RU2849375C1 - Method for obtaining lyophilized blood plasma or its components, device for implementing method, device for storing, transporting, and rehydrating lyophilized blood plasma or its components - Google Patents

Abstract

FIELD: biotechnology; medicine.

SUBSTANCE: invention relates to the field of biotechnology and medicine and concerns a method for obtaining lyophilized blood plasma or its components, as well as a device for carrying out this method. The method for obtaining lyophilized blood plasma or its components consists in using fresh or freshly thawed blood plasma, drying is carried out in a container, filling it with 250±50 ml of blood plasma, intended for drying blood plasma or its components, adding a buffer and optionally a cryoprotectant, while primary drying is carried out in two stages, in the second stage of primary drying, the temperature is increased over a period of 5 hours every 15 minutes and maintained for 8-10 hours; and secondary drying is carried out over a period of 6-9 hours at 40°C. The total drying time for the claimed volume of blood plasma does not exceed 21-26 hours. The container is a device for implementing this method and is a closed, elastic, airtight, and sterile system consisting of two parts that form a single internal space with a reusable bridge between the parts and connecting tubes. The internal dimensions of the vapor-permeable and vapor-impermeable parts are 2.0-2.5, and one of the connecting tubes contains a built-in filter.

EFFECT: invention allows for a shorter process time for the lyophilization of blood plasma or its components compared to known methods, while ensuring the sterility of the process and maintaining the reliability and quality of the dried blood plasma or its components.

26 cl, 2 ex

Description

Field of technology to which the invention relates

The invention relates to the field of medicine and concerns a method for obtaining lyophilized blood plasma or its components, as well as a device for implementing this method.

Prior art

Russian Patent No. 2743609, published on February 20, 2021, describes a dual container for blood components, consisting of two containers connected along one perimeter. The opposite side of the first container contains a tube, while the second has nozzles and a tube equipped with a filter, clamp, and polymer needle. The first container is made of a waterproof film material, while the second container has one surface made of a waterproof material and the other of a water-repellent and vapor-permeable material. The lyophilized blood component is transferred to the first container for storage, rehydration, and transfusion after opening the seam that isolates the second container from the first. The freeze-drying time ranged from 4 to 6 days.

Russian Patent No. 2808342, published on November 28, 2023, describes a flexible container made of two film membranes, one of which is hydrophobic and gas-permeable but impermeable to microbial contaminants and blood components. The second, transparent membrane is gas- and water-impermeable. The container contains connecting elements and allows for the preparation of blood components for lyophilization and lyophilization outside of aseptic conditions. The method enables lyophilization, sealing of the gas-permeable membrane after lyophilization, sterile sampling, and storage of the compact, lightweight container with the lyophilisate in a folded, vacuum-sealed, moisture- and gas-impermeable bag. The lyophilization time was 4 to 6 days.

A container is known that allows for the lyophilization of a blood component, storage, transportation, rehydration, and transfusion of the rehydrated blood component lyophilisate within a single, closed, sterile system. This system is described in Russian Patent No. 2740839, published on January 20, 2021. The container is made of a film material in the form of a flattened vessel with connecting elements necessary for these functions. One surface of the container is made of a water-, gas-, and vapor-impermeable material, while the other is made of a water-, gas-, and vapor-permeable material. At least one tube is hermetically inserted into the container at one end, the other end of which is connected via a brancher in a specific sequence to several tubes terminating in connecting elements for various purposes. Drying time did not exceed 4-5 days.

Russian Patent No. 2749633, published on June 16, 2021, describes a system for lyophilizing, storing, and using biological material. It comprises two containers, each hermetically sealed with a straight seam on three sides. The open sides of the containers overlap each other with the hermetically sealed seam, forming a single internal cavity. A peelable heat-sealed seam separates the containers, allowing for sterile opening from the outside. A single container consists of a connection on the top and bottom of two materials that are highly wear- and puncture-resistant and compatible with the lyophilization process. The Tyvek material used on the top of the container also offers breathability and microbial resistance. This container also contains a tube located on one side for filling it with biological material. The second container is made of polyvinyl chloride (PVC), suitable for storing and using the lyophilisate. After filling, the container is sealed at the open end, and the used container is discarded. However, the invention does not specify the parameters for lyophilization of the products or their characteristics.

None of the above devices allow for rapid lyophilization. Drying takes an average of 4 to 5 days.

Disclosure of the essence of the invention

The objective of the present invention is to manufacture a container for carrying out the process of lyophilization of blood plasma or its components, including cryoprecipitate, and to improve the process of lyophilization of blood plasma or its components in order to reduce the time it takes to carry it out.

The technical result of the invention is to reduce the time required for the lyophilization process of blood plasma or its components while ensuring the sterility of the process, while simultaneously ensuring the reliability of use and maintaining the quality of the dried plasma.

The technical result is achieved by implementing the following inventions:

A method for producing lyophilized blood plasma or its components, which consists in using fresh or freshly thawed blood plasma or its components for sublimation drying, which is carried out in a container consisting of at least two communicating chambers, one of which is vapor-permeable and the other is vapor-impermeable, the chambers are united by a common space through a connecting region of the seam, which has a jumper to prevent spontaneous plasma flow, the vapor-permeable chamber has at least one lock with a connecting tube, the vapor-impermeable part has two locks with a connecting tube each, wherein one of the tubes has a built-in disposable infusion filter and a plug, and the ratio of the areas of the internal dimensions of the communicating chambers is 2.0-2.5, characterized in that it includes primary drying and secondary drying, the primary drying is carried out in two stages: at the beginning, the temperature is increased to 0 ^o C, then they move on to the second stage, during which the temperature is increased above 0 ^o C, while provide a temperature increase mode in which, at the first stage of primary drying, the rate of temperature increase exceeds the rate of temperature increase at the second stage of primary drying, and secondary drying is carried out at a constant temperature.

A method characterized in that the rate of temperature increase in the first stage of primary drying exceeds the rate of temperature increase in the second stage of primary drying by 1.5–4.5 times.

A method characterized in that the duration of the second stage of primary drying exceeds the duration of the second stage of primary drying by 1.5–3.5 times.

A method characterized in that the duration of the second part of the second stage of primary drying exceeds the duration of the first part of the second stage of primary drying by 1.5–3.5 times.

A method characterized by the fact that the total drying time does not exceed 21–26 hours.

A method characterized in that the duration of the first stage of primary drying does not exceed 2 hours.

A method characterized in that, at the first stage of primary drying, the temperature is increased every 15 minutes by 5 ^o C until it reaches 0 ^o C.

A method characterized in that the duration of the first part of the second stage of primary drying does not exceed 5 hours.

A method characterized in that in the first part of the second stage of primary drying the temperature is increased every 15 minutes by 2 ^o C until it reaches 40 ^o C.

A method characterized in that the duration of the second part of the second stage of primary drying does not exceed 8–10 hours.

A method characterized in that in the second part of the second stage of primary drying, a constant temperature of 40 ^o C is maintained.

A method characterized in that the duration of secondary drying does not exceed 6–9 hours.

A method characterized in that at the secondary drying stage a constant temperature of 40 ^o C is maintained.

A method characterized in that the vapor-permeable membrane is made of Tyvek and EVA materials.

A container for carrying out sublimation drying of blood plasma or its components, which consists of at least two communicating chambers, one of which is vapor-permeable and the other is vapor-impermeable, the chambers are united by a common space through a connecting area of the seam, having a jumper to prevent spontaneous flow of plasma or its components, the vapor-permeable chamber has at least one lock with a connecting tube, the vapor-impermeable part has two locks with a connecting tube each, wherein one of the tubes has a built-in disposable infusion filter and a plug, and the ratio of the areas of the internal dimensions of the communicating chambers is 2.0–2.5.

A container characterized by being made of flexible material.

A container characterized in that it is made of soft polyvinyl chloride plasticized with dioctyl phthalate.

A container characterized in that its tubes are equipped with additional external locking devices.

A container characterized in that it is equipped with at least one indicator.

A container characterized by being made with a width of 100–160 mm and a length of 400–650 mm on the inside.

A container characterized by being made with a width of 110–160 mm and a length of 400–660 mm along the outer part.

A container for storing, transporting and rehydrating lyophilized blood plasma or its components, which contains a container for sublimation drying of the blood plasma or its components, as described above, wherein the container is made of a double-sided vapor-impermeable transparent flexible material with a tensile strength of at least 1000 N/ ^cm2 and a relative elongation of at least 450%, which is obtained by sealing across the entire width of the vapor-impermeable part of the container for sublimation drying of the blood plasma or its components at a distance of 0–4 cm from the dividing seam between the vapor-permeable and vapor-impermeable parts of the container for sublimation drying of the blood plasma or its components.

A container characterized by being made of double-sided transparent flexible material.

A container characterized in that at least one of the connecting tubes contains a built-in disposable membrane filter.

A container characterized by being made with a width of 90–160 mm and a length of 100–180 mm along the inside.

A container characterized in that it is made with a width of 110–170 mm and a length of 110–190 mm along the outer part.

The group of inventions is carried out as follows:

The method for producing lyophilized blood plasma or its components involves using fresh or freshly thawed blood plasma or its components. Drying is carried out in a special container by filling it with the volume of blood plasma or its component intended for drying blood plasma, adding a buffer and, optionally, a cryoprotectant, characterized in that the primary drying is carried out in two stages: in the first stage of primary drying, the temperature of the shelves in the sublimation chamber is increased every 15 minutes by 5 ^o C over the course of 2 hours, starting from -35 ^o C to 0 ^o C; in the second stage of primary drying, the temperature is increased every 15 minutes by 2 ^o C up to 40 ^o C over the course of 5 hours (for a total of 5 hours) and maintained at this temperature for 8–10 hours; and secondary drying is carried out for 6–9 hours at 40 ^o C; the total drying time for the declared volume of blood plasma or its components does not exceed 21–26 hours. A special container is a device for implementing this method and is a closed elastic, hermetic and sterile system consisting of two parts (vapor-permeable and vapor-impermeable), forming a single internal space with the possibility of a reusable jumper between the parts and connecting tubes made of soft polyvinyl chloride plasticized with dioctyl phthalate, while the ratio of the areas of the internal dimensions of the vapor-permeable and vapor-impermeable parts is 2.0–2.5, and one of the connecting tubes contains a built-in disposable membrane filter with a pore diameter of 170–230 μm.

The container may have the following overall internal dimensions: width 100–160 mm (preferably 120–140 mm, preferably 120 mm); length 400–650 mm (preferably 420–615 mm, preferably 390–450 mm).

The container may have the following overall external dimensions: width 110–160 mm (preferably 125–150 mm, preferably 120–130 mm); length 400–660 mm (preferably 425–625 mm, preferably 420–460 mm).

The vapor-permeable part of the device is a chamber with internal dimensions: width 90–120 mm (preferably 100–110 mm, preferably 100–105 mm); length 300–450 mm (preferably 330–420 mm, preferably 350–390 mm).

The vapor-proof chamber can have the following internal dimensions: width 100–150 mm (preferably 120–130 mm, preferably 120 mm); length 100–200 mm (preferably 120–185 mm, preferably 130 mm).

The vapor-permeable and vapor-impermeable chambers are connected by a common space through a connecting area of a seam measuring 100–160 mm in width and 5–20 mm in length (preferably 8–15 mm, preferably 10–13 mm).

The connecting seam between the two parts of the device may include a seal to prevent plasma from leaking from one chamber to the other. This seal may be implemented using a volume-isolating device, such as an external, non-removable flat clamp with a latch or an internal, double-sided zipper, such as a ZipLock.

The vapor-permeable chamber is made of vapor-permeable opaque flexible material with the following characteristics:

- compatible with blood components (organic buffering agents, anticoagulants, preservatives);

- the vapor permeability value ranges from 1500 to 1680 g/ ^m2 /24 h;

- the air permeability of the material ranges from 575 to 638 ml/min;

- the water-repellent capacity of the material ranges from 140 to 160 cm of water column;

- the logarithm of the reduction in protection against bacterial penetration through the material ranges from 3.2 to 5.2;

- tensile strength of at least 60 N/ ^cm2 ;

- the relative elongation of the material is not less than 20%.

The vapor-proof chamber is made of double-sided vapor-proof transparent flexible material with the following characteristics:

- compatible with blood components (organic buffering agents, anticoagulants, preservatives, saline solution, water for injection);

- the vapor permeability value ranges from 0.04 to 0.1 g/ ^m2 /24 h;

- the air permeability of the material ranges from 0.1 to 638 ml/min;

- the water-repellent capacity of the material ranges from 140 to 160 cm of water column;

- the logarithm of the reduction in protection against bacterial penetration through the material ranges from 3.2 to 5.2;

- tensile strength of at least 1000 N/ ^cm2 ;

- the relative elongation of the material is not less than 450%.

Alternatively, the vapor-permeable chamber can be made of two materials: Tyvek and EVA.

The vapor-permeable portion of the device can have two airlocks, each connected to two infusion tubes 10–25 cm long. Both tubes have Luer Lock plugs to maintain sterility. Both tubes can be equipped with additional external, non-removable, flat clamps with snap latches for additional security. A design with one airlock and one infusion tube is also possible, allowing for alternate filling of the opaque chamber with plasma and the required components (buffer, cryoprotectant), if necessary.

The vapor-impermeable portion of the device has two airlocks, each connected to two 10–25 cm long infusion tubes. The first tube has an inlet with a standard needleless connector for attaching a bag of saline, water for injection, or similar solutions. The second tube has a built-in disposable 170–230 µm infusion filter (designed to retain undissolved solid particles of the lyophilisate) and a Luer Lock plug to maintain sterility and allow for quick connection to a blood transfusion system. Both tubes must be equipped with additional external shutoff devices for additional safety. One tube is designed to connect the saline solution delivery system. The other is designed to connect the blood transfusion system and its components using standard adapters, such as Luer Lock components.

In one embodiment, the container may be equipped with two indicators: a sterility indicator and a temperature indicator. The sterility indicator is required to monitor the container's sterilization process and is selected based on the chosen method (e.g., a chemical steam sterilization indicator). The temperature indicator on the container is required to monitor the storage and transportation temperature (e.g., a disposable thermochemical temperature indicator).

The device can be housed in a transparent shipping container. It can be vacuum-sealed to reduce its size.

The invention also relates to a container for storing, transporting and rehydrating lyophilized blood plasma or its components, made of a double-sided vapor-impermeable transparent flexible material with a tensile strength of at least 1000 N/ ^cm2 and a relative elongation of at least 450%, which is obtained by sealing across the entire width of the vapor-impermeable portion of the container for lyophilizing blood plasma or its components at a distance of 0-4 cm from the dividing seam between the vapor-permeable and vapor-impermeable portions of the container for lyophilizing blood plasma or its components. The container for storing, transporting and rehydrating lyophilized blood plasma or its components may have the following dimensions: width 90-160 mm and length 100-180 mm along the inner part, width 110-170 mm and length 110-190 mm along the outer part. The container for storage, transportation and rehydration of lyophilized blood plasma or its components contains two tubes, one of which has a built-in disposable membrane filter with a pore diameter of 170–230 µm.

The invention is illustrated by the following examples, but is not limited thereto.

Example 1

The method for obtaining lyophilized blood plasma is as follows:

Fresh blood plasma is taken. Lyophilization is carried out in a special container, filling it with the volume of blood plasma intended for blood plasma drying, adding a buffer and, if necessary, a cryoprotectant. Drying is carried out in 2 stages: primary drying is carried out in two steps: in the first stage of primary drying, the shelf temperature in the sublimation chamber is increased by 5 ^° C every 15 minutes over 2 hours, starting from -35 ^° C to 0 ^° C; in the second stage of primary drying, the temperature is increased by 2 ^° C every 15 minutes over 5 hours up to 40 ^° C and maintained at this temperature for 8 hours; secondary drying is carried out for 6 hours at 40 ^° C.

The total drying time for the stated volume of blood plasma is 21 hours. A special container is a device for implementing this method and is a closed, elastic, hermetically sealed, and sterile system consisting of two parts: a vapor-permeable and a vapor-impermeable part, forming a single internal space with the possibility of a reusable bridge between the parts and connecting tubes made of soft polyvinyl chloride plasticized with dioctyl phthalate, while the ratio of the internal dimensions of the vapor-permeable and vapor-impermeable parts is 2.5, and one of the connecting tubes contains a built-in disposable membrane filter with a pore diameter of 170-230 μm.

The container has overall internal dimensions: width 110 mm; length 430 mm.

The container has overall external dimensions: width 130 mm; length 450 mm.

The vapor-permeable part of the device is a chamber with internal dimensions: width 110 mm; length 300 mm.

Vapor-proof chamber with internal dimensions: width 110 mm, length 120 mm.

The vapor-permeable and vapor-impermeable chambers are connected by a common space through a connecting seam area measuring 110 mm in width and 10 mm in length.

The connecting area of the seam between the two parts of the device includes a seal that prevents the plasma from leaking from one part of the chamber to the other. The seal can be implemented using a volume-isolating device, such as an external, non-removable, flat clamp with a latch.

The vapor-permeable chamber is made of vapor-permeable opaque flexible material Tyvek.

The vapor-permeable portion of the device has two airlocks, each connected to two 10-cm-long infusion tubes. Both tubes have Luer Lock plugs to maintain sterility. Both tubes are equipped with additional external, non-removable, flat clamps with snaps for additional security.

The vapor-impermeable portion of the device has two ports, each connected to two 10-cm-long infusion tubes. The first tube has an inlet with a standard needleless connector for attaching a bag of saline, water for injection, or similar solutions. The second tube has a built-in disposable infusion filter designed to retain undissolved solids of the lyophilisate and a Luer Lock plug to maintain sterility and allow for quick connection to a blood transfusion system. Both tubes are equipped with additional external shutoff devices for additional safety. One tube is designed to connect to a saline solution delivery system. The other is designed to connect a blood transfusion system and its components using standard fittings, such as Luer Lock components.

For storage, transportation and rehydration of lyophilized blood plasma, the lyophilization container is packed into another container for storage, transportation and rehydration of lyophilized blood plasma. The container for storage, transportation and rehydration of lyophilized blood plasma is made of a double-sided vapor-impermeable transparent flexible material with a tensile strength of 1000 N/ ^cm2 and a relative elongation of 450%, which is obtained by sealing along the entire width of the vapor-impermeable part of the plasma lyophilization container at a distance of 4 cm from the dividing seam between the vapor-permeable and vapor-impermeable parts of the plasma lyophilization container. The container for storage, transportation and rehydration of lyophilized blood plasma has the following dimensions: width 120 mm and length 160 mm along the inner part, width 130 mm and length 170 mm along the outer part. The container for storage, transportation and rehydration of lyophilized blood plasma contains two tubes, one of which has a built-in disposable membrane filter.

The invention makes it possible to reduce the time required for the process of lyophilization of blood plasma in comparison with known methods, ensuring the sterility of the process, while simultaneously ensuring the reliability of use and maintaining the quality of the dried plasma.

Example 2

The method was carried out similarly to Example 1, except that cryoprecipitate was used instead of blood plasma. This method also resulted in a shorter lyophilization time compared to known methods, ensuring the sterility of the process while simultaneously ensuring the reliability of use and maintaining the quality of the dried product.

Claims (26)

1. A method for producing lyophilized blood plasma or its components, which consists in using fresh or freshly thawed blood plasma or its components for sublimation drying, which is carried out in a container consisting of two communicating chambers, one of which is vapor-permeable and the other is vapor-impermeable, the chambers are united by a common space through a connecting area of the seam, having a jumper to prevent spontaneous plasma flow, the vapor-permeable chamber has at least one lock with a connecting tube, the vapor-impermeable part has two locks with a connecting tube each, wherein one of the tubes has a built-in disposable infusion filter and a plug, and the ratio of the areas of the internal dimensions of the communicating chambers is 2.0-2.5, characterized in that it includes primary drying and secondary drying, the primary drying is carried out in two stages: at the beginning, the temperature is increased to 0 ° C, then they move on to the second stage, during which the temperature is increased above 0 ° C, while provide a temperature increase mode in which, at the first stage of primary drying, the rate of temperature increase exceeds the rate of temperature increase at the second stage of primary drying, and secondary drying is carried out at a constant temperature. 2. The method according to paragraph 1, characterized in that the rate of temperature increase in the first stage of primary drying exceeds the rate of temperature increase in the second stage of primary drying by 1.5–4.5 times. 3. The method according to paragraph 1, characterized in that the duration of the second stage of primary drying exceeds the duration of the second stage of primary drying by 1.5–3.5 times. 4. The method according to paragraph 1, characterized in that the duration of the second part of the second stage of primary drying exceeds the duration of the first part of the second stage of primary drying by 1.5–3.5 times. 5. The method according to claim 1, wherein the total drying time does not exceed 21–26 hours. 6. The method according to paragraph 1, characterized in that the duration of the first stage of primary drying does not exceed 2 hours. 7. The method according to claim 1, characterized in that at the first stage of primary drying the temperature increases every 15 minutes by 5°C until it reaches 0°C. 8. The method according to paragraph 1, characterized in that the duration of the first part of the second stage of primary drying does not exceed 5 hours. 9. The method according to claim 1, characterized in that in the first part of the second stage of primary drying the temperature is increased every 15 minutes by 2°C until it reaches 40°C. 10. The method according to paragraph 1, characterized in that the duration of the second part of the second stage of primary drying does not exceed 8–10 hours. 11. The method according to claim 1, characterized in that in the second part of the second stage of primary drying, a constant temperature of 40°C is maintained. 12. The method according to paragraph 1, characterized in that the duration of secondary drying does not exceed 6–9 hours. 13. The method according to paragraph 1, characterized in that at the secondary drying stage a constant temperature of 40°C is maintained. 14. The method according to claim 1, wherein the vapor-permeable membrane is made of Tyvek and EVA materials. 15. A container for carrying out sublimation drying of blood plasma or its components, which consists of two communicating chambers, one of which is vapor-permeable and the other is vapor-impermeable, the chambers are united by a common space through a connecting area of the seam, which has a jumper to prevent spontaneous flow of blood plasma or its components, the vapor-permeable chamber has at least one lock with a connecting tube, the vapor-impermeable part has two locks with a connecting tube each, wherein one of the tubes has a built-in disposable infusion filter and a plug, and the ratio of the areas of the internal dimensions of the communicating chambers is 2.0–2.5. 16. The container according to paragraph 15, characterized in that it is made of flexible material. 17. The container according to item 15, characterized in that it is made of soft polyvinyl chloride plasticized with dioctyl phthalate. 18. The container according to item 15, characterized in that its tubes are equipped with additional external locking devices. 19. The container according to item 15, characterized in that it is equipped with at least one indicator. 20. A container according to item 15 with a width of 100–160 mm and a length of 400–650 mm along the inside. 21. A container according to item 15 with a width of 110–160 mm and a length of 400–660 mm along the outer part. 22. A container for storing, transporting and rehydrating lyophilized blood plasma or its components, which contains a container for carrying out freeze-drying according to paragraph 15, wherein the container is made of a double-sided vapor-impermeable transparent flexible material with a tensile strength of at least 1000 N/ ^cm2 and a relative elongation of at least 450%, which is obtained by sealing across the entire width of the vapor-impermeable part of the container for carrying out freeze-drying according to paragraph 15 at a distance of 0–4 cm from the dividing seam between the vapor-permeable and vapor-impermeable parts of the container for carrying out freeze-drying. 23. The container according to item 22, characterized in that it is made of double-sided transparent flexible material. 24. The container according to claim 22, characterized in that at least one of the connecting tubes contains a built-in disposable membrane filter. 25. A container according to item 22 with a width of 90–160 mm and a length of 100–180 mm along the inside. 26. A container according to item 22 with a width of 110–170 mm and a length of 110–190 mm along the outer part.