RU2801095C1 - Container for dividing into doses, storage and clinical use of blood components, cell suspensions and liquids (options) - Google Patents

Abstract

FIELD: biotechnology, pharmacy, medicine, and transfusiology.

SUBSTANCE: multi-chamber polymer container for uniform, reproducible dosing and storage of liquids for further use includes a body, a connecting tube for filling and removing excess air, and technological ears for hanging the container and uniformly dividing the liquid into chambers. The body has at least two internal chambers and a connecting channel for free uniform distribution of contents among the chambers. The chambers are separated by internal vertical partitions with through perforation along the entire length of the partitions with the possibility of separating from each other along the sealing and perforation lines after sealing the connecting channel. Each chamber is equipped with a fitting with an internal membrane valve and a first opening control element, ears for hanging during use, and has a length of at least 10 mm along the side of the fitting. An alternative embodiment of the container is disclosed.

EFFECT: providing a uniform reproducible dosing of liquid components, in particular blood and cell suspensions, by volume for the purpose of their further dosed use.

12 cl, 2 dwg, 2 ex

Description

The invention relates to the field of biotechnology, pharmacy, medicine (in particular, to transfusiology) and provides a uniform reproducible dosing of liquids, including cell suspensions, for the purpose of their further storage and dosed use (in particular, for medicinal purposes), including after defrosting. The invention ensures the preservation of uniform characteristics of the content, does not depend on the presence of additional equipment that provides sterile environmental conditions, and can be used in rooms of any cleanliness class.

When compiling the description of the invention, the following concepts are used.

By "reproducible dosing of liquids" is meant the proximity of the volumes of liquids in two or more chambers of a multi-chamber container for dividing into doses and storing drugs when used under identical conditions, in different institutions.

By "non-peelable label" is meant that the label must not peel off or wrinkle under the conditions of fogging of its surface.

Relevance of development:

1. Dosing of mononuclear cells

Extracorporeal photopheresis, in particular, the method of cryopreservation of mononuclear cells [1], is increasingly used for the treatment of autoimmune diseases, skin T-cell lymphomas, in transplantation of solid organs (in order to prevent transplant rejection, including lungs, heart, kidneys) with the goal of therapy for acute and chronic forms of graft-versus-host disease.

In the method for cryopreservation of mononuclear cells, the concentrate of mononuclear cells after photopheresis before program freezing is divided into parts (doses), each of which is poured into containers for cryopreservation in an amount sufficient to carry out a full or part of a course of prevention or treatment. It should be noted that the therapeutic effect does not depend on the number of mononuclear cells injected in one procedure, which makes it possible to use them in the minimum allowable and/or convenient doses for clinical use (for example, from 1 ml).

Features of this procedure:

- sterile environmental conditions are required, which are ensured by carrying out work in "clean zones" (rooms) or using equipment with the creation of "clean zone" conditions (laminar box);

- dividing the concentrate of mononuclear cells into doses involves the use of syringes and additional containers, which is accompanied by an increase in the risk of bacterial contamination of the concentrate of mononuclear cells, an increase in the probability of erroneous distribution of the concentrate of mononuclear cells between containers, the need to use additional consumables, and also requires a significant amount of time for medical personnel.

2. Dosing of blood components for use in children

Procurement of donor blood components is made from each donor in the volumes required for transfusion by adults (the volume of the container is about 300 ml). However, the volume of transfusion for children is calculated taking into account their body weight and averages 10-15 ml/kg [2]. So, for example, for the transfusion of erythrocyte-containing components to a child weighing 2 kg, only 20-30 ml should be used. According to paragraph 99 of the Decree of the Government of the Russian Federation of June 22, 2019 No. 797 [3]: “In order to ensure safety, transfusions from one container to several recipients are prohibited.” Thus, in addition to the transfused required 20-30 ml, the remaining volume of erythrocyte-containing components contained in the container is disposed of.

The prepared blood and (or) its components are used irrationally - the remaining contents of the 300 ml container are disposed of - which significantly increases the cost of treatment, while there is no possibility of accurate and reproducible dosing, leading, among other things, to post-transfusion reactions or complications, for example, cardiac overload - the vascular system, or the use of less / more than necessary, the amount of the donor blood component.

However, it should be noted that according to GOST R 52938-2008 [4], it is allowed to assign "a unique number of a given product unit from among all product units received as a result of this donation." Thus, when using the claimed invention, after dividing the contents of one container obtained as a result of donation, each individual container will have its own unique number, which cannot be regarded as "transfusion from one container to several recipients."

The above features of the dosing procedures for the obtained products (liquids, cell suspensions) determine the relevance of optimizing these procedures. A possible solution may be the development of a container model that allows for uniform, reproducible dosing of liquids, including cell suspensions, for their further storage and use (in particular, for medicinal purposes), which increases the convenience and safety of their storage and use.

The vast majority of containers for blood components known from the prior art are designed to be divided into fractions, and not into doses of cell suspensions, canned blood received in these containers, storage and clinical use of the donor blood components resulting from division. Containers are also known for storing and mixing components contained in the container prior to use, such as drugs and parenteral nutrition products.

Known container for storing blood cells in liquid nitrogen, consisting of a housing and an input node [5]. This container is intended for storage (at low temperatures) and use of cell suspensions.

The disadvantages of a container are:

- the inability to use part of its contents without first defrosting the container;

- the need to ensure sterile environmental conditions, which are ensured by carrying out work in "clean zones" (rooms) or using equipment with the creation of "clean zone" conditions (laminar box).

Known multi-chamber container with a weakened sealing part, designed for storage and mixing of drugs during their use [6].

The design of the container, which consists of several chambers, involves mixing the contents of the chambers immediately before use and does not imply the dosing of liquids, including cell suspensions, and does not provide uniform, reproducible dosing of liquids, including cell suspensions, for the purpose of their further use (in particular, for medicinal purposes).

Known container for collecting, dividing, storing and using blood components [7].

The design of this container determines the possibility of obtaining, dividing into fractions prepared from a donor, canned blood, storage and clinical use of the components of donor blood resulting from the division. This container does not provide a uniform, reproducible dosing of liquids, including cell suspensions, for the purpose of their further storage and use (in particular, for medicinal purposes).

A multi-chamber container CryoStore™ CryoStore FLEX Bag [8] (having several chambers and a connecting channel between them) is known for dividing cell suspensions into doses, cryopreservation, thawing and using the required number of doses of cell suspensions placed in this container. This container is the closest analogue of the container we proposed for dividing into doses and storing drugs.

The disadvantages of this container are:

- the need to use a syringe when placing the cell suspension in this container and when removing excess air from the container,

- the volume of each of the chambers and the total volume of the container are limited by the design for the methods described above (dosing of mononuclear cells, dosing of blood components for use in children),

- the need to ensure sterile environmental conditions, which are ensured by carrying out work in "clean zones" (rooms) or using equipment with the creation of "clean zone" conditions (laminar box).

Thus, the object of the present invention is to provide a container that allows:

Ensure uniform, reproducible dosing of blood components and other liquids by volume, including cell suspensions, for the purpose of their storage (while maintaining the characteristics of individual doses and the entire contents of the container) and further dosed use (in particular, for medicinal purposes).

Ensure dividing the contents with a dose volume of 1 ml.

Minimize the risk of bacterial contamination.

Minimize personnel errors when dosing blood components and other fluids.

Improve convenience and reduce the cost of dosing blood and other fluid components by minimizing the use of additional equipment.

The problem is solved by creating a soft-walled multi-chamber polymer container for dosing (dividing) by volume and storing blood components and other liquids, including cell suspensions (drugs and / or blood components), for the purpose of their further dosed use, consisting of:

Cases (1) with internal vertical partitions (2) - divide the container into several chambers (3) (at least two). Partitions have through perforation (6). Each chamber is equipped with a fitting (4) with an internal membrane valve and a "first opening" control element, has a length along the fitting attachment side of at least 10 mm and a volume of 1 ml. Each chamber is supplied with a factory non-peelable label (7) and, if necessary, a scale indicating volume units. Each chamber is provided with lugs (11) for hanging the container chamber during use.

Connecting channels (9) connect the chambers to each other. The connecting channels are made in such a way as to ensure a uniform, reproducible volume distribution of the contents between the chambers according to the principle of communicating vessels. The diameter of the connecting channels and the material of manufacture make it possible to seal them (8) using a sealer for polymer tubes.

Connecting tube (5) with a clamp - for connection with other containers in order to fill the multi-chamber container and remove excess air from it and technological ears (10) for hanging the multi-chamber container in order to uniformly divide the liquid into chambers.

The technical result of the invention is:

- in the possibility of dividing the initial volume of liquid (for example, cell suspensions) into the required number of parts (doses) according to the calculated number of doses and / or the calculated dose volume with the possibility of their storage (including cryopreservation) and / or separation and dosed use,

- in a reproducible division of the contents of a single-chamber container (for example, cell suspensions or other liquids) into the required number of parts (doses) by volume, including from 1 ml, without violating sterility and the need to use additional equipment that ensures sterile environmental conditions (i.e. e. can be used in rooms of any cleanliness class),

- in reducing time costs and the absence of the need for long-term additional training of medical personnel through the use of standard additional equipment,

- in the possibility of serial connection of containers, if it is necessary to increase the number of doses due to the serial connection to the fittings of containers for dividing (dosing) and storing drugs, in total containing the required number of chambers.

In this case, in the case of using a container for dosing blood components, the total volume of the container is limited by the amount of donation.

The essence of the invention is illustrated on the graphic materials (options).

Fig. 1 - Container . Version with one connecting channel, where:

1 - body,

2 - internal vertical partition,

3 - camera,

4 - fitting with a membrane valve and a "first opening" control element,

5 - connecting tube,

6 - through perforation line,

7 - factory non-peelable label,

8 - sealing line,

9 - connecting channel,

10 - technological eye,

11 - eyelet for hanging the chambers of the container during use.

Fig. 2 - Container . Version with connecting channels in the upper and lower parts of the container, where:

1 - body,

2 - internal vertical partition,

3 - camera,

4 - fitting with a membrane valve and a "first opening" control element,

5 - connecting tube,

6 - through perforation line,

7 - factory non-peelable label,

8 - sealing line,

9 - connecting channel,

10 - technological eye,

11 - eyelet for hanging the chambers of the container during use.

The essence of the invention lies in a new approach for dosing components of blood and other liquids, including cell suspensions, their subsequent storage, including in a frozen (cryopreserved) state, and further dosed use for its intended purpose through the use of a multi-chamber container, which has in its composition at least two chambers that are interconnected by means of connecting channels that ensure free flow of fluid between the chambers due to the law of communicating vessels, a connecting tube with a clamp designed to be connected to another container or an apparatus for filling a multi-chamber container and removing excess air from it, technological ears for hanging a multi-chamber container in order to uniformly divide the liquid into chambers. Each chamber is equipped with a fitting with an internal diaphragm valve and a “first opening” control element, ears for hanging the container chamber during use, a factory non-peeling label and, if necessary, a scale indicating volume units. The inner chamber has a length of at least 10 mm along the fitting side. Internal vertical partitions have through perforation throughout. This design allows, when sealing the connecting channels, to divide into several parts (doses) by volume from 1 ml, the product poured from another (for example, single-chamber) container or apparatus, use (including partially) and / or store the product in a dose-divided form, including in a frozen state, to carry out subsequent dosed use of the product by separating the chambers of the container along the perforation and sealing lines. For sealing the connecting channels and the connecting tube, a sealer for polymer tubes is used. Due to the combination of design features: a multi-chamber container, the chambers of which are connected by means of connecting channels, there is a uniform distribution of liquid between the chambers, which ensures reproducible dosing of blood components and other liquids, including cell suspensions.

The essence of the invention is illustrated by examples of use that do not limit the scope of legal protection.

Stages and sequence of actions when using a multi-chamber container

The method of using the developed container consists of the following steps:

close the clamp on the connecting tube of the multi-chamber container,

connect the source container (single-chamber container) (for example, using a device for sterile connection of tubes of plastic containers) with a connecting tube with a clamp of a multi-chamber container,

mix the contents in the source container,

open the clamp on the connecting tube,

pour the contents of the source container into a multi-chamber container,

after filling the multi-chamber container, close the clamp on the connecting tube and turn the container over and hang it with the help of technological ears to evenly divide the contents into the chambers of the multi-chamber container using the method of communicating vessels,

after dividing the contents into chambers, turn the multi-chamber container upside down with the connecting tube, open the clamp on the connecting tube and remove excess air from the multi-chamber container into the source container,

close the clamp and make a seal on the connecting tube, separate the source container from the multi-chamber container,

mark each chamber with a label containing a unique number of this unit of production from among all units of production,

make seals on the connecting channels using a tube sealer; one or more chambers can be used and/or cryopreserved with the possibility of subsequent storage,

at any period of storage, one or more chambers for dosed use can be separated along the sealing and perforation lines; storage of the remaining cameras can be continued,

separated chambers can be subjected to defrosting and/or heating to the required temperature by any available method, for example, in a device for thawing and heating blood components,

connect a drip infusion device to the fitting with an internal membrane valve and a “first opening” control element. Ready to use.

Thus, a uniform, reproducible dosing of the contents is ensured for the purpose of further storage, cryopreservation, transportation and dosed use, including after defrosting.

Example 1 Use in relation to the method of cryopreservation of mononuclear cells

To use a multi-chamber container for dosing a cell suspension of mononuclear cells obtained as a result of extracorporeal photopheresis, a single-chamber container with mononuclear cells in which they were irradiated is used as the contents of the source container.

The use is carried out as described above in the Method for using the developed container.

Thus, a uniform reproducible dosing of the cell suspension is ensured for the purpose of its further storage (including cryopreservation) and dosed use, including after defrosting. The claimed method increases the availability of using a suspension of mononuclear cells (the initial division into doses makes it possible to use the cells during the entire course of treatment; the use of cell cryopreservation makes it possible to transport the cells to a medical organization at the patient's place of residence). The possibility of transporting cells for the purpose of their further clinical use in any medical organization is extremely important due to the limited nature of medical organizations (in accordance with the order of the Ministry of Health of Russia No. 738n, Russian Academy of Sciences No. 3 dated 10.11. transplantation of human organs and (or) tissues”, the number of organizations in which human tissues are harvested and prepared is limited and the indicated institutions are distributed unevenly in the territory of the Russian Federation, they are not represented in a number of subjects of the Russian Federation).

Example 2. Use of a container for dosing donated blood and/or its components

To use a multi-chamber container for dosing donated blood and (or) its components, including in volumes acceptable for transfusion to children with different body weights, a container with donor blood and (or) its components is used as a source container.

The use is carried out as described above in the Method for using the developed container. In addition to the sequence of actions described in the Method for using the developed container, after connecting the container with donor blood and (or) its components to the multi-chamber container, it is necessary to apply a technological (intermediate) marking to each of the chambers of the multi-chamber container.

Thus, a uniform, reproducible dosing of donor blood and (or) its components is ensured for the purpose of further storage and dosed use of only the required volume of donor blood and (or) its components, without disposing of the remaining contents.

List of literature sources:

1. RF patent No. 2743816, Method for obtaining cryopreserved mononuclear cells, application No. 2020109644, 03/05/2020, publ. 02/26/2021.

https://www.vair-journal.com/jour/article/view/233.

2. Decree of the Government of the Russian Federation dated June 22, 2019 No. 797 “On approval of the Rules for the procurement, storage, transportation and clinical use of donated blood and its components and on the invalidation of certain acts of the Government of the Russian Federation”

GOST R 52938-2008. Donor blood and its components. Containers with preserved blood or its components. Marking.

3. RF patent No. 2127578, Freezing bag, method for freezing red blood cells, application No. 95108323/14, 03/01/1995, publ. 03/20/1999.

4. Application of the Russian Federation for the invention No. 2012143906, 03/16/2011, Multi-chamber container for medical use, a method for identifying the mixing of drugs with its use and a multi-chamber container filled with drugs for medical use, publ. 04/27/2014.

5. Utility model application CN2375299, 2000-04-26, Multi-chamber plastic bag integral device for collecting, separating and storing blood.

https://www.origen.com/products/cryopreservation/cryostore-flex-bag.

Claims (18)

1. A multi-chamber polymer container for uniform, reproducible dosing and storage of liquids for further use, including a body (1), a connecting tube (5) for filling and removing excess air, and technological ears (10) for hanging the container and uniform separation of the liquid between the chambers, while the body has at least two internal chambers (3) and a connecting channel (9) for free uniform distribution of contents among the chambers, the chambers are separated by internal vertical partitions (2) with through perforation along the entire length of the partitions (6) with the possibility of separating from each other along the sealing (8) and perforation (6) lines after the connecting channel (9) has been soldered, in addition, each chamber is equipped with a fitting (4) with an internal membrane valve and a first-opening control element, ears (11) for hanging during use, and has a length along the fitting attachment side of at least 10 mm. 2. A multi-chamber polymer container for uniform, reproducible dosing and storage of liquids for their further use, including a body (1), a connecting tube (5) for filling and removing excess air, and technological ears (10) for hanging the container and uniform separation of the liquid over cameras at the same time, the body has at least two internal chambers (3) and two connecting channels (9) for free uniform distribution of contents among the chambers, located in the upper and lower parts of the container, the chambers are separated by internal vertical partitions (2) with through perforation along the entire length of the partitions (6) with the possibility of separating from each other along the sealing (8) and perforation (6) lines after the connecting channels (9) have been soldered, in addition, each chamber is equipped with a fitting (4) with an internal membrane valve and a first-opening control element, ears (11) for hanging during use, and has a length along the fitting attachment side of at least 10 mm. 3. The container according to any one of paragraphs. 1, 2, characterized in that the partitions (2) are made with the possibility of sealing the connecting channels (9) using a sealer for polymer tubes. 4. Container according to claim 1, characterized in that the connecting channel (9) is preferably located in the upper part of the container on the side of the connecting tube (5). 5. The container according to any one of paragraphs. 1, 2, characterized in that the fitting (4) has the ability to connect to an intravenous drip infusion system or for connection. 6. Container according to any paragraphs. 1, 2, characterized in that the container contains a drug, blood components, blood products or cell suspension. 7. The container according to any paragraphs. 1, 2, characterized in that its contents are divided into parts by volume. 8. Container according to any one of paragraphs. 1, 2, characterized in that it is made of a material used for cryopreservation. 9. The container according to any one of paragraphs. 1, 2, characterized in that the volume of the chamber (3) is about 1 ml or more. 10. The container according to any one of paragraphs. 1, 2, characterized in that the chambers (3) have an equal volume. 11. The container according to any one of paragraphs. 1, 2, characterized in that each chamber (3) is provided with a factory non-peelable label (7). 12. The container according to any one of paragraphs. 1, 2, characterized in that it contains a clamp on the connecting tube (5).