JPH0362427B2 - - Google Patents

Description

[Detailed description of the invention]

Because platelets have a relatively short shelf life in a viable state, US regulations require platelets to be stored at 22°C for no longer than 3 days before use. While storing platelets at 22°C,
It is known that PH usually decreases. PH is
When reaching 6.0, platelets undergo morphological changes and lose their viability. Murphy and Gardner: “Blood”, 46, 209−
218 (1975), platelet concentrate
Discloses that when containers constructed of polyvinyl chloride are used to store (concentrate), at 22°C, the pH often falls to such low levels (PH < 6.0) that viability is lost. are doing.
They disclose that a smaller decrease in pH was observed in bags constructed of polyethylene. As a result of studying the conditions necessary to maintain viability during a 3-day storage period, they found that (1) production of lactic acid due to glycolysis of platelets and residual CO ₂ under certain circumstances (2) The rate of decrease in PH is approximately inversely proportional to the number of platelets; (3) Polyethylene allows gases to pass through it better, but in doing so, it allows CO ₂ to escape from the stored platelet concentrate. O ₂ into it
When the partial pressure of _O2 increases, glycolysis is inhibited by the pasteur effect; (4) Adequate agitation and container dimensions are critical to obtain advantageous effects with polyethylene. (5) Generally, platelets stored in polyethylene containers are
Although CO ₂ escape will cause a harmful PH increase, it has excellent in vivo viability; (6) 10%
Storage in a CO ₂ atmosphere prevents these deleterious PH increases without compromising platelet viability that would otherwise be compromised; and (7) similar to those found for polyethylene. They concluded that the same results apply to polyvinyl chloride as long as it is thinned to allow gases to pass through it more easily. Gajewski et al., U.S. Pat. a block copolymer having the properties of a thermoplastic rubber with a central block of butadiene copolymer and end blocks of polystyrene; and (3) an optional third component consisting of a polyethylene or poly(ethylene-vinyl acetate) softener. A clear, pressure cookerable, blow moldable plastic composition for medical and other applications is disclosed comprising: A blood bag made of this composition is also disclosed. US Pat. No. 4,222,379 points out that this composition exhibits good carbon dioxide transfer properties and is suitable for use as a transfer bag for storing platelets. Smith U.S. Patent issued September 16, 1980
4222379 is a multiple blood bag system in which the first bag,
A second bag and conduit means providing a sealed fluid passage therebetween are disclosed.
The first bag is made of a polymer substance different from the polymer substance of the second bag, and the polymer substance of the first bag exhibits properties that inhibit hemolysis of blood cells during long-term storage. The patent further states that the first (donor) bag may be made of a transparent, flexible, sterilizable material containing a blood extractable plasticizer, while the second (transfer) bag may be made of a transparent, flexible, sterilizable material containing a blood extractable plasticizer. ) The bag is a translucent, flexible, sterilizable material;
It is disclosed that it does not contain plasticizers that can be extracted by blood and may be made of a material that increases the diffusion rate of carbon dioxide during platelet storage and reduces the PH drop of platelets during storage. A platelet storage container that increases the shelf life during which viability can be maintained would provide clear benefits to medical practice. Hospitals are now less subject to variations in supply and demand, and traditionally, because of regulations,
This would also be less of an inconvenience during these long weekends, where the platelet supply was often nearly depleted before the end of the weekend. Providing such a container made from relatively thin materials using easy processing techniques would meet mechanical and commercial interests as desirable goals. The present invention can be heat sealed at low temperatures and has an oxygen permeability of at least about 1.8×10 ⁵ μm ³
(STP)/( ^m2・sec・Pa) [100cc(STP)/(24
time - atmospheric pressure - 645 cm ² )], and the carbon dioxide permeability is about 4.4 x 10 ⁵ to about 8.0 x
10 ⁵ μm ³ (STP) / (m ²・sec・Pa) [250 or approx.
450cc (STP)/(24 hours - atmospheric pressure - 645cm2 ⁾ ], the tensile strength is at least about 8mPa, the seal strength is at least about 1000g/cm, and the stiffness is at least about 1000g/cm. low enough that the container can be expanded by liquid to a capacity of about 275 ml, durable enough to give a dart drop value of at least about 100, and thickness of about 0.08 mm to about 0.23 mm. Compared to prior art platelet storage containers, increased oxygen permeability is desirable, and excessively high carbon dioxide permeability is not only detrimental, but survival at 22°C for at least 5 days, and often 7 days. It has been discovered that in order to maintain capacity, the oxygen permeability of the material of which the container is constructed must have certain minimum limits and the carbon dioxide permeability must be within a certain range. Additionally, the container or its materials of construction must also possess certain other physical properties. The present invention is an improvement on platelet storage containers currently available on the market. Accordingly, the containers of the present invention have the same dimensions, shapes, and surface areas as those currently commercially available (hereinafter referred to as "standard dimensions, shapes, and surface areas"). These containers must not allow air to be evacuated to introduce the liquid into the container;
It has been found that it must be possible to expand so that air must not be introduced to remove liquid from the container. Actually, after putting 275 ml of plasma into a container, the plasma and platelets are centrifuged. Most of the plasma is then removed leaving about 2 ml of platelets in about 48 ml of plasma in the container. Therefore, the container is approximately 275ml depending on the liquid.
It must be made of a polymeric material with sufficiently low stiffness that it can be expanded to a capacity of . In addition to the novel properties described above, the container of the present invention also meets this expansibility requirement. Copolymer film materials suitable for constructing the containers of the present invention have a size of at least about 1.8×10 ⁵ μm ³
(STP)/( ^m2・sec・Pa) [100cc(STP)/(24
time - atmospheric pressure - 645 cm ² )], preferably at least about 2.7
×10 ⁵ μm ³ (STP) / (m ²・sec・Pa) [150cc
(STP)/(24 hours - atmospheric pressure - 645 cm ² )]. As mentioned above, platelets usually have approximately 2
It is stored in approximately 50 ml liquid units consisting of 1 ml of platelets and approximately 48 ml of plasma. The total number of platelets present for this 50 ml of fluid (hereinafter referred to as platelet concentrate) is approximately 3×10 ¹⁰ to greater than 12×10 ¹⁰ . at least 2.7
×10 ⁵ μm ³ (STP) / (m ²・sec・Pa) [150cc
A preferred oxygen permeability of (STP) / (24 hours - atmospheric pressure - 645 cm ² )] is based on the total platelet counts encountered during collection and storage.
This provides sufficient oxygen for about 95% of all platelets (encountered), or as high as 12×10 ¹⁰ total platelets. Copolymer film materials suitable for constructing the containers of the present invention also include from about 4.4 x 10 ⁵ to about 8.0
×10 ⁵ μm ³ (STP) / (m ² · sec · Pa) [250 to about 4500cc (STP) / (24 hours - atmospheric pressure - 645 cm ² )],
Preferably from about 5.3×10 ⁵ to about 7.3×10 ⁵ μm ³
(STP) / ( ^m2・sec・Pa) [300 to about 415cc
It must have a carbon dioxide permeability of (STP)/(24 hours - atmospheric pressure - 645 cm ² )]. The above range of CO ₂ permeability allows sufficient CO ₂ to escape for 75% of the total number of platelets encountered, i.e. about 5 to 10 x ¹⁰ platelets, whereas the preferred range is Provides sufficient CO ₂ transfer to accommodate 92% of the platelet count, ie approximately 3-12×10 ¹⁰ platelets. about
4.4×10 ⁵ μm ³ (STP) / (m ²・sec・Pa) [250c.c.
(STP) / (24 hours - atmospheric pressure - 645 cm ² )] lower than
CO ₂ permeability does not allow enough CO ₂ to escape from the container and therefore the PH of the platelet-containing fluid
decreases. The above-mentioned level of CO ₂ permeability, together with the above-mentioned oxygen permeability, will reduce the pH of the platelet concentrate when stored in air at 22°C with a total number of about 3 to 12 x 10 ¹⁰ platelets in a container. For storage up to 5 days and sometimes up to 7 days, it will ensure that it remains in the range of about 6-7.5. If CO ₂
Transmittance is 8×10 ⁵ μm ³ (STP)/(m ²・sec・Pa)
If it is significantly larger than [450CC(STP)/(24 hours - atmospheric pressure - ^645cm2 )], the pH of the fluid containing platelets is 7.5.
They grow larger and lose their ability to survive. It should be understood that the permeability used here is the permeability at the thickness selected for use with the copolymer film material, and is the value obtained when measured in ambient air. . The copolymer film materials used to construct the containers of the present invention have a carbon dioxide permeability to oxygen permeability ratio of up to about 4.5:1. The preferred range of permeability described above corresponds to a rather unusual polymer film having a permeability ratio of 2:1 to 3:1 or less. In contrast, polyvinyl chloride films currently used commercially in the construction of platelet storage containers have a permeability ratio of about 6. In addition to the permeability requirements set forth above, the copolymer film material used in the construction of the containers of the present invention has a tensile strength of at least about 8 mPa, preferably at least about 9 mPa, and a tensile strength of at least about 1000 mPa.
It is necessary to have a sealing strength of g/cm. The copolymer material also has low temperature
It must be able to be heat sealed at 0.degree. C. to provide the sealing strength described above. It is easy to make containers from materials that meet this requirement. The thickness of the copolymer film material selected for use in constructing the containers of the present invention will depend on the permeability and mechanical durability per unit thickness of the polymeric material. For example, if the material has a relatively high oxygen and carbon dioxide permeability, a relatively thick material can be used. Conversely, if the material's oxygen permeability at a particular thickness is marginally low and its carbon dioxide permeability at that thickness is low enough to be near the low end of said range, the material has relatively high mechanical durability. If so, a thinner thickness can be used. Generally, the thickness of the material will be about 0.08 mm to about 0.23 mm. 0.915
For copolymers of ethylene and 1-butene or 1-octene having a density of from 0.925 g/cm 3 to 0.925 g/cm ³ , the thickness of the film material will be from about 0.10 mm to about 0.14 mm. Copolymer film materials must be mechanically durable. That is, it must be able to resist rough handling at the selected thickness. Generally, suitable materials will have a dart drop value of at least about 100 as measured by the ASTM 1709 method at their chosen thickness. The materials of construction must also be compatible with plasma proteins. "compatibility"
means that the material does not interact with or dissolve into plasma material that would be harmful to the plasma, platelets, or recipient. Water vapor permeability of polymer material is 40℃ (400〓)
and at 90% relative humidity, should be less than about 25 g/24 hours/m ² as measured by ASTM-E96 test. As used herein, the expression "copolymer film material" means a film material in which each layer is made from a single copolymer or homopolymer, and at least one layer is made from a single copolymer. Suitable polymeric materials for use in constructing the containers of the present invention are at least translucent and include: copolymers of ethylene and alpha-olefins of 4 to 10 carbon atoms, 0.915 to 0.925 g; / ^cm3 (so-called linear low-density polyethylene), and a typical α-olefin is 1-
Includes butene, hexene, 1-octene and 1-decene; ionomers, such as copolymers of ethylene and acrylic or methacrylic acid or derivatives thereof, neutralized with sodium or zinc; and ionomers/polyester elastomers and linear low density polyethylene elastomer laminates or coextrudates. A preferred composition is a copolymer of ethylene and an alpha-olefin of 4 to 10 carbon atoms,
It has a density of ~0.925 g/ ^m3 . These copolymers of ethylene and α-olefins of 4 to 10 carbon atoms contain the latter component in about 3 to 5
Including mole%. Preferably, the α-olefin is 1-
Butene or 1-octene is preferred, with 1-octene being more preferred. These preferred materials provide containers with improved transparency.
These materials exhibit a haze of 12-15%. When the platelet concentrate is stored in the containers of the present invention, thorough agitation is provided as is conventional in the art. Stirring may be carried out by methods well known in the art, such as by using a back-and-forth plate bed stirrer operating at about 70 cpm (cycles per minute), or by using a "ferris-wheel" stirrer at about 5 rpm. You can do it by doing this. Currently commercially available platelet storage containers have a surface area of approximately 277 cm ² (43 square inches). Containers are typically affixed with labels having an area of about 77 cm ² (12 square inches), which covers about 28% of the container's surface area. This label reduces the permeability of the container by this area. The above permeability requirements are for unlabeled containers. Currently, for commercial applications the label is attached completely to the surface of the container, but the label can also be attached at only one end, on a specially made flap on the container, Alternatively, it could be mounted in such a way that it does not obstruct any of the effective surface area of the container. If the label is to be fully adhered to the surface of the container, the permeability of the polymeric material used in the construction of the container must be such as to compensate for the reduction in permeability caused by the label. Although the present invention is not limited by theory, the permeability requirements described above are such that the platelet storage container maintains platelet viability for at least 5 days, and often up to 7 days. It is believed that the effective permeability, P _eff , is sufficient to ensure sufficient oxygen uptake and sufficient carbon dioxide exhaustion during use. The effective transparency is given by the inverse addition: 1/P _eff = 1/P _filn + 1/P _lr + 1/P _label where P→ _label acts only within the area of the label and P → _l
.
r. is the liquid resistance permeability. In the present invention, P→ _eff , P→ _eff , O ₂ for oxygen is at least about 1.2×10 ⁵ μm ³
(STP)/( ^m2.sec.Pa ) [66 cc/(24 hours - atmospheric pressure - 645 ^cm2 )], preferably at least about 1.3 x ¹⁰⁵ (74). _O2 permeability is above
1.8×10 ⁵ μm ³ (STP)/( ^m2・sec・Pa) [100cc/
(24 hours - atmospheric pressure - 645 cm ² )], then P → _eff , O ₂ is at least about 1.2 × 10 ⁵ μm ³ (STP) / (m ² · sec ·
Pa) [66 cc/(24 hours - atmospheric pressure - 645 cm ² )]. Since blood banks often do not know in advance what number of platelets to expect, the containers of the present invention can be stored at 22°C for about 75-80% of the total platelet numbers encountered. It ensures that platelet viability is maintained for at least 5 days, and often up to 7 days. Indeed, the preferred permeability provides such viability for approximately 92% of the total platelet numbers encountered. The platelet storage container of the present invention will typically be in the form of a bag. When a multi-bag system is desired, the platelet storage container of the present invention is placed in a separate bag according to the European Patent Publication No.
The sterile docking system described and claimed in No. 0044204 can be used to aseptically connect. Because the platelet storage container of the present invention is made from a copolymer film rather than a polymer mixture, the film is homogeneous and provides relatively constant permeability. Additionally, since the container is manufactured from a film rather than using blow molding techniques, the wall thickness is more uniform and therefore there is less variation in permeability at different locations on the container. The above-mentioned properties of the present invention are measured as follows. 1 Permeability - ASTM D-1434 2 Tensile Strength - ASTM D-882 3 Sealing Strength - The film samples are heat sealed using conventional methods to provide a welded seal with minimal run-out of the sealed portion. First, two sheets of the same material are heat sealed along a line with a hot bar to form a sealed pair.
Cut a 2.54 cm wide sample from near the center of this sealed pair so that the seal line is near one end of the sample. The resulting free end of the sample is attached to the grip of a peel tester, which essentially applies a shock test to the seal and measures the strength of the seal in grams per seal width. . 4 Viability - In the text, "viability" means the ability of platelets to circulate in the body. In vivo measurements of viability can be performed by labeling platelets with ⁵¹ Cr and reinjecting them into the original normal volunteer. Viability, as used in the text, refers to shape change, morphology seore, dispersion of platelet size distribution, and percent aggregation.
aggre-gation). Shape change measures the deviation from the platelet's normal disc-like shape, and Holme and
Murphy: Journal of Laboratory and Clinical
Medicine, 92, pages 53-64 (1978). The dispersion test is a measure of the degree of platelet disintegration, Holmes et al., Blood, 52, 425-435
(1978) using a method similar to that described by Coulter counter. The morphology value gives the percentage of disk-like shapes and is measured using a phase contrast microscope. Aggregation rate is an indication of the ability of platelets to perform a hemostatic function and is also measured by light transmission. The test methods used for morphology values and aggregation were similar to those described in the Holme et al. article supra. Murphy, at the AABBMeeting in Montreal, November 9-12, 1980, said that shape change and dispersion were measured in vivo by reinjecting platelets labeled with ⁵¹ Cr into the original normal volunteers. It was shown that there is a quantitative relationship with in vivo survival (% in vivo recovery of ⁵¹ Cr). Shape change was used as an in vitro measure of intended recovery. Murphy reported that morphology values are similarly accepted as a good measure of platelet survival. There are only a few cases in which platelets did not circulate despite good morphological values, and although morphological measurement results were poor either in terms of shape change or visual counting, in vivo results were poor. No good examples were known at all. According to Murphy's findings, a shape change of 1.07 corresponds to ~30% in vivo recovery; shape change is proportional to % in vivo recovery, and a shape change of 1.21 corresponds to 65% recovery. A morphology value of 300 on a scale of 1 to 800 is the minimum acceptable value and corresponds to a recovery of 25-30%. Immediately after platelet collection, the morphology values range from approximately 650 to 700, corresponding to a recovery ( ⁵¹ Cr) of 65 to 75%.
Therefore, within the range of 300 to 700, the in vivo recovery%
is considered to be estimated by form value/10. The invention is further illustrated by the following examples. In the examples, all temperatures are in °C unless otherwise specified.
and all percentages are weight percent except for in vivo recovery.
It is. % in vivo recovery is a % by number. Platelet count values and permeability are each accurate to approximately ±20%. The PH values described in the Examples were measured at 22°C. Examples 1-5 Platelet storage bags of standard dimensions, shapes and surface areas are made from films of the following copolymer film materials. (a) Ethylene (approximately 97 mol%) with a density of 0.919 g/cm ³
and 1-butene copolymer (LLDPE), (b) coextrudate of 20% polybutylene (polytetramethylene glycol) terephthalate (10-30% polyether) and 80% LLDPE, and (c) density 0.918 g/ cm ³ of ethylene and 1-octene copolymer (LLDPE). The properties of the obtained platelet storage bag are shown in the table. Both bags have sufficiently low stiffness that they can hold approximately
Can be expanded to a capacity of 275ml.

[Table] means.
Example 6 Using four bags similar to those described in Example 3,
Approximately 50 ml of platelet concentrate are each stored for 7 days at 22° while stirring with a plate-bed stirrer. The concentration of platelets in the bag ranged from approximately 1.2 to 1.7 x ¹⁰⁹ /cc. 1 from each bag for each of 1, 3 and 7 days.
~4 ml samples are taken and platelet shape changes are measured at each period. The maximum pH on the first day is 7.36 and the minimum pH on the seventh day is 7.12. The average shape change over 7 days was 1.16, corresponding to an intended in vivo platelet recovery of 55%. Example 7 Using 10 bags similar to those described in Example 3, approximately 50 ml of platelet concentrate was placed in a Ferris wheel.
Store for 7 days at 22°C while stirring with a wheel type stirrer. The concentration range of platelets in the bag is 0.96-2.77
× ¹⁰⁹ /cc, and the total platelet count ranges from 5.7 to 13×
10 ¹⁰ /cc. Samples of 1-4 ml are taken from each bag on each of the 3rd and 7th days and the morphological values are determined during these periods. Morphological values on the 7th day
The average value for the 10 bags was approximately 490, corresponding to an intended in vivo platelet recovery of 49%. The average PH of platelet concentrate is 7.2 on day 3 and 7.07 on day 7. Control Test Approximately 50 ml of platelet concentrate is stored at 22° for 7 days in each of 10 prior art platelet storage bags of standard size, shape and surface area. These bags are
PVC with thickness 0.38mm (15mil)
It is composed of film. The oxygen and carbon dioxide permeability of this film are 7.1×10 ⁴ and 4.2×10 ⁵ μm ³ (STP)/(m ² sec Pa) [40
and 240cc (STP) / 24 hours - atmospheric pressure - 645cm ² )]
It is. The tensile strength of the film is approximately 20 mPa, and the sealing strength is approximately 1200 g/cm. The stiffness of each bag is low enough that it can be expanded with liquid to a capacity of approximately 275ml. Platelet concentration in the bag is 0.86 ~
The total platelet count is in the range of 2.50×10 ⁹ /cc, and the total platelet count is 4.64 ~
It is 11.5×10 ¹⁰ . The average 7-day morphology value for the 10 bags was 249, corresponding to the intended in vivo platelet recovery of 25%. Average pH of platelet concentrate was 6.6 for 3 days
and 6.1 for 7 days. Example 8 Using 9 bags similar to those described in Example 5, approximately 50 ml of platelet concentrate is stored for 7 days at 22° while stirring with an average bed stirrer. The concentration range of platelets in the bag is 1.22-2.49×10 ⁹ /cc, and the range of total platelet count is 5.9-12.6×10 ¹⁰ . 0, 3,
A sample of 1-3 ml is taken from each bag on each of the 5th and 7th days and the morphological values at each period are determined. The mean morphology value for the 9 bags over 7 days was 517, corresponding to an intended in vivo platelet recovery of 52%. Average pH of platelet concentrate
is 7.18 on days 0, 3, 5 and 7 respectively,
7.27, 7.18 and 6.97. Example 9 Seven bags similar to those described in Example 5 are used, approximately 50 ml of platelet concentrate is placed in each bag and stored at 22° with oval agitation for 7 days. The platelet concentration in the bag ranges from 1.10 to 2.55 x ¹⁰⁹ , and the total platelet count ranges from 5.3 to 12.9 x ¹⁰¹⁰ . 1-3ml each for 0, 3, 5 and 7 days from each bag
Collect samples and measure the morphological values at each period. The mean value for the 7-day morphology value for the 7 bags was 515, corresponding to the intended in vivo platelet recovery of 52%. The average pH of platelet concentrate at 0, 3, 5 and 7 days was 7.18, respectively.
7.30, 7.12 and 7.02.

Claims (1)

[Claims] 1. It can be heat-sealed at a low temperature, and at least 1.8×10 ⁵ μm ³ (STP)/(m ² ·sec ·
Pa) oxygen permeability, 4.4×10 ⁵ to 8.0×10 ⁵ μm ³ (STP)/(m ²・sec・
carbon dioxide permeability of at least 4.5:1, tensile strength of at least 8 mPa, seal strength of at least 1000 g/cm
strength), stiffness so low that the container can be expanded by liquid to a capacity of 275 ml, and a dart drop value (dart drop value) of at least 100.
Copolymers of ethylene and α-olefins of 4 ^to 10 carbon atoms and ionomers ( ionomer)
A platelet storage container made from a copolymer film material selected from the group consisting of: 2. A container according to claim 1, comprising:
The copolymer film material comprises at least
One with an oxygen permeability of 2.7×10 ⁵ μm ³ (STP)/(m ²・sec・Pa). 3. A container according to claim 2, comprising:
The copolymer film material has a particle size of 5.3×10 ⁵ to 7.3
One with a carbon dioxide permeability of ×10 ⁵ μm ³ (STP)/(m ²・sec・Pa). 4. A container according to claim 1, comprising:
The copolymer film material has at least 9
It has a tensile strength of mPa. 5. A container according to claim 1, comprising:
The α-olefin of 4 to 10 carbon atoms is 1-
butene or 1-octene, and said copolymer film material has a thickness of 0.10 to 0.14 mm. 6. A container according to claim 5, comprising:
The α-olefin is 1-octene. 7. A method for storing platelet concentrates, which can be heat sealed at low temperatures and have a storage capacity of at least 1.8×10 ⁵ μm ³ (STP)/(m ² sec.
Pa) oxygen permeability, 4.4×10 ⁵ to 8.0×10 ⁵ μm ³ (STP)/(m ²・sec・
carbon dioxide permeability of at least 4.5:1, tensile strength of at least 8 mPa, seal strength of at least 1000 g/cm
strength), stiffness so low that the container can be expanded by liquid to a capacity of 275 ml, and a dart drop value (dart drop value) of at least 100.
Drop value) and durability of 0.08 ~
from a copolymer film material selected from the group consisting of copolymers of ethylene and α-olefins of 4 to 10 carbon atoms and ionomers having a density of 0.915 to 0.925 g/cm ³ with a thickness of about 0.23 mm placing the concentrate in the prepared platelet storage container; sealing the container;
A method consisting of maintaining a temperature of 22°C and agitating the container. 8. The method according to claim 7, wherein the film material forming the container has a length of at least 9 m.
A method that has a tensile strength of Pa. 9. The method of claim 7, wherein the 4 to 10 carbon atom α-olefin is 1-butene or 1-octene, and the copolymer film material has a diameter of 0.10 to 0.14 mm. A method that has thickness. 10. The method of claim 9, wherein the α-olefin of 4 to 10 carbon atoms is 1-octene.