DE102006011534A1 - Plasma Lyophilisate - Google Patents

Abstract

The present invention relates to the use of blood plasma in an essentially water-free form in a sterile closed, essentially water vapor-impermeable container, the internal volume of which can comprise at least a volume corresponding to the final plasma volume, for long-term storage and subsequent production of liquid blood plasma for volume replacement or volume replacement therapy.

Description

The The present invention relates to a use of blood plasma in the volume replacement or volume exchange therapy as well as a procedure for the manufacture of a blood plasma conserve for use in the volume replacement or volume exchange therapy.

at massive blood loss, under emergency conditions or perioperatively in the hospital, has the maintenance of the volume of the blood admittedly the highest Priority. Only then follow in the priority order Ensuring a sufficient oxygen transport function of the blood and then the assurance of hemostasis (Hiippala: Replacement of massive blond loss. Vox Sang 1998; 74 (Suppl. 2): 399-407). Differences of opinion exist only with regard to the question of when an acute blood loss only with a volume replacement (blood plasma or synthetic volume replacement) and from when a blood loss with the administration of oxygen carriers (erythrocytes) to treat.

Similar Opinion differences exist in the discussion of the question of which Volume replacement is optimal for a loss of blood volume to balance with the patient. In addition to crystalloid solutions (electrolyte solutions) There are numerous colloidal volume replacement solutions to disposal, the colloidal volume replacement solutions being both natural (human albumin different concentration) as well as synthetic colloids (Dextran, gelatin, hydroxyethyl starch). Furthermore will also raise the question of whether plasma preparations, e.g. Frozen plasma (GFP), including self-frozen plasma (= autologous GFP (AGFP)), suitable for volume replacement or not, controversial.

While the "National Institutes of Health "(Consensus Conference: Fresh frozen plasma, indications and risks. JAMA 1985; 253: 551-553) no justification for the use of GFP as a volume expander at the time as there were safer therapeutic alternatives, such as e.g. the aforementioned crystalloids on the one hand and the colloidal ones on the other solutions on the other hand, Heim et al. (Use of FFP in the operational area below special consideration of the own FFP. Infusionsther 1990; 17 (Supp 2): 34-36) in the use of preoperatively obtained autologous frozen plasma (AGFP), which in the context of a self-blood donation ago the operation was won, a necessary addition.

The German Medical Association after all puts in your "guidelines for the therapy with blood components and plasma derivatives "(3. Aufl., Deutscher Ärzteverlag Cologne 2003) found that at acute blood loss crystalloids and artificial colloids for maintenance or ensuring the desired blood volume would be preferred, and that too Human albumin solutions can be used in the indication area volume replacement, however only if the possibilities a protein-free Volume replacement previously exhausted were. The guidelines further note that the gift of GFP is not indicated as a volume replacement therapy, except for initial emergency treatment.

To the opinion of the German Medical Association In the case of long-term predictable operations, experience shows that this is foreseeable great Blood loss associated with the preoperative recovery of several Units AGFP by means of plasmapheresis, however, a significant possibility perioperatively also a "physiological" volume replacement in case of loss big To carry quantities of blood. As a clear indication for the administration of frozen plasma (GFP), is in the guidelines, only the exchange transfusion, e.g. in case of intoxication.

frozen plasma is therefore at least in the exchange transfusion the means of Choice and also to compensate for large blood losses with advantage used.

frozen Fresh plasma (GFP), also called fresh frozen plasma (FFP), is derived from at least one whole blood donation, either from a single donor or from a few hundred blood donors (pool plasma) was won. The recovered whole blood is usually centri fugiert and the resulting obtained plasma pressed into a transfer bag. The recovered plasma will no later than Shock frozen after 24 h and then stored at -30 ° C.

One Disadvantage of the plasma preparations prepared in this way is that the deep-frozen Plastic bags are slightly fragile. In addition, the plasma may after thawing, to be brought to body temperature only with specially approved equipment, because an overheating on more than + 42 ° C must be avoided become. After thawing must be ensured be that all protein precipitation solved are.

Other disadvantages of the conventional freeze plasma are its low storage capacity, the 12 months, and the high storage costs, since conventional frozen plasma canned food needs a lot of storage space and the storage temperature must be at least -30 ° C. Due to the limited storage time, according to the Paul-Ehrlich-Institut, of the 1.5 million GFP preparations produced annually in Germany, only 66% are transfused, while the remainder expire.

In spite of the medical-physiological benefits of using plasma, especially in certain indications, it is mainly because of the high storage costs and the limited durability as volume replacement or for volume exchange barely applied, and when used becomes, then almost exclusively in the form of self-plasma, that before elective Surgery gained and as a perioperative physiological volume replacement is used.

The The object of the present invention was therefore to provide a solution which makes it possible the use of blood plasma in volume replacement and volume exchange therapy improve by making the application easier and less expensive can be done so far.

These Task is solved by the use of blood plasma in substantially anhydrous form in a sterile closed, substantially wasserdampfundurchlässigen container whose Inner volume at least one of the plasma end volume corresponding Volume may include, for long-term storage and subsequent production from liquid Blood plasma for the volume replacement or volume exchange therapy.

The present invention over the prior art possibility ready to make blood plasma now easier and more cost effective for volume replacement therapy or the volume exchange therapy to provide by the Blood plasma in substantially anhydrous form in a sterile stored sealed, substantially water-vapor-tight container becomes.

By the removal of water from the blood plasma reduces that Volume of blood plasma, usually in a bag stored and provided, clearly, so that for example a Plasma volume of 1 liter is reduced to the volume, the one Bag in DIN A5 to DIN A4 format occupies only about Contains 75 g of plasma solids. Accordingly, the weight of the plasma is also slightly over 1 kg to the aforementioned 75 g plus reduced bag weight. As a result, the present has Invention over the conventional one Blood plasma for the use in volume replacement and volume exchange therapy the advantages that the Blood plasma conserves according to the invention are significantly space-saving and transport cost-saving.

Furthermore can Blood plasma preserves according to the present Invention also clearly over Be stored for 12 months, so that by their use of conventional annual Committee of 34%, which was determined by the Paul-Ehrlich-Institut (see above), which leads to significant cost savings, since overall much less Blood plasma canned must be prepared to a certain amount on stored blood plasma to store a period of more than one year.

Further can the storage costs due to the use of blood plasma in substantially anhydrous form according to the present Be significantly reduced because the storage of the substantially anhydrous blood plasma at room temperature, ie essentially uncooled, can be done, whereas the storage temperature for conventional Frozen plasma preservatives -30 ° C got to. However, you can also the storage of blood plasma in accordance with the invention in moderate air-conditioned rooms (temperatures between 15 and 25 ° C) be preferred.

The Advantages of the present invention are particularly pronounced when the blood plasma in almost complete stored in anhydrous condition, taking complete freedom from water Here at least the degree of drying is understood, the blood plasma by conventional Can achieve freeze-drying or vacuum centrifugation.

at a preferred embodiment the use according to the invention autologous blood plasma, ie self-plasma, is used. That Plasma, which is taken from a specific person to later this plasma To use again treatment of this person. This possibility opens up for one huge Circle of patients due to the vorlie invention for the first time, since the storage of the intrinsic plasma in essentially anhydrous Form, as previously stated, economical and over a long time now for in principle anyone possible is.

The Storage in this form can now under the simplest conditions done so that the donor / patient his own blood plasma easily, for example in a suitable place in his household, can keep. this has again the advantage that basically everyone Donor / patient is able to create his own, suitable for him blood plasma depot create, which can be used if necessary, without that he relies on foreign plasma, which in turn a very expensive and expensive diagnostics would have to be subjected to the compatibility of foreign plasma for to protect the respective patient. Also, this system is through also excluded the risk of infection by foreign plasma.

Besides that is It is due to the low weight and low requirements of the essentially anhydrous plasmas now also possible, at least a certain "emergency ration", for example during stays in Regions with relatively poor medical care, with themselves respectively.

Of the Building one too for the extreme case of sufficient deposits of self-plasma may be due the almost unlimited shelf life of the blood plasma conserves according to the invention for the Volume replacement and volume exchange therapy cumulatively over a Period of several years or even decades. To the current rules may be over the Plasma separation per single donation maximum 600 ml. The total volume of blood plasma withdrawn per year and per person can be up to 25 l (Hiller et al .: indications for therapy with fresh frozen plasma. Dtsch med Wschr 1989; 114: 1371-1374). That means that yourself a young person over For several years, a virtually unlimited durable volume replacement depot which he can later on as a possible patient can fall back. Of particular interest this for member those occupational groups in which there is an increased risk of injury, and for People who have a blood type, for the regularly too little plasma available are.

The Storage time for that according to the invention used blood plasma in substantially anhydrous form is preferably longer than 1 year. Particularly preferred are storage times of at least 5 years or even at least 10 years.

Preferably The water is extracted from the blood plasma by lyophilization away. In an alternative embodiment, the water removed by vacuum extraction from the withdrawn blood plasma. In further alternatives of the present invention, the water at least partially by lyophilization and / or vacuum extraction removed, the two aforementioned methods either separately or in combination with other drying methods used in the State of the art are known, can be combined.

Preferably the blood plasma is after removal and before further processing with a stabilizer solution added. This stabilizer solution is preferably a citrate-containing stabilizer solution. Suitable for this solutions and their concentrations and the per blood plasma volume to be added Volume of citrate solution are known in the art. In an alternative embodiment can instead of a citrate-containing stabilizer solution or in addition also Heparin be added to the blood plasma for clot inhibition.

at A whole blood donation will usually carry 450 ml of blood Add 63 ml of a citrate-phosphate-dextrose solution (CPD solution), being supplied Blood is weighed into a bag in which the CPD solution is already was submitted. In a hematocrit of 45% (more usual Thus, 247.5 ml of plasma (55%) are diluted with 63 ml of CPD solution, i. to a final concentration of 20.2% by volume.

Should only plasma can be won the erythrocytes are returned to the patient. In this In this case, 495 ml of plasma are collected and 126 ml of CPD solution are added (20.2% by volume). The total volume is then 621 ml.

The Use of heparin or its derivatives may be compared to Use of citrate solutions be advantageous because citrate solutions have a slightly alkalizing effect on the plasma preparation can. In alternative embodiments However, if this alkalizing effect is desired, then that at these embodiments Again, the use of citrate solution is preferred.

In the plasma collection today CPD solution (citrate-phosphate-dextrose solution) or ACD solution (aqua-citrate-dextrose solution) are used as stabilizer solutions for the prevention of blood clotting. According to the invention, the use of these commercially available solutions is not mandatory neces This is because phosphate and dextrose (glucose) are advantageous only for the storage of the erythrocytes separated from the donation and stored separately. For the stabilization of the plasma as such, the use of a pure citrate solution is sufficient according to the invention. As a result, the plasma dilution by the stabilizer solution can also be advantageously reduced if a correspondingly highly concentrated citrate solution is used.

The stabilizer solutions (CPD solution, ACD solution, citrate solution) have the following compositions (solvent = water):

Preferably is as a container for holding the liquid, frozen or dried blood plasma used a container whose internal volume is variable, with a corresponding container preferably at least partially made of flexible material, with the proviso that the flexible Material as well as the rest Components of the container, the one with the inside of the container are in direct contact, are substantially wasserdampfundurchlässig.

"Essentially water vapor impermeable "means that substantially gaseous Water not from the outside through the material of the container in the interior of the container can penetrate. In preferred embodiments, gaseous water however, from the inside out through the container material pass. That is, that Water of liquid or frozen blood plasma, which is filled in such a container, through the material of the container can be removed. In alternative embodiments, however, in essentially no gaseous Water, neither from outside inside, still inside out, through the container material pass.

ever after how tight the water vapor barrier of the material respectively is, must some essentially anhydrous blood plasma specimens in particular dry rooms be kept. To save this somewhat increased storage costs, is in preferred embodiments the material is chosen so that the passage of gaseous Water completely excluded by this material at least from outside to inside is. Be beneficial as containers for the Blood plasma samples used plastic bag. Appropriate plastic materials with barrier properties or with barrier coatings on the interior or outside are known. When using plastic materials such Water vapor barrier properties not or not in sufficient Own dimensions, may be the use of a secondary packaging, z. As aluminum, be advantageous.

When Plasma end volume is for the purposes of this application the volume of for the Administration to a patient designated resolubilized plasma. In preferred embodiments the maximum internal volume of the container is at least 5% greater than the final plasma volume. This is especially when filling and the removal of an improved handling of the bag in the Use according to the present Achieved invention.

It understands that all materials used and measures taken during use so chosen or performed Need to become, that the sterility of blood plasma, independently of its consistency, always maintained.

This applies equally to the inventive method for producing a blood plasma for use in the volume replacement or volume exchange therapy, in which one takes a donor / patient under sterile conditions withdrawn blood plasma in a sterile, substantially wasserdampfundurchlässiges container, then the blood plasma in the water Essentially completely withdraws, then the container waterproof and sterile seals and then kept the substantially anhydrous blood plasma in the container and the container then reopens only at a desired or required time, introduces sterile water into the container to the substantially anhydrous blood plasma to dissolve in physiological concentration to obtain liquid blood plasma. This reconstituted liquid blood plasma is then ready for use in volume replacement or volume exchange therapy after ensuring that all components of the dry plasma are completely dissolved.

at a preferred embodiment the method according to the invention is centrifuged to recover the blood plasma taken whole blood and squeezed the plasma obtained in a transfer bag. at an alternative embodiment the plasma is obtained by a machine apheresis method.

in the Ideally, the freshly obtained plasma is directly within Dried for 24 hours or lyophilized. Alternatively, the plasma but also first Shock frozen within 24 h and then stored at -30 ° C or below before it is thawed in due course and further processed according to the invention. In pool plasma or other plasma donations that are not own plasma In any case, the release for use takes place at the earliest after four months of quarantine storage and if at a later Blood sample of donor / donor transfusion-relevant infection markers are still undetectable. Even with your own plasma, the Compliance with this quarantine phase and the subsequent review of the Donors on transfusion-relevant infection markers advantageous be. The plasma can also after expiry of the quarantine storage virus inactivation and depletion, such as it is known in the art (e.g., SD plasma, solvent / detergent method). The transfusion is exclusively blood group specific, So ABO equal.

at an alternative embodiment the blood plasma is not immediately after removal in the im essential water vapor impermeable container but first frozen and then weighed in frozen state in this container. In another alternative embodiment, the blood plasma becomes dried before it is in this essentially anhydrous state in the aforementioned container is weighed.

The Removal of water from the introduced into the substantially water vapor-impermeable container Blood plasma takes place at least in part by lyophilization and / or by vacuum extraction. Preferably, the removal of the Water completely by lyophilization and / or vacuum extraction.

One Advantage of the invention produced Plasma preparations is that the dry plasma faster and with less technical effort body temperature can be brought as conventional Freezing plasma that only with specially approved equipment thawed and warmed up can be to ensure that no overheating of the Plasmas at more than + 42 ° C he follows.

As previously mentioned, All steps must be carried out under the condition that the sterility of the blood plasma not impaired becomes.

Further Features and characteristics of the invention as well as advantages arising from individual characteristics or combinations of characteristics or combinations of feature groups, will be exemplified below described special embodiment of the present invention. When considering this exemplary embodiments It should be noted that not in all embodiments according to the present Invention all in the exemplary embodiment realized features must be realized to the present invention implement and enjoy their To get benefits.

example 1

Preparation of a plasma preparation (525 ml final plasma volume including stabilizer)

The The following procedure is based both on the current one Methods of blood and plasma collection as well as the goal, in the preparation in practice, round volumes of Aqua least. use.

For the use according to the invention of blood plasma for long-term storage and subsequent use in volume replacement or volume exchange therapy will be in this For example, a single donor in a conventional manner two whole-blood single donations (2 times 450 ml), wherein the blood 106 ml CPD solution (stabilizer solution) for Anticoagulant be added, an amount that is 20% by volume corresponds to the final volume of pure plasma.

Subsequently, will that with stabilizer solution staggered blood centrifuged, with all cellular components from the plasma be separated. Thereafter, the cell-free plasma is transferred to a transfer bag abgepeeßt and within 24 hours of the further processing described below subjected to lyophilization. Unless immediate processing the plasma is frozen within 24 hours, stored at -30 ° C until further processing and at the latest processed within 12 months.

For further processing 525 ml of plasma are placed in a sterile closable and substantially water vapor impermeable storage bag introduced, which has a capacity of about 550 ml, d. H. approximately 5% more than the plasma volume. This is followed essentially full Withdrawal of water (500 ml) by lyophilization on or in one Freeze dryer.

The completeness Water removal can be determined at given times by weight determination the dried sample are checked. In the present case, the blood plasma preparation is essentially anhydrous, if only about 38 g of dry matter (plasma lyophilisate) in Pouch present. If this condition is reached, then the sterile takes place close of the bag and the subsequent Store at room temperature. Depending on the intended use is the Bag containing the manufacturer, date of manufacture and name, Date of birth and, if applicable, passport photograph of the donor.

in the If necessary, the blood plasma prepared in this way resorted by the storage bag is connected sterile with a container, the contains about 500 ml of distilled water. This volume will then into the dry plasma container to release of the lyophilisate under visual control and then stands already very fast for the purpose of volume replacement or volume exchange therapy ready for transfusion to patients.

Becomes The plasma can also be taken as a machine apheresis plasma an ACD stabilizer solution (aqua citrate dextrose solution) in an amount of 18.5 vol .-% based on the final volume of the pure plasma be used. In this case, directly 525 ml of plasma including 18.5% by volume ACD stabilizer. The further processing takes place as for the single donation described.

The ratio of the weight of the dry substance (plasma lyophilisate) to the removed water is determined as follows:
Plasma has a dry matter content of about 80 g / l at a density of 1.0269 kg / l and a water content of 945 g / l. The stabilizer (CPD solution or ACD solution) has a dry matter content of about 56 g / l and a water content of about 990 g / l. Accordingly, when adding 20% by volume of stabilizer solution to the plasma, the total water content is increased to about 954 g / l and the dry matter content is reduced to about 75 g / l. 525 ml of plasma including 20% by volume of stabilizer solution give about 500 g or ml of water during lyophilization and about 37.5 g of dry substance remain. If this preparation is then filled up with 500 ml of distilled water, the result is again a plasma volume of 525 ml including stabilizer solution.

Claims (11)

Use of blood plasma in substantially anhydrous form in a sterile sealed, essentially water vapor Container, the inner volume of which corresponds at least to the plasma end volume Volume may include, for long-term storage and subsequent production of liquid Blood plasma for the volume replacement or volume exchange therapy. Use according to claim 1, characterized that as Plasma plasma is used. Use according to one of Claims 1 and 2, characterized that this maximum internal volume of the container at least 5% larger as the plasma end volume. Use according to one of Claims 1 to 3, characterized the existence container is used, whose internal volume is variable, the container at least partly made of flexible material. Use according to one of Claims 1 to 4, characterized that this Blood plasma is lyophilized and / or vacuum extracted. Use according to one of claims 1 to 5, characterized in that the storage time is longer than 1 year, wherein the storage time is preferably at least 5 years, more preferably at least 10 years. Use according to one of claims 1 to 6, characterized that this Blood plasma is mixed with a stabilizer solution, preferably is mixed with a citrate-containing stabilizer solution. Use according to one of claims 1 to 7, characterized that this container only in the direction from the outside inwardly substantially impermeable to water vapor and from the inside to Outside water vapor permeable is. Process for the preparation of a blood plasma conserve for the Use in volume replacement or volume exchange therapy where you have: a) sterile blood plasma into a sterile, substantially -vapor permeable container brings, b) substantially completely withdrawing the water from the blood plasma, c) the container waterproof sterile closes, d) the substantially anhydrous blood plasma stored in the container e) the container to the desired Time opens again and f) sterile water into the container for dissolving the substantially anhydrous Blood plasma to obtain liquid Introduces blood plasma in physiological concentration. Method according to claim 8, characterized in that that stage b) the process at least in part by lyophilization and / or realized by vacuum extraction. Method according to one of claims 8 and 9, characterized that all Procedural steps proceed under conditions that limit the sterility of the blood plasma do not interfere.