DE102009034132A1 - Plasma adapted and balanced gelatin solution - Google Patents

Abstract

The present invention describes a pharmaceutical preparation comprising an aqueous composition comprising gelatin and / or a physiologically acceptable gelatin derivative. The pharmaceutical preparation is suitable for the prophylaxis and therapy of hypovolemia. In addition, the present invention relates to uses of the pharmaceutical preparation as a volume substitute and as an erythrocyte-protective washing solution.

Description

The The present invention relates to a pharmaceutical preparation, comprising an aqueous composition, the gelatin and / or a physiologically acceptable gelatin derivative. The pharmaceutical Preparation is suitable for the prophylaxis and treatment of hypovolemia. Moreover, the present invention relates to uses the pharmaceutical preparation as a volume replacement agent and erythrocyte-protective Wash solution.

One Circulatory failure is one of the most common observed clinical shock states. It is through a reduced circulating blood volume (hypovolemia) characterized by absolute losses of blood, plasma or extracellular Liquids on the one or relative deficits (distribution disorders) on the other side. The losses of blood or plasma have either traumatic causes (hemorrhagic Trauma) or are due to increased blood loss as a result surgical measures. Primary extravascular Liquid deficits, which are also the same extent affect the circulating blood volume caused by diminished Fluid intake or abnormal fluid loss (eg due to excessive sweating, vomiting, gastrointestinal losses). Vasoactive substances as well as diverse Interactions between mediators and hormones, also through traumatic events or serious illnesses may be caused lead to relative volume deficiencies through vasodilation or distribution disorders; they also wear in addition to maintaining a possibly already existing shock condition. Finally, you can Volume deficits from generalized dysfunctions of the vascular endothelium, which is an extravasation, d. H. the passage of plasma fluid over cause the endothelial barrier in the surrounding tissue, such. B. in inflammatory diseases such as sepsis.

ever according to the extent of the volume deficit and the influence of the Mediators is cardiac function degraded. When the hypovolemia lasts longer, the compensatory abilities are sufficient of the myocardium, the z. In an increase in contractility and heart rate do not stop, so the circulation failure takes a progressive course.

A Hypovolemia or failure of the great circulatory system, d. H. the macrocirculation, u. a. As a result, that too Microcirculation, d. H. the perfusion of tissues and organs, in Be affected; the resulting, as ischemia designated vacuity of one or more organs leads to Undersupply of the tissues concerned with oxygen and for limitation of cellular metabolism. With appropriate duration The deficiency comes through the death of cells to damage of the organ and for the first reversible, finally irreversible organ failure.

Yet before all medical and other measures the restoration of the circulating blood volume is supreme therapeutic target in all forms of hypovolemic Circulatory failure or shock. This is done by infusion of crystalloid or colloidal volume replacement solutions or - at extensive blood loss and correspondingly reduced oxygen transport capacity - through Transfusion of blood or blood components. The volume substitution and the accompanying filling of the circulation increase the venous return of the blood to the heart and improve the heart ejection performance; through the Increasing perfusion of the tissues will be during the Ischemia reoccurring oxygen deficiency lifted and the metabolism started again.

In principle, crystalloid (isotonic electrolyte solutions) and colloidal volume replacement solutions (solutions which additionally contain a high molecular weight constituent, a so-called hydrocolloid, in an electrolyte-containing medium) are equally well suited for eliminating acute hypovolemia and the associated macrocirculation disorder , As hydrocolloids find on the one hand either endogenous proteins use such as human albumin or chemically modified proteinaceous substances such as certain modifications of gelatin, which in turn comes from collagenous material. On the other hand, the colloids contained in the volume replacement solutions can be polysaccharides (dextrans) or, in turn, chemically modified derivatives of polysaccharides, as is the case with hydroxyethyl starch (HES). These high molecular weight components of the colloidal volume replacement solutions, in contrast to the crystalloid solutions for a more pronounced and sustained binding of liquid in the circulation, so for a stronger and longer-lasting volume or filling effect. The reason for this is mainly to be seen in the molecular size of the hydrocolloids, whose effect is further enhanced by electrical charge carriers and / or the presence of large hydrate shells on the hydrocolloid. As a result, the distribution of colloidal volume replacement solutions initially limited only to the circulation, ie the intravascular space, while the components of the crystalloid solutions can permeate the vascular barrier freely, so that they a priori in the distribute the entire extracellular space, which is about four times larger than the intravascular space. Therefore, crystalloid volume replacement solutions must also be used in approximately four times the amount of colloidal solutions to achieve the same circulatory filling, which also lasts less or requires more frequent post-infusions than colloidal solutions. Due to the simultaneous fluid influx in the extracellular space - when infused crystalloid solutions - there is a risk that accumulate fluid (edema) there; and when the ability to excrete salt and fluid is reduced, as may often be the case after trauma on surgery or in severe disease, the use of crystalloid solutions is associated with the risk of fluid overload. For these reasons, for the purpose of intravascular volume replacement, colloidal solutions are generally preferred over crystalloids.

Out the group of colloidal volume replacement solutions those made of artificial colloids, namely hydroxyethyl starch and gelatin, existing solutions over those with natural colloids (albumin) in the current clinical practice largely enforced. This is because of their commitment much less expensive than the use of albumin solutions, without having regard to those disadvantages, what the immediate effectiveness in hemodynamic stabilization and the outcome of the shock treatment in general. Only Dextran solutions are in recent years because of them own mostly unwanted influence on blood clotting and the complication of the required prophylaxis of a Anaphylactic shocks have receded into the background or out of the clinical practice as good as disappeared.

While Infused hydroxyethyl starch in the body complicated Removal and conversion processes is subject, which also complications Can include storage phenomena Gelatin and gelatin derivatives in the human organism through there existing enzyme systems (mainly proteases) to smaller ones Fragments degraded and finally eliminated renal as soon as the size of the fragments the Kidney threshold has fallen below. Within the first 24 hours the recovery rate in urine is about 60% of those administered Dose; Over the course of a week, it rises to over 95%. This is the rate of metabolism and elimination of gelatin those of other artificial colloids used as volume replacement agents find (eg hydroxyethyl starch), superior. According to current knowledge, gelatin and the gelatin derivatives in the organism or predestined organs not saved, so from this page no organ complications are to be expected. It is also advantageous in comparison with others artificial colloids lower or completely missing Influencing the blood clotting, which allows gelatin or gelatin derivatives to infuse intravenously in higher doses, than other artificial colloids or the like produced volume substitutes is the case.

In medicine and in the pharmaceutical industry, gelatin or its derivatives is commonly used in the well-known art in the production of hard and soft capsules and also in infusion solutions for the treatment of volume deficiency shock. For example, the following gelatin preparations with gelatin or a gelatin derivative with an average molecular weight of 20,000 to 35,000 are available as volume replacement agents: for example, for oxypolygelatins. Gelifundol ^® , for urea-crosslinked gelatin z. B. Haeamaccel ^® and succinylated gelatin z. B. Gelafundin ^® (also known as Gelofusine ^®), Gelafusal ^® and Thomaegelin ^®.

In In medicine, the application of gelatin-containing volume replacement solutions but not uncritical. For example, some of the currently used ones contain Gelatinelösungen too high a chloride content, with the risk of developing hyperchloraemic acidosis connected is. Volume replacement solutions, whether they are gelatin or other colloids have their major indications in the treatment of hypovolemic circulatory failure and shocks. The associated with these clinical conditions Inferior perfusion of the tissue, in turn, inevitably generates an acidosis caused by the infusion of volume replacement solutions rapidly eliminated, but not by their acidotic properties strengthened or even extended. All the more so as the severity of acidosis with the occurrence correlates with a coagulopathy, which includes the traumatic or Operatively related blood loss as the major cause of hypovolemic shock states contribute. Other unwanted consequences of hyperchloraemic metabolic acidosis consists in electrolyte imbalances, resuming diuresis after traumas and operations delay or with neurological dysfunctions such as Somnolence or postoperative nausea and vomiting (PONV) can be connected.

Other gelatin solutions can only be used with great restraint in patients with brain injury or neurosurgery, given the risk of increasing cerebral edema. The reason for this lies in the hypotonicity of the solutions in question, which is due to the inverse proportionality between The solution or plasma osmolality and the intracranial pressure influence a clinically relevant worsening of the prognosis in space-occupying processes.

In front this background and the otherwise so advantageous properties gelatin such as the lack of tissue storage, organ load, Coagulation and dose limitation are more urgent Need for gelatin solutions that are so composed that they are the homeostasis of the acid-base and electrolyte balance leave untouched to be used in clinical situations may, in which this is specific, from hypotension the solutions of resulting risks so far not possible was and the overall higher application security exhibit.

Surprised was found by setting a specific electrolyte pattern in conjunction with gelatin and / or physiologically acceptable gelatin derivatives and / or gelatinous proteins and / or polypeptides in corresponding aqueous solutions the problems described in the prior art could be solved. The accessible in this way become due to pharmaceutical preparations their isotonicity and better approach to the ionogram the plasma used in a much wider scale and safer be as previous gelatin preparations. The strict isotonicity In particular, reduces the risks of peripheral edema and the fluid overload in general and improves the compatibility of the solution for the cellular components of the blood. This expresses z. B. as erythrocyte protective effect, the already existing Strengthens the effects of gelatin and the solution u. a. as erythrocyte washing solution for the machine Autotransfusion makes particularly suitable.

Of Another was found surprising that at the Infusion of an aqueous solution of gelatin and / or physiologically acceptable gelatin derivatives in conjunction with the Here, electrolyte patterns revealed the temporary adherence and firm adhesion of the leukocytes to the vascular endothelium more effectively than when administering a otherwise similar gelatin solution in 0.9% NaCl. Such diminished leukocyte-endothelial interactions counterbalance to the leukocyte activation by hemorrhagic Trauma, shock and inflammatory stimuli triggered is and - by possible follow-up reactions such as endothelial lesion and extravasation of activated leukocytes reinforced - in a failure of the organs concerned can lead. To the extent that leukocyte-endothelial interactions also reduce the microcirculation-promoting improve Properties of the gelatin electrolyte solution.

• a) 20 bis 80 g/L Gelatine und/oder eines physiologisch akzeptablen Gelatinederivates und/oder eines gelatineartigen Proteins und/oder gelatineartigen Polypeptids, sowie die Ionenanteile
• b) 150 bis 160 mmol/L Natrium,
• c) 4 bis 5 mmol/L Kalium,
• d) 1 bis 2 mmol/L Calcium,
• e) 1 bis 2 mmol/L Magnesium,
• f) 82 bis 105 mmol/L Chlorid, und
• g) 24 bis 30 mmol/L Acetat und/oder Gluconat.

An object of the present invention is thus an aqueous pharmaceutical preparation, comprising:

• a) 20 to 80 g / L gelatin and / or a physiologically acceptable gelatin derivative and / or a gelatinous protein and / or gelatinous polypeptide, and the ionic proportions
• b) 150 to 160 mmol / L sodium,
• c) 4 to 5 mmol / L potassium,
• d) 1 to 2 mmol / L calcium,
• e) 1 to 2 mmol / L magnesium,
• f) 82 to 105 mmol / L chloride, and
• g) 24 to 30 mmol / L acetate and / or gluconate.

In a particular embodiment, the preparation according to the invention contains, in addition to the abovementioned electrolytes, 1 to 2 mmol / L of phosphate. Phosphates according to the present invention include both the PO ₄ ^3- and hydrogen phosphates and dihydrogen phosphates and phosphate derivatives, such as glycerophosphate.

gelatin is the degradation product of one occurring in mammals macromolecular protein, called collagen, which is easily accessible and cost-effective to isolate and over can be stored for a long time without degradation. In spite of Gelatine shows only a very small amount of its protein nature antigenic potential. Native gelatin possesses due to its high Molecular weight of the property, highly viscous solutions to form, which gel at lower temperatures and therefore not suitable for the production of parenteralia. By chemical modification or derivatization of gelatin can be this disadvantage but handle it.

One of these modifications was developed by Tourtelotte in 1952 ( Tourtelotte, D. and HE Williams, in: Stainsby, G., Gelatin and Glue Research, 1958 ), It consists in the reaction with succinic acid or its anhydride and leads to succinylated gelatin (gelatin polysuccinate). Another method, the Was developed by Schmidt-Thome in 1962 ( Schmidt-Thome, J., A. Mager and HH Schone, Arzneim.-Forsch. 12, 378 (1962) ), the crosslinking of the gelatin chains is based on urea bridges (urea-crosslinked gelatin, polygelatine). Gelatin derivatives can also be prepared by decalcifying gelatin, condensing with glyoxal and oxidizing with hydrogen peroxide. These are so-called. Oxypolygelatine, their preparation of Campbell, DH et al., Texas Rep. Biol. Med. 9, 235 (1951). . Bonhard, K., Arzneim.-Forsch. 21, 1667 (1971) such as Nitschmann and Stoll, Pharm. Ztg. 42, 1594 (1968) has been described. More recently, gelatin or gelatinous proteins and polypeptides have also been synthesized recombinantly and proposed as such for use in the production of parenteralia, especially volume replacement agents ( DE 60207053T2 ),

In a preferred embodiment contains the Preparation according to the invention by recombinant route prepared gelatinous proteins and / or polypeptides.

urea Networked Gelatine is prepared by adding the and hot water treatment resulting gelatin strands, which have a molecular weight of 12000-15000, one Undergoes treatment with hexamethylene diisocyanate. It happens for condensation between a free carboxyl and a free one Amino group, wherein a peptide bond between individual gelatin strands arises. The resulting condensation product has a middle Number average molecular weight of 24,500 in a scattering range from about 5000-50000 daltons.

The Polypeptide chains, of which the synthesis of succinylated gelatin starting, have a molecular weight of above 20,000, and they are reacted with succinic anhydride. Different to however, this does not happen with urea-crosslinked gelatine to a cross-linking of the strands and their molecular weight remains unchanged as a result. As with the chemical Modification of a basic amino group by an acidic carboxyl group is replaced, results in a derivative with a lower isoelectric Point and a stronger negative charge. This stronger negative charge and not an increased molecular weight it is that at physiological pH levels - among other things due to the Donnan effect on vascular endothelium - too an extension of the residence time in the cycle leads. It also comes through the charge change a conformational change of the modified gelatin molecules to a more open, less compact structure through which the diffusion capacity across the vessel wall diminished and the retention time in the intravascular space is extended accordingly.

The physiologically acceptable gelatin derivatives to be used according to the invention may be urea-crosslinked or-preferably-succinylated gelatin derivatives. The latter are also referred to as "modified liquid gelatin" (MFG) or "gelatin polysuccinate"; the average molecular weight is for example between 20,000 and 32,000 (M _w = weight average) and between 18,000 and 28,000 (M _n = number average). A corresponding preparation of B. Braun Melsungen is commercially available in Germany under the trade name "Gelafundin", in most other countries under the name "Gelofusine". The starting material for succinylation or crosslinking with urea is gelatin from bovine bone; this is commercially available, for. Via Gelita AG, Ebersbach (Germany), or Rousselot SAS, Isle sur la Sorgue (France).

preferred Embodiments of the present invention include physiological acceptable gelatin derivatives such as succinylated gelatin derivatives, non-succinylated gelatin derivatives, urea-crosslinked gelatin derivatives, Oxypolygelatine and gelatin polysuccinate as well as recombinant gelatinous Proteins and / or polypeptides.

In a preferred embodiment contains the Pharmaceutical preparation 20 according to the invention to 80 g / L gelatin and / or a physiologically acceptable gelatine derivative and / or a gelatinous protein and / or a gelatinous one Polypeptides, preferably 30 to 60 g / L and particularly preferably 40 up to 50 g / L, for example 40 g / L.

The according to the invention, isotonic aqueous pharmaceutical preparations are infused intravenously and are therefore in a preferred embodiment as Infusion solution.

There the goal of administering plasma-adapted solutions This is the homeostasis of plasma electrolyte concentrations They are also called "balanced" solutions designated. If certain, known to those skilled manufacturing technology Conditions are met, is also the partial exchange of chloride by pyruvate or bicarbonate (rather than by acetate and / or Gluconate) possible and in the inventive pharmaceutical preparation preferred.

According to the invention while advantageously used such salts, in the relevant Pharmacopoeias are recommended and monographed, as u. a. the European Pharmacopeia / European Pharmacopeia and the United States Pharmacopeia.

Thus, in a preferred embodiment, salts selected from the group consisting of sodium chloride, sodium acetate × 3H ₂ O, sodium hydrogen phosphate × 2H ₂ O, sodium hydroxide, D-gluconic acid sodium salt, potassium chloride, potassium acetate, calcium D-gluconate × H _{2 are used} O, calcium chloride × 2 H ₂ O and magnesium chloride × 6H ₂ O.

to Avoiding infections during intravenous Infusion are the pharmaceutical according to the invention Preparations preferably sterile filtered or heat sterilized. For the purpose of sterile filtration, in particular fine-pored filter cartridges, as they are offered commercially by different manufacturers. For example, filter cartridges with a pore diameter are suitable from 0.2 to 3.0 μm. The invention Pharmaceutical preparations can be about it Be heat sterilized without causing a decomposition the ingredients comes. Preferably, the heat sterilization at a temperature above 100 ° C, more preferably between 105 and 150 ° C, in particular between 110 and 130 ° C. made, depending - depending on the container material - either a temperature of for example 121 ° C, over a period of up to 30 minutes, preferably up to 28 minutes, especially between 23 and 25 minutes or a temperature of for example, 112 ° C, over a period of up to 100 minutes, especially between 70 and 90 minutes to Application comes.

Volume replacement are used to replenish intravascular fluid deficits used in humans and animals. Special application you will find for the prophylaxis and therapy of hypovolemia. It is it does not matter whether the hypovolemia is from the immediate Loss of blood or body fluids results such as acute bleeding, trauma, surgery, burns, etc. or from distributional disturbances between macro and microcirculation such as in sepsis, or if it is a regional limited, z. B. artificially induced interruption the blood flow acts as in the clamping of vessel sections or creating a tourniquet lock.

One Another object of the present invention is the use the pharmaceutical preparation as a volume replacement agent.

The Pharmaceutical preparation according to the invention is suitable Therefore, in a further embodiment in particular Measures for the prophylaxis and therapy of hypovolemia

It It has been found that the pharmaceutical according to the invention Preparation significantly increases the microcirculation.

One Another object of the invention is therefore the invention pharmaceutical preparation for improving microcirculation.

by virtue of the special properties of the pharmaceutical preparation especially as erythrocyte-protective washing solution.

One Another object of the present invention relates to the use the pharmaceutical preparation according to the invention as erythrocyte-protective washing solution.

example

Table 1 shows by way of example the composition of a pharmaceutical preparation according to the invention. ingredient concentration Gelatinepolysuccinat 40 g / L sodium 153 mmol / L potassium 4 mmol / L calcium 1.5 mmol / L magnesium 1.25 mmol / L chloride 99 mmol / L acetate 24 mmol / L phosphate 1.5 mmol / L gluconate 2.75 mmol / L

The can be reproduced in Table 1 composition by weighing and releasing in auqa ad iniectibilia ad 1000 mL reach: 40 g gelatin polysuccinate, 95 mmol sodium chloride, 24 mmol sodium acetate, 4 mmol potassium chloride, 1.5 mmol calcium gluconate, 1.25 mmol magnesium gluconate, 1.5 mmol sodium glycerophosphate [glycerol-1 (2) dihydrogen phosphate mixture the disodium salt] and about 35 mmol sodium hydroxide (the exact Need for sodium hydroxide results from the adjustment of the pH to 7.4 (7.1-7.7) required amount.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• - DE 60207053 T2 [0018]

Cited non-patent literature

• - Tourtelotte, D. and HE Williams, in: Stainsby, G., Gelatin and Glue Research, 1958 [0018]
• Schmidt-Thome, J., A. Mager and HH Schone, Arzneim.-Forsch. 12, 378 (1962) [0018]
• Campbell, DH et al., Texas Rep. Biol. Med. 9, 235 (1951). [0018]
• - Bonhard, K., Arzneimittel.-Forsch. 21, 1667 (1971) [0018]
• Nitschmann and Stoll, Pharm. Ztg. 42, 1594 (1968) [0018]

Claims (15)

Aqueous pharmaceutical preparation, full: a) 20 to 80 g / L gelatin and / or a physiological acceptable gelatin derivatives and / or a gelatinous protein and / or a gelatinous polypeptide, as well as the ion proportions b) 150 to 160 mmol / L sodium, c) 4 to 5 mmol / L potassium, d) 1 to 2 mmol / L calcium, e) 1 to 2 mmol / L magnesium, f) 82 to 105 mmol / L chloride, and g) 24 to 30 mmol / L acetate and / Gluconate. Pharmaceutical preparation according to claim 1, characterized in that the gelatin and / or the physiological acceptable gelatin derivative and / or gelatinous protein and / or gelatinous polypeptide has a numerical average molecular weight from 18,000 to 30,000. Pharmaceutical preparation according to at least one of the preceding claims, characterized that it is the physiologically acceptable gelatin derivative is a succinylated gelatin species. Pharmaceutical preparation according to at least one of claims 1 or 2, characterized in that it is the physiologically acceptable gelatin derivative to a non-succinylated gelatin species. Pharmaceutical preparation according to at least one of claims 1 or 2, characterized in that it is the physiologically acceptable gelatin derivative to a urea-crosslinked gelatin. Pharmaceutical preparation according to at least one of claims 1 or 2, characterized in that it is the physiologically acceptable gelatin derivative to a Oxypolygelatine is. Pharmaceutical preparation according to at least one of claims 1 or 2, characterized in that the physiologically acceptable gelatin derivative is gelatin polysuccinate is. Pharmaceutical preparation according to at least one of the preceding claims, comprising 30-60 g / L gelatin and / or a physiologically acceptable gelatin derivative. Pharmaceutical preparation according to at least one of the preceding claims comprising 40-50 g / L gelatin and / or a physiologically acceptable gelatin derivative. Pharmaceutical preparation according to at least one of the preceding claims, characterized that they contain recombinantly produced gelatinous proteins and / or Having polypeptides. Pharmaceutical preparation according to at least one of the preceding claims, characterized that it is present as an infusion solution. Use of the pharmaceutical preparation according to at least one of the preceding claims as a volume replacement agent. Pharmaceutical preparation according to at least one of claims 1 to 11 for prophylaxis and therapy hypervolemia. Pharmaceutical preparation according to at least any one of claims 1 to 11 for improving the microcirculation. Use of the pharmaceutical preparation according to at least any one of claims 1 to 11 as Erythrozytenprotektive Wash solution.