DE102009034130A1 - Aqueous pharmaceutical preparation, useful for the prevention of renal failure, comprises an aminoglycoside antibiotic, gelatin and/or its derivatives and/or a gelatin-like protein or polypeptide and sodium chloride - Google Patents

Abstract

Aqueous pharmaceutical preparation (I) comprises: 1-15 mg/ml of at least one aminoglycoside antibiotic; 20-100 mg/ml of gelatin and/or its derivatives and/or a gelatin-like protein or polypeptide; and up to 10 mg/ml of sodium chloride. An independent claim is included for a kit comprising at least a portion that contains aminoglycoside antibiotic and at least one further portion comprising a formulation of gelatin and/or its derivatives and/or a gelatin-like protein or polypeptide and sodium chloride. ACTIVITY : Nephrotropic. MECHANISM OF ACTION : None given.

Description

The The present invention relates to a pharmaceutical preparation and an antibiotic pharmaceutical preparation for Prophylaxis of aminoglycoside antibiotics induced renal failure. Moreover, the present invention relates to the use the pharmaceutical preparation as an infusion solution and the use of gelatin or a physiologically acceptable one Gelatin derivatives in an aminoglycoside antibiotics containing Formulation for reducing aminoglycoside antibiotics induced nephrotoxicity.

Aminoglycoside antibiotics have been extensively used as a standard therapy for more than 50 years severe caused by gram-negative or gram-positive pathogens Infections. Although they face significant therapeutic benefits have other antiobiotics, however, show some significant Side effects. Because no metabolism of aminoglycoside antibiotics in the organism, they have to go beyond the Kidney are excreted. However, kidney passage occurs for the partial reabsorption of a part of the aminoglycoside antiobitics and their uptake into the endothelial cells of the proximal tubules. The accumulation in the cells in question leads to cell death and in this way to worsening kidney function up towards complete kidney failure.

From These nephrotoxicity are dependent on the individually used aminoglycoside antiobiotics and the respective Dose regimen 5 to 15% of those with these aminoglycoside antiobiotics affected patients. For example, gentamicin, one of the most common aminoglycoside antibiotics, responsible for acute renal failure in 10 to 20% of the treated Patients. Such treatment with gentamicin over more than seven days is associated with nephrotoxicity, It is necessary to discontinue therapy in 30% of patients power.

Under Pharmacokinetic considerations have been used since then For years, this nephrotoxicity of aminoglycoside antibiotics has been tried attenuate by introducing new dose regimens. Thus it could be shown that the admission of the Aminoglykosid antibiotics through the proximal tubular cells of a saturation subject to and with a further increase in drug concentration no further increase in aminoglycoside antibiotics in the serum he follows. On the other hand, the desired bactericidal effect and their entry with the level of aminoglycoside levels correlate, it was natural to change the dosage to a daily Gift ("Once Daily Dose", abbreviated to "ODD", or "Extended Interval Dosing").

meanwhile There are several clinical studies documenting the ODD concept and an increase due to higher peak levels antibacterial activity without concomitant increase nephrotoxicity (the latter due to lower "trough levels" and - over the time unit seen - lower aminoglycoside concentration on kidney cortex). The risk of nephrotoxicity is due to the ODD concept, however, lowered only relative to the effectiveness and not completely eliminated.

It Thus, there is still an urgent need for improvement regarding avoidance or reduction of nephrotoxicity the administration of aminoglycoside antibiotics.

task The present invention was therefore, aminoglycoside-containing Preparations to provide which the previously occurring nephrotoxicity avoid.

In In this context, it was surprisingly found that the Use of gelatin and / or gelatin derivatives in corresponding pharmaceutical preparations such as. B. an infusion solution drastically reduce the nephrotoxicity of aminoglycosides and even eliminate it.

On This was the basis of the present invention Task by a pharmaceutical preparation according to claim 1 to be solved.

The subject of the present invention is therefore an aqueous pharmaceutical preparation comprising
1 to 15 mg / ml of at least one aminoglycoside antibiotic,
20 to 100 mg / ml gelatin and / or a physiologically acceptable gelatin derivative and / or a gelatinous protein or polypeptide,
and up to 10 mg / ml sodium chloride.

With aminoglycoside antibiotics are those known in the art and be in relevant literature meant aminocyclitols which are α-glycosidically linked to two or three sugars as tri- or tetrasaccharide and which are effective as broadband spectrum antibiotics as inhibitors of protein biosynthesis against gram-negative and sometimes gram-positive bacterial species, mycobacteria and protozoa. This effect is clinically relevant for example against enterobacteriaceae, staphylococci and pseudomonads. Typical relevant representatives include streptomycin, neomycin, paromomycin, amikacin, gentamicin, kanamycin, netilmicin and tobramycin. The most commonly prescribed aminoglycoside antibiotics in clinical practice are gentamicin, tobramycin and amikacin, and streptomycin, which is an important treatment for tuberculosis, brucellosis or tularemia.

In a preferred embodiment is the antibiotic the aqueous pharmaceutical according to the invention Preparation from the group consisting of streptomycin, neomycin, Paromomycin, Amikacin, Gentamicin, Kanamycin, Netilmicin and Tobramycin and their physiologically acceptable derivatives and / or their salts (eg, sulfates) and any mixtures thereof.

Prefers include the pharmaceutical according to the invention Preparations Amikacin and / or gentamicin and / or tobramycin.

The Total concentration of aminoglycoside antibiotics in the inventive aqueous pharmaceutical preparation preferably 1 to 12 mg / ml and more preferably 1 to 10 mg / ml (based on the particular aminoglycoside antibiotic in his underivatized form).

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 In terms of its protein nature, gelatine shows very little antigenicity Properties. In solution has native gelatin due high molecular weight disadvantage, highly viscous solutions to form, which gel at lower temperatures. This attribute can be achieved by chemical modification or derivatization bypass the gelatin however.

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, 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 of the original collagen resulting gelatin strands having a molecular weight of 12000-15000, a treatment with hexamethylene diisocyanate subjects. This leads to the condensation between a free Carboxyl and a free amino group, wherein a peptide bond arises between individual gelatin strands. The resulting Condensation product has a number average molecular weight of 24500 with a range of about 5000-50000 Dalton.

The polypeptide chains from which the synthesis of succinylated gelatin originates have a molecular weight above 20,000 and are reacted with succinic anhydride. Unlike the urea-crosslinked gelatin, however, there is no cross-linking of the strands and their molecular weight consequently remains unchanged. Since the chemical modification replaces a basic amino group with an acidic carboxyl group, a derivative with a lower isoelectric point and a stronger negative charge results. This stronger negative charge and not an increased one It is molecular weight that leads to a prolongation of the residence time in the circulation at physiological pH values, inter alia as a result of the Donnan effect on the vascular endothelium. In addition, the charge change results in a conformational change of the modified gelatin molecules to a more open, less compact structure which reduces the diffusion capacity across the vessel wall and correspondingly extends the retention time in the intravascular space.

gelatin and the mentioned gelatin derivatives can be used in human Organism by enzyme systems present there (mainly Proteases) to smaller fragments and finally mined renal eliminated as soon as the size of the Fragments fell below the kidney threshold. Within In the first 24 hours the recovery rate is Urine about 60% of a given dose; rises in the course of a week to over 95%. This is the Metabolisierungs- and Elimination rates of gelatin other artificial Colloids that find use as volume replacement agents (eg, hydroxyethyl starch) are superior. To current knowledge, gelatin and gelatin derivatives in the organism or predestined organs not stored, so that no organ complications are to be expected from this side. It is also advantageous in comparison with other artificial Colloids less or completely missing influence 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 and its derivatives are commonly used in the art of hard and soft capsule production, well known to those skilled in the art, and also in infusion solutions for the treatment of volume deficiency shock. For example, the following gelatin preparations with gelatin or a gelatin derivative having an average molecular weight of from 20,000 to 35,000 are available as bulking agent: for oxypolygelatins, for example. Gelifundol ^® , for urea-crosslinked gelatin z. B. Haeamaccel ^® and succinylated gelatin z. B. Gelafundin ^® (also known as Gelofusine ^®), Gelafusal ^® and Thomaegelin ^®.

Surprisingly has now been found to be through the use of gelatin and / or a physiologically acceptable gelatin derivative and / or a gelatinous protein or polypeptide in aminoglycoside antiobitics containing aqueous pharmaceutical preparations and Infusion solutions induced by aminoglycoside antibiotics Nephrotoxicity can be reduced.

One Another object of the present invention therefore relates to Use of gelatin and / or a physiologically acceptable Gelatin derivative and / or a gelatinous protein or polypeptide in a formulation containing aminoglycoside antibiotics Reduction of aminoglycoside antibiotics induced nephrotoxicity.

at the invention to be used gelatin and / or the physiologically acceptable gelatin derivative and / or the gelatinous Protein or polypeptide are preferably such variants with a weight average molecular weight of up to 40,000, more preferably from 10,000 to 30,000.

In a further preferred embodiment include the pharmaceutical preparations according to the invention one or more physiologically acceptable gelatin derivative (s) from the group consisting of succinylated gelatin, urea-crosslinked Gelatin, oxypolygelatin and gelatinous proteins or polypeptides and any mixtures thereof. The total concentration of gelatin and / or physiologically acceptable gelatin derivatives is preferred between 20 and 100 mg / ml.

The pharmaceutical preparations according to the invention are preferably infused intravenously and therefore lie preferably as isotonic aqueous solutions. to Isotonization can be all osmotically active substances used as far as physiologically harmless and good are compatible such. As mineral salts, glucose, glucose substitutes (Fructose, sorbitol, xylitol) or glycerin. In a special embodiment isotonization with sodium chloride, preferably in one Concentration of 0.45-1.35%, more preferably 0.9%. A 0.9% solution of sodium chloride in water is called "physiological Saline ", as they are the same osmotic pressure and a similar sodium concentration as human blood plasma has and therefore intravenous Administration is particularly well suited. Because gelatin is a polyanion represents aqueous solutions of Gelatin neutralized with sodium hydroxide solution and in this way in the solution introduced concentration of sodium ions sodium chloride addition in a manner familiar to those skilled in the art be credited to the principles of electroneutrality, isotonicity and plasma-like sodium concentration to take account as far as possible.

In another preferred embodiment the pharmaceutical preparations according to the invention except sodium chloride additional and plasma typical Electrolytes contain, in particular the cations potassium, calcium and magnesium as well as the anions phosphate and bicarbonate or bicarbonate precursors such as lactate, acetate, malate, gluconate, citrate or succinate. Examples for such solutions with plasma-adapted electrolytes are the so-called Ringer's solution, Ringer's lactate or Ringer acetate solution and their newer ones, called "balanced solutions" Modifications in which the chloride content by additional partial exchange of sodium chloride metabolizable by sodium salts Anions such as sodium gluconate, malate, citrate or succinate on can be lowered. As the target of administration of plasma-adapted Solutions consists in 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.

It has proven beneficial for compatibility and effectiveness of the pharmaceutical according to the invention Prepared when the inventive aqueous pharmaceutical preparation electrolyte components contains, regarding their electrolyte composition are plasma-adapted and those of an isotonic balanced full electrolyte solution correspond.

• a) 150 bis 160 mmol/l Natrium,
• b) 4 bis 5 mmol/l Kalium,
• c) 0.5 bis 2.0 mmol/l Calcium,
• d) 1.0 bis 2.0 mmol/l Magnesium,
• e) 70 bis 105 mmol/l Chlorid,
• f) ggf. 1.0 bis 2.0 mmol/l Phosphat,
• g) 22 bis 30 mmol/l Acetat und/oder Gluconat.

In a further preferred embodiment, the aqueous pharmaceutical preparation according to the invention comprises electrolyte components corresponding to a single-zone, solid electrolyte solution which has the following ionic proportions in the following concentrations:

• a) 150 to 160 mmol / l sodium,
• b) 4 to 5 mmol / l potassium,
• c) 0.5 to 2.0 mmol / l calcium,
• d) 1.0 to 2.0 mmol / l magnesium,
• e) 70 to 105 mmol / l chloride,
• f) optionally 1.0 to 2.0 mmol / l of phosphate,
• g) 22 to 30 mmol / l acetate and / or gluconate.

Phosphates for the purposes of the present application are both the PO ₄ ^3- and the hydrogen phosphates and dihydrogen phosphates and phosphate derivatives such as glycerophosphate.

The aqueous pharmaceutical according to the invention Preparations are preferably applied as infusion solution.

One Another object of the present invention is therefore the use the aqueous pharmaceutical according to the invention Preparation as ready-to-use solution for infusion.

One Another object of the present invention is a medicament comprising the aqueous according to the invention pharmaceutical preparation.

The pharmaceutical preparations according to the invention reduce significantly or avoid this by aminoglycoside antibiotics induced renal failure.

One Another object of the present invention is therefore an antibiotic acting pharmaceutical preparation, as inventive Pharmaceutical preparation is formulated for the prophylaxis of Aminoglycoside antibiotics induced renal failure.

It It has been found that the aminoglycoside antibiotics and the gelatin-containing formulation also as separate Components, preferably in the form of a kit, stored and only at the application can be merged. One Another object of the present invention is therefore a kit comprising a serving containing at least one aminoglycoside antibiotic and at least one portion containing a formulation comprising gelatin and / or a physiologically acceptable gelatin derivative and / or a contains gelatinous protein or polypeptide as well as sodium chloride, wherein the joining of the portions preferably to a pharmaceutical preparation according to the invention leads.

• ¹⁾: mg/ml
• ²⁾: μmol/ml

By way of example, some compositions of the aqueous pharmaceutical preparation according to the invention may be mentioned in Table 1. The values given in Table 1 are listed in mg / ml and μmol / ml. Table 1: Examples of aqueous pharmaceutical preparations according to the invention example 1 Example 2 Example 3 Example 4 Example 5 amikacin 5,0 ¹⁾ - - 10.0 ¹⁾ - gentamicin - - 1,0 ¹⁾ - 3.0 ¹⁾ tobramycin - 3.0 ¹⁾ - - - Gelatinepolysuccinat 40 ¹⁾ 40 ¹⁾ - 80 ¹⁾ - Urea-crosslinked gelatin - - 35 ¹⁾ - 35 ¹⁾ sodium 154 ^{2 )} 153 ^{2 )} 145 ^{2 )} 154 ^{2 )} 145 ²⁾ potassium - 4 ²⁾ - - - calcium - 1.5 ²⁾ - - - magnesium - 1,25 ²⁾ - - chloride 120 ^{2 )} 99 ^{2 )} 145 ^{2 )} 86 ^{2 )} 145 ²⁾ acetate - 24 ²⁾ - - - gluconate - 2,75 ²⁾ - - - phosphate - 1.5 ²⁾ - - -

• ¹⁾ : mg / ml
• ²⁾ : μmol / ml

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 [0017]

Cited non-patent literature

• - Tourtelotte, D. and HE Williams, in: Stainsby, G., Gelatin and Glue Research, 1958 [0016]
• Schmidt-Thome, J., A. Mager and HH Schone, Arzneim.-Forsch. 12, 378 (1962) [0016]
• Campbell, DH et al., Texas Rep. Biol. Med. 9, 235 (1951). [0016]
• - Bonhard, K., Arzneimittel.-Forsch. 21, 1667 (1971) [0016]
• Nitschmann and Stoll, Pharm. Ztg. 42, 1594 (1968) [0016]

Claims (18)

Aqueous pharmaceutical preparation, full: a) 1 to 15 mg / ml of at least one aminoglycoside antibiotic, b) 20 to 100 mg / ml gelatin and / or a physiologically acceptable Gelatin derivatives and / or a gelatinous protein or Polypeptides, as well c) up to 10 mg / ml sodium chloride. Pharmaceutical preparation according to claim 1, wherein the aminoglycoside antibiotic consisting of the group from streptomycin, neomycin, paromomycin, amikacin, gentamicin, kanamycin, Netilmicin and tobramycin and their physiologically acceptable derivatives and salts. Pharmaceutical preparation according to claim 1 or 2, characterized in that the gelatin and / or the physiologically acceptable gelatin derivative and / or the gelatinous Protein or polypeptide has an average molecular weight of up to 40,000, preferably from 10,000 to 30,000. Pharmaceutical preparation according to at least one of the preceding claims, characterized that the physiologically acceptable gelatin derivative selected is from the group consisting of succinylated gelatin, urea crosslinked Gelatin and oxypolygelatin and any mixtures thereof. Pharmaceutical preparation according to at least any one of claims 1 to 3 comprising a non-succinylated Gelatin species. Pharmaceutical preparation according to at least one of the preceding claims comprising amikacin. Pharmaceutical preparation according to at least any one of claims 1 to 5 comprising gentamicin. Pharmaceutical preparation according to one of claims 1 to 5 comprising tobramycin. Pharmaceutical preparation according to at least one of the preceding claims, characterized that the preparation 1 to 12 mg / ml of at least one aminoglycoside antibiotic contains. Pharmaceutical preparation according to claim 9, characterized in that the preparation 1 to 10 mg / ml at least an aminoglycoside antibiotic. Pharmaceutical preparation according to at least one of the preceding claims, comprising a plasma-adapted balanced full electrolyte solution, which are the following Ionic proportions in the following concentrations: a) 150 to 160 mmol / l sodium, b) 4 to 5 mmol / l potassium, c) 0.5 to 2.0 mmol / l calcium, d) 1.0 to 2.0 mmol / l magnesium, e) 70 to 105 mmol / l chloride, f) optionally 1.0 to 2.0 mmol / l of phosphate, G) 22 to 30 mmol / l acetate and / or gluconate. Pharmaceutical preparation according to at least one of the preceding claims, characterized that they contain recombinantly produced gelatinous proteins and / or Having polypeptides. Antibiotic pharmaceutical preparation according to at least one of the preceding claims for the prophylaxis of aminoglycoside antibiotics-induced renal failure. Use of the pharmaceutical preparation according to at least one of the preceding claims as an infusion solution. Medicament comprising the pharmaceutical preparation according to at least one of claims 1 to 13. Use of gelatin or a physiological acceptable gelatin derivative in an aminoglycoside antibiotic containing formulation for aminoglycoside antibiotics induced nephrotoxicity. Use of the pharmaceutical preparation according to at least any one of claims 1 to 12 for the manufacture of a medicament for the prophylaxis of aminoglycoside antibiotics-induced renal failure. Kit comprising at least one serving that at least contains an aminoglycoside antibiotic and at least one Portion containing a formulation comprising gelatin and / or a physiologically acceptable gelatin derivative and / or gelatinous Contains protein or polypeptide, as well as sodium chloride, wherein the joining of the portions preferably to a pharmaceutical preparation according to the invention according to one of claims 1 to 13 leads.