chain can randomly attack adjacent ester bonds, leading to ester bond breakage and the formation of cyclic oligomers. Applications of PGA-PCL include products such as PGA-PCL / PP partially absorbable hernia repair patches; in the process of replacing or strengthening weak tissues, achieving defect repair and long-term stability, such products are usually required to maintain their initial anti-adhesion properties (e.g., reducing contact with abdominal organs) and initial mechanical strength (e.g., tensile strength, elongation at break), and degrade according to a predetermined period.β-tricalcium phosphate blended glycolide-lactide copolymer resin (PLGA / β-TCP) possesses excellent flexibility and biocompatibility, and is widely used in absorbable bone screw products; these products typically require maintaining initial fixation strength and degrading according to a predetermined period during implantation. The clinical safety and efficacy of the aforementioned absorbable materials are highly dependent on the stability of the material properties after sterilization.

[0022] Unless otherwise specified, "humidity" as used in this document refers to relative humidity (RH), which is the ratio of the actual partial pressure of water vapor in a gas to the saturated vapor pressure of water at a given temperature, and is expressed as a percentage. Unless otherwise specified, the humidity mentioned refers to the relative humidity of the working chamber environment within the sterilization apparatus.

[0023] The "dry nitrogen" mentioned herein refers to high-purity nitrogen with a purity of not less than 99.99% and an extremely low moisture content. In this application, "dry" specifically means that the dew point temperature of this nitrogen is consistently lower than the gas temperature inside the sterilization device under the operating temperature and pressure conditions of the sterilization process, ensuring that no additional moisture is introduced into the instruments to be sterilized during injection, replacement, and cleaning. The moisture content of the dry nitrogen is typically characterized by its atmospheric dew point not exceeding -40°C or an equivalent degree of dryness (e.g., a moisture volume fraction not exceeding 100 ppm).

[0024] The “nitrogen replacement cycle” described in this article refers to the operation of filling the working chamber of the sterilization device with dry nitrogen after one or more vacuuming processes before injecting ethylene oxide, thereby replacing the original gas (usually air and the oxygen and water vapor contained therein) in the sterilization device, and thus providing a low-oxygen and low-humidity gas environment during the subsequent ethylene oxide exposure stage.

[0025] The “nitrogen cleaning cycle” mentioned in this article refers to the process of repeatedly evacuating and filling with dry nitrogen after the removal of ethylene oxide, in order to remove adsorbed or residual ethylene oxide from the surface and interior of absorbable medical devices.

[0026] The "drying cycle" described herein refers to the process of repeatedly vacuuming and filling with dry nitrogen after nitrogen purging to further remove moisture from the product. In the sterilization method provided in this application, the drying cycle completely replaces the air purging and ventilation steps in the conventional ethylene oxide sterilization process.

[0027] The term "desorption" as used herein refers to the process of desorbing and removing ethylene oxide and its byproducts (such as chloroethanol, ethylene glycol, etc.) adsorbed on the interior and surface of an absorbable medical device (optionally including its packaging material). In the sterilization method provided in this application, the desorption process is achieved through continuous nitrogen purging and drying cycles within the sterilization device, eliminating the need for transfer to a separate desorption chamber.

[0028] The "separate placement" mentioned in this article refers to arranging multiple absorbable medical devices in a sterilization device in a way that prevents them from touching each other and maintains sufficient gaps between them. This ensures that the surface of each device is fully exposed to the gaseous environment inside the sterilization device, and that ethylene oxide gas and dry nitrogen gas can fully contact the device surface during the cleaning and drying process. This avoids sterilization dead spots, moisture residue, or insufficient desorption caused by stacking, sticking together, or blocking each other of the devices.

[0029] 2. Implementation Plan One embodiment of this application is as follows: A sterilization method for an absorbable medical device includes the following steps: S1. Place the absorbable medical device in a sterilization device and perform 1 to 5 nitrogen replacement cycles under the conditions of temperature 30-45℃ and humidity 10-20% RH. Each nitrogen replacement cycle includes: evacuating to -75 kPa to -50 kPa, and then injecting dry nitrogen to -15 kPa to -5 kPa. S2. Inject ethylene oxide to a concentration of 300-450 mg / L and expose the product to ethylene oxide for 60 to 180 minutes. S3. Perform 40 to 50 nitrogen cleaning cycles; each nitrogen cleaning cycle includes: evacuating to -75 kPa to -50 kPa, then injecting dry nitrogen to charge to -15 kPa to -5 kPa; S4. Perform 40 to 50 drying cycles; each drying cycle includes: evacuating to -75 kPa to -50 kPa, and then injecting dry nitrogen to -15 kPa to -5 kPa.

[0030] In some specific implementations, the purity of the dried nitrogen gas is not less than 99.99%, and the volume fraction of moisture does not exceed 100 ppm.

[0031] In some specific implementations, the sterilization device includes a working chamber, a vacuum system, a nitrogen supply system, a temperature control system, and an ethylene oxide supply system.

[0032] In some specific implementations, the sterilization device is any one of a sterilization cabinet, sterilizer, sterilization box, sterilization room, sterilization autoclave, sterilization tank, and sterilization chamber.

[0033] In some specific implementations, the absorbable medical devices are placed separately from each other within a sterilization device.

[0034] In some specific implementations, the absorbable medical device is contained or supported within a sterilization apparatus by a carrier.

[0035] In some specific implementations, the carrier is a pallet, a bracket, or a basket.

[0036] In some specific implementations, the support device is made of plastic.

[0037] In some specific implementations, the water content of the carrier is not higher than 1000 ppm.

[0038] In some specific implementations, the sterilization method further includes a transportation process before and / or after sterilization; the transportation process includes: transporting the absorbable medical device in a vacuum chamber; the relative pressure inside the vacuum chamber is -0.08 MPa to -0.01 MPa.

[0039] In some specific implementations, the sterilization method further includes packaging and transporting the absorbable medical device.

[0040] In some specific implementations, the packaging uses barrier bags.

[0041] In some specific implementations, the barrier packaging bag is made of aluminum foil, aluminized film, ethylene-vinyl alcohol copolymer, polyvinylidene chloride, polyester, nylon, or any combination thereof.

[0042] In some specific implementations, the barrier packaging bag is a sealed packaging bag or a packaging bag with a ventilated window; the sealed packaging bag is removed before step S1; the packaging bag with a ventilated window may or may not be removed before step S1.

[0043] In some specific implementations, the ventilation window is medical dialysis paper or high-density polyethylene nonwoven fabric.

[0044] In some specific implementation schemes, the absorbable medical device is selected from any one of hemostatic clips, sutures, hernia repair patches, suture anchors, bone plates, bone screws, tissue engineering scaffolds, anti-adhesion membranes, stapler cartridges, and embolization microspheres.

[0045] In some specific implementations, the matrix material of the absorbable medical device includes any one or any combination of the following: PPDO, PLGA, PGA-PCL copolymer, PGA, and PCL.

[0046] In some specific implementations, the absorbable medical device further includes one or more non-absorbable matrix materials.

[0047] In some specific implementations, the absorbable medical device further includes one or more fillers.

[0048] In some specific implementations, the absorbable medical device further includes one or more modified components.

[0049] Another implementation scheme of this application is as follows: The application of any of the aforementioned sterilization methods in the production of absorbable medical devices; wherein the sterilization method is used for terminal sterilization of the absorbable medical device.

[0050] In some specific implementations, the sterilization method enables the absorbable medical device to achieve a sterility assurance level (SAL=10). -6 ). Detailed Implementation

[0051] The following specific embodiments are used to further describe the implementation of the present invention and do not limit the scope of the present invention.

[0052] Example 1: Absorbable sterilization and validation of PPDO absorbable ligation clips A batch of absorbable ligature clips made of PPDO material was sealed in aluminum foil bags, placed into vacuum containers, and transported to the sterilization contractor. Within 30 minutes of arrival, the products were removed from the vacuum containers, the aluminum foil bags were cut open, and the products were evenly placed in high-density polyethylene sterilization baskets. The sterilization baskets containing the products were divided into a control group and an experimental group, and placed in different sterilization cabinets. The control group used a conventional low-temperature, low-humidity sterilization process, while the experimental group used the sterilization process of this invention, with the specific parameters as follows: Control group: The sterilization temperature was set at 42℃, and the vacuum was reduced to -75 kPa. Two nitrogen purging cycles were performed. The sterilization humidity was set at 30% RH, and ethylene oxide was injected to a concentration of 350 mg / L for 120 min. After EO removal, two nitrogen purging cycles were performed, each cycle including vacuuming to -75 kPa and then filling with dry nitrogen to -5 kPa. After the nitrogen purging cycles, three air purging cycles were performed, each cycle including vacuuming to -75 kPa and then filling with air to -5 kPa. After the air purging cycles, a ventilation process was performed at -5 kPa for approximately 30 minutes to remove residual gases. After sterilization, the product was transferred to a forced desorption chamber, the desorption temperature was set at 45℃, and the process holding time was set at 2880 min. After desorption, the sample was removed for testing.

[0053] Experimental group: The sterilization temperature was set to 42℃, and the vacuum was evacuated to -75 kPa. Two nitrogen purging cycles were performed. The humidification valve of the equipment was manually closed, and the humidification pressure was set to 0 kPa to ensure that no additional water vapor was introduced during the sterilization process, and the humidity inside the cabinet was maintained at 10-20% RH. Ethylene oxide was injected to a concentration of 350 mg / L, and the exposure time was 120 min. During the exposure, the humidity inside the cabinet was monitored online and found to be 12±2%. After EO removal, 50 nitrogen purging cycles were performed, each cycle including evacuation to -55 kPa and then filling with dry nitrogen to -5 kPa. 50 drying cycles were performed, each cycle including evacuation to -55 kPa and then filling with dry nitrogen to -5 kPa.

[0054] After the process was completed, samples were taken from the sterilization cabinet for testing, and the results are shown in Table 1. Compared with conventional low-temperature and low-humidity sterilization processes, the sterilization method provided in this application, when used for sterilizing PPDO absorbable ligation clips, achieves lower ethylene oxide residue (3.6 μg / g) and higher molecular weight retention (i.e., a lower Mn decrease rate). Specifically, the moisture content of the product in the control group after sterilization was severely excessive (3100 ppm), while the moisture content of the product in the experimental group (236 ppm) was controlled within the acceptable range. These results demonstrate that the sterilization method provided in this application, when used for sterilizing absorbable medical devices made of PPDO material, possesses comprehensive advantages in terms of low ethylene oxide residue, moisture control, and performance protection.

[0055] Table 1. Performance testing of PPDO absorbable ligation clips after sterilization

[0056] Example 2: Absorbable sterilization and validation of PPDO absorbable barbed sutures Take single-strand barbed PPDO yarn of different diameters (2-0#, 0#), wind them onto a thread plate, and directly pack them into vacuum containers without packaging. Transport the containers to the sterilization contractor. Within 30 minutes of arrival, remove the products from the vacuum containers, evenly distribute them into high-density polyethylene sterilization trays, and place them in the sterilization cabinet.

[0057] Sterilization process: The sterilization temperature was set to 42℃, and the vacuum was evacuated to -75 kPa. Two nitrogen purging cycles were performed. The humidification valve of the equipment was manually closed, and the humidification pressure was set to 0 kPa to ensure that no additional water vapor was introduced during the sterilization process, and the humidity inside the cabinet was maintained at 10-20% RH. Ethylene oxide was injected to a concentration of 350 mg / L, and the exposure time was 120 min. During the exposure, the humidity inside the cabinet was monitored online and found to be 13±2%. After EO removal, 50 nitrogen purging cycles were performed, each cycle including evacuation to -55 kPa and then refilling with dry nitrogen to -5 kPa. 50 drying cycles were performed, each cycle including evacuation to -55 kPa and then refilling with dry nitrogen to -5 kPa.

[0058] After the process was completed, the sterilization cabinet was opened to take samples for testing, and the results are shown in Table 2.

[0059] Table 2. Performance testing of PPDO absorbable barbed sutures after sterilization

[0060] Example 3: Absorbable sterilization and validation of PGA-PCL / PP partially absorbable hernia repair patch A batch of partially absorbable hernia repair patches made of PGA-PCL / PP material was sealed in aluminum foil top bags, placed in vacuum containers, and transported to the sterilization contractor. Within 30 minutes of arrival, the products were removed from the vacuum containers without opening the bags and divided into a control group and an experimental group. The two groups of products were then evenly distributed and placed in different sterilization cabinets. The control group underwent conventional low-temperature, low-humidity sterilization, while the experimental group underwent the sterilization process of this invention, with the specific parameters as follows: Control group: The sterilization temperature was set at 42℃, and the vacuum was reduced to -75 kPa. Two nitrogen purging cycles were performed. The sterilization humidity was set at 30% RH, and ethylene oxide was injected to a concentration of 350 mg / L for 120 min. After EO removal, two nitrogen purging cycles were performed, each cycle including vacuuming to -75 kPa and then filling with dry nitrogen to -5 kPa. After the nitrogen purging cycles, three air purging cycles were performed, each cycle including vacuuming to -75 kPa and then filling with air to -5 kPa. After the air purging cycles, a ventilation process was performed at -5 kPa for approximately 30 minutes to remove residual gases. After sterilization, the product was transferred to a forced desorption chamber, the desorption temperature was set at 45℃, and the process holding time was set at 2880 min. After desorption, the sample was removed for testing.

[0061] Experimental group: The sterilization temperature was set to 42℃, and the vacuum was evacuated to -75 kPa. Two nitrogen purging cycles were performed. The humidification valve of the equipment was manually closed, and the humidification pressure was set to 0 kPa to ensure that no additional water vapor was introduced during the sterilization process, and the humidity inside the cabinet was maintained at 10-20% RH. Ethylene oxide was injected to a concentration of 350 mg / L, and the exposure time was 120 min. During the exposure, the humidity inside the cabinet was monitored online and found to be 17±2%. After EO removal, 50 nitrogen purging cycles were performed, each cycle including evacuation to -55 kPa and then filling with dry nitrogen to -5 kPa. 50 drying cycles were performed, each cycle including evacuation to -55 kPa and then filling with dry nitrogen to -5 kPa.

[0062] After the process was completed, samples were taken from the sterilization cabinet for testing, and the results are shown in Table 3. Compared with conventional low-temperature and low-humidity sterilization processes, the sterilization method provided in this application, when used for sterilizing PGA-PCL / PP partially absorbable hernia repair patches, achieves superior mechanical properties after sterilization. Specifically, the longitudinal tear strength reaches 45.0–73.4 N, the transverse tear strength reaches 74.0–108.1 N, and the bursting strength reaches 592.9–785.6 N. Furthermore, the moisture content of the sterilized products in the control group was severely excessive (1288.5 ppm), while the moisture content of the experimental group (272.2 ppm) was controlled within the acceptable range. These results indicate that the sterilization method provided in this application, when used for sterilizing absorbable medical devices made of PGA-PCL / PP material, combines excellent mechanical property retention with significant moisture control advantages.

[0063] Table 3. Performance Testing of PGA-PCL / PP Partially Absorbable Hernia Repair Patch after Sterilization

[0064] Example 4: Absorbable sterilization and validation of PLGA / β-TCP absorbable anchors with wires A batch of absorbable anchors with thread, made of PLGA / β-TCP material, was sealed in aluminum foil top bags and then transported to the sterilization contractor in vacuum containers. Within 30 minutes of arrival, the products were removed from the vacuum containers without opening the bags and divided into a control group and an experimental group. The two groups of products were then evenly distributed and placed in different sterilization cabinets. The control group underwent conventional low-temperature, low-humidity sterilization, while the experimental group underwent the sterilization process of this invention, with the specific parameters as follows: Control group: The sterilization temperature was set at 42℃, and the vacuum was reduced to -75 kPa. Two nitrogen purging cycles were performed. The sterilization humidity was set at 30% RH, and ethylene oxide was injected to a concentration of 350 mg / L for 120 min. After EO removal, two nitrogen purging cycles were performed, each cycle including vacuuming to -75 kPa and then filling with dry nitrogen to -5 kPa. After the nitrogen purging cycles, three air purging cycles were performed, each cycle including vacuuming to -75 kPa and then filling with air to -5 kPa. After the air purging cycles, a ventilation process was performed at -5 kPa for approximately 30 minutes to remove residual gases. After sterilization, the product was transferred to a forced desorption chamber, the desorption temperature was set at 45℃, and the process holding time was set at 2880 min. After desorption, the sample was removed for testing.

[0065] Experimental group: The sterilization temperature was set to 42℃, and the vacuum was evacuated to -75 kPa. Two nitrogen purging cycles were performed. The humidification valve of the equipment was manually closed, and the humidification pressure was set to 0 kPa to ensure that no additional water vapor was introduced during the sterilization process, and the humidity inside the cabinet was maintained at 10-20% RH. Ethylene oxide was injected to a concentration of 350 mg / L, and the exposure time was 120 min. During the exposure, the humidity inside the cabinet was monitored online and found to be 15±2%. After EO removal, 50 nitrogen purging cycles were performed, each cycle including evacuation to -55 kPa and then filling with dry nitrogen to -5 kPa. 50 drying cycles were performed, each cycle including evacuation to -55 kPa and then filling with dry nitrogen to -5 kPa.

[0066] After the process was completed, samples were taken from the sterilization cabinet for testing, and the results are shown in Table 4. Compared with conventional low-temperature and low-humidity sterilization processes, the sterilization method provided in this application for the sterilization of PLGA / β-TCP absorbable wire anchors achieved a greater degree of preservation of the product's key performance characteristics, including higher fixing strength (365 N) and higher intrinsic viscosity (1.5 dL / g). In addition, the moisture content of the sterilized product (0.17%) was significantly lower than that of the control group (0.27%).

[0067] Table 4. Performance Testing of PLGA / β-TCP Absorbable Thread Anchors After Sterilization

[0068] All equivalent structural or procedural transformations made using the content of this application's specification, directly or indirectly applied to the same or related technical fields as this application, are included within the scope of patent protection of this application. For those skilled in the art, this invention can be implemented in a wide range with equivalent parameters, formulations, and conditions without departing from its spirit and scope, and without the need for unnecessary experimentation. Although this application includes specific conditions in its embodiments, it should be understood that the conditions of each embodiment can be combined in any suitable manner where technically feasible. To avoid unnecessary repetition, this application will not further describe the various possible combinations. In summary, any changes, modifications, substitutions, and variations made using conventional techniques known in the art based on the principles of this invention are considered to be disclosed in this application.

Claims

1. A sterilization method for an absorbable medical device, characterized in that, Includes the following steps: S1. Place the absorbable medical device in a sterilization device and perform 1 to 5 nitrogen replacement cycles under conditions of 30-45℃ and 10-20% RH. Each nitrogen purging cycle includes: evacuating to -75 kPa to -50 kPa, and then injecting dry nitrogen to -15 kPa to -5 kPa; S2. Inject ethylene oxide to a concentration of 300-450 mg / L and expose the product to ethylene oxide for 60 to 180 minutes. S3. Perform 40 to 50 nitrogen cleaning cycles; each nitrogen cleaning cycle includes: evacuating to -75 kPa to -50 kPa, then injecting dry nitrogen to charge to -15 kPa to -5 kPa; S4. Perform 40 to 50 drying cycles; each drying cycle includes: evacuating to -75 kPa to -50 kPa, then injecting dry nitrogen to charge to -15 kPa to -5 kPa; The matrix material of the absorbable medical device includes any one or any combination of the following: PPDO, PLGA, PGA-PCL copolymer, PGA, and PCL.

2. The sterilization method for absorbable medical devices according to claim 1, characterized in that, The purity of the dry nitrogen gas is not less than 99.99%, and the volume fraction of moisture does not exceed 100 ppm.

3. The sterilization method for absorbable medical devices according to claim 1, characterized in that, The sterilization device includes a working chamber, a vacuum system, a nitrogen supply system, a temperature control system, and an ethylene oxide supply system.

4. The sterilization method for absorbable medical devices according to claim 1, characterized in that, The absorbable medical devices are placed separately from each other within the sterilization device.

5. The sterilization method for absorbable medical devices according to claim 1, characterized in that, The sterilization method further includes a transportation process before and / or after sterilization; the transportation process includes: transporting the absorbable medical device in a vacuum chamber; the relative pressure inside the vacuum chamber is -0.08 MPa to -0.01 MPa.

6. The sterilization method for absorbable medical devices according to claim 1, characterized in that, The absorbable medical device is selected from any one of the following: hemostatic clips, sutures, hernia repair patches, suture anchors, bone plates, bone screws, tissue engineering scaffolds, anti-adhesion membranes, stapler cartridges, and embolization microspheres.

7. The sterilization method for absorbable medical devices according to claim 1, characterized in that, The absorbable medical device also includes one or more non-absorbable matrix materials.

8. The sterilization method for absorbable medical devices according to claim 1, characterized in that, The absorbable medical device is contained or supported within the sterilization apparatus by a carrier.

9. The application of the sterilization method according to claim 1 in the production of absorbable medical devices, characterized in that, The sterilization method is used for terminal sterilization of the absorbable medical device.

10. The application according to claim 9, characterized in that, The sterilization method ensures that the sterility level of the absorbable medical device does not exceed 10. -6 .

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