Pharmaceutical composition for the parenteral administration of ultrashort-effective β-adrenoreceptor antagonists

Abstract

The present invention relates to a pharmaceutical composition in the form of a storage-stable solution for the parenteral administration of ultrashort-effective β-adrenoreceptor antagonists, comprising a) an ultrashort-effective β-adrenoreceptor antagonist and/or a pharmaceutically acceptable salt thereof, b) water, and c) a cyclodextrin and/or a functional cyclodextrin derivative. The composition according to the invention has high stability, even without the presence of additional adjuvants.

Claims

1. A pharmaceutical composition comprising: a) landiolol or a pharmaceutically acceptable salt thereof at a concentration from 0.005 to 2% (w/v); b) water; and c) 2-hydroxypropyl-β-cyclodextrin at a concentration from 0.1 to 20% (w/v).

2. The pharmaceutical composition of claim 1, wherein the pH value of the composition is 3 to 7.5.

3. The pharmaceutical composition of claim 2, wherein the pH value of the composition is 5 to 7.

4. The pharmaceutical composition of claim 1, wherein the concentration of 2-hydroxypropyl-β-cyclodextrin is 0.1% to 15% (w/v).

5. The pharmaceutical composition of claim 4, wherein, the concentration of 2-hydroxypropyl-β-cyclodextrin is 0.25% to 7% (w/v).

6. The pharmaceutical composition of claim 5, wherein the concentration of 2-hydroxypropyl-β-cyclodextrin is 0.5% to 4%.

7. The pharmaceutical composition of claim 1, wherein the concentration of the landiolol or pharmaceutically acceptable salt thereof is 0.01% to 1.0% (w/v).

8. The pharmaceutical composition of claim 1, wherein the composition has an osmolarity of 270 mosmol/l to 310 mosmol/l.

9. The pharmaceutical composition of claim 8, wherein the composition has an osmolarity of 280 mosmol/l to 300 mosmol/l.

10. The pharmaceutical composition of claim 1, wherein the composition is present in the form of a sales unit selected from the group consisting of: 1 ml solution containing 5-20 mg landiolol or a salt thereof, 2 ml solution containing 5-40 mg landiolol or a salt thereof.

11. A method of reducing heart beat frequency in a patient comprising administering a composition of claim 1 to a patient, whereby the heart beat frequency in the patient is reduced.

12. The method of claim 11, wherein the patient has atrial fibrillation, atrial flutter, sinus tachycardia, atrioventricular tachycardia, AV node tachycardia, supraventricular tachycardia, ventricular arrhythmias, perioperative ischaemia, unstable angina pectoris, or acute myocardial infarction.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) The invention will be explained in more detail below with the aid of examples of embodiment and figures.

(2) FIG. 1 shows the accelerated breakdown of a 5% esmolol reference solution and compositions according to the invention at 75° C.

(3) FIG. 2 shows the influence of freeze-drying on the accelerated breakdown of esmolol-cyclodextrin complexes in water at 75° C.

(4) FIG. 3 shows the influence of the concentration of a-cyclodextrin on the stability of esmolol at 75° C.

(5) FIG. 4 shows the influence of hydroxypropyl-β-cyclodextrin on the stability of esmolol at 75° C.

(6) FIG. 5 shows the influence of α-cyclodextrin in increasing concentrations on the stability of landiolol in aqueous solution at 70° C.

(7) FIG. 6 shows the influence of 2-hydroxypropyl-β-cyclodextrin in increasing concentrations on the stability of landiolol in aqueous solution at 70° C.

(8) FIG. 7 shows the influence of γ-cyclodextrin in increasing concentrations on the stability of landiolol in aqueous solution at 70° C.

(9) FIG. 8 shows the influence of the pH value on the stability of landiolol in aqueous solution at 70° C.

(10) FIG. 9 shows the influence of cyclodextrins (2%, w/v) in which landiolol was stored by means of concentrated suspensions on the stability of aqueous landiolol solutions of 0.25% (w/v) at 70° C.

DETAILED DESCRIPTION

Example 1

Production of (2-hydropropyl)-β-cylodextrin-esmolol Complexes

(11) An equimolar quantity of (2-hyroxypropyl)-β-cyclodextrin was added to a 5% esmolol solution and stirred for 6 hours.

Example 2

Production of α- and γ-cyclodextrin-esmolol Complexes

(12) An equimolar quantity of α-cyclodextrin (Cavamax W6 Pharma, manufacturer Wacker Chemie AG) (example 2a) or γ-cyclodextrin (Cavamax W8 Pharma, manufacturer Wacker Chemie AG) example 2b) was added to a 5% esmolol solution and stirred for 18 hours.

Example 3

Production of Cyclodextrin-Esmolol Complexes

Example 3a

(13) Esmolol and α-cyclodextrin are dissolved in final concentrations of 5% (w/v) (esmolol) and 14% (w/v) α-cyclodextrin) in water for injection purposes and stirred for 24 hours at room temperature.

Example 3b

(14) Esmolol and optionally additionally α-cyclodextrin are dissolved in a final concentration of 5% (w/v) (esmolol) or 14%, 7%, 4%, 2%, 1% and 0% (w/v) (α-cyclodextrin) in water for injection purposes and stirred for 24 hours at room temperature.

Example 3c

(15) Esmolol and optionally additionally hydroxypropol-β-cyclodextrin are dissolved in a final concentration of 5% (w/v) (esmolol) or 7% and 0% (w/v) (hydroxypropyl-β-cyclodextrin) in water for injection purposes and stirred for 24 hours at room temperature.

Example 4

Example of Comparison

Production of a State-of-the-Art 5% Esmolol Solution for Injection

(16) A parenteral solution was produced in accordance with the recipe set out in table 1.

(17) TABLE-US-00001 TABLE 1 Composition of the parenteral esmolol solution Substances Quantity Esmolol HCl   500 mg Sodium acetate   34 mg Glacial acetic acid 3.674 mg Propylene glycol   518 mg Ethanol   402 mg HCl or NaOH for pH 3.5-5.5 q.s. Water ad 10 ml

Example 5

Investigations of the Stability of Parenteral Esmolol Solutions

(18) With solution described in examples 1 to 3, accelerated stability tests were carried out at a temperature of 75° C. After 0, 24, 45 and 70 hours samples were taken which were diluted with distilled water (20 μl sample+180 μl water). The accelerated breakdown was determined by HPLC as follows:

(19) For the qualitative and quantitative analyses a Hitachi Elite LaChrom HPLC device with a diode array detector and a Waters Nova-Pak C18 4 μm 3.9×150 mm column were used. The mobile phase consisted of (A) H.sub.3PO.sub.4 (10 g/l) in water, adjusted to pH 2.35 with triethylamine (TEA) and (B) acetonitrile. The gradient used is set out in table 2.

(20) TABLE-US-00002 TABLE 2 HPLC method Time (min) A (%) B (%)  0 82 18  7 82 18  8 60 40 13 60 40 14 70 30 20 70 30 21 82 18 30 82 18

(21) The flow rate was 1 ml/minute, the injection volume 20 μl. Esmolol hydrochloride was detected at 274 nm. The retention time of esmolol hydrochloride was on average 3.9 minutes, that of the principal degradation product (“contaminant A” in table 3 below) was 1.7 minutes. To determine degradation the ratio of the principal degradation product to remaining esmolol hydrochloride was calculate and indicated in percent (“degraded esmolol (%)”).

(22) The results of these studies show a decisively increased stability of the solutions containing cyclodextrin.

(23) FIG. 1 shows the accelerated degradation at 75° C. of the 5% esmolol reference solution and esmolol cycoldextrin complexes in water [(⋄) 5% esmolol comparison solution with 0% cyclodextrin—example 3b; (X) 5% esmolol+γ-cyclodextrin—example 2b]; (.square-solid.) 5% esmolol+(2-hydroxypropyl)-β-cyclodextrin—example 1); (.box-tangle-solidup.) 5% esmolol+α-cyclodextrin—example 2a]. The values are mean values of 3 tests±SD.

(24) FIG. 2 shows the influence of freeze drying on the accelerated degradation of esmolol-cyclodextrin complexes in water at 75° C. [(⋄) 5% esmolol comparison solution with 0% cyclodextrin—example 3b; (X) 5% esmolol in 14% α-cyclodextrin solution without freeze drying—example 3a; (.square-solid.) 5% esmolol+α-cyclodextrin—example 2a with subsequent freeze drying and reconstitution in water]. The values are mean values of 3 tests±SD.

(25) FIG. 3 shows the influence of the concentration of α-cyclodextrin on the stability of an aqueous 5% esmolol solution at 75° C. [(.box-tangle-solidup.) 5% esmolol comparison solution with 0% α-cyclodextrin—example 3b; (+) 5% esmolol+1% α-cyclodextrin—in accordance with example 3b; (○) 5% esmolol+2% α-cyclodextrin—in accordance with example 3b; (.square-solid.) 5% esmolol+4% α-cyclodextrin—in accordance with example 3b; (.box-tangle-solidup.) 5% esmolol+7% α-cyclodextrin—in accordance with example 3b; (.circle-solid.) 5% esmolol+14% α-cyclodextrin—in accordance with example 3b;]. The values are mean values of 3 tests±SD.

(26) FIG. 4 shows the influence of hydroxypopyl-β-cyclodextrin on the stability of an aqueous 5% esmolol solution at 75° C. [(.square-solid.) 5% esmolol comparison solution with 0% hydroxypropyl-β-cyclodextrin—example 3c; (○) 5% esmolol+7% hydroxypropyl-β-cyclodextrin—in accordance with example 3c]. The values are mean values of 3 tests±SD.

Example 6

Storage Stability of Esmolol Cyclodextrin Complexes

(27) Table 3 shows the storage stability of esmolol cyclodextrin complexes (example 3a) compared with a state-of-the-art formulation (example 4) on the basis of the increase in degradation products (=contaminants).

(28) TABLE-US-00003 TABLE 3 Stability tests Stability tests 25° C./60% r.h. Storage time 0 6 0 6 months months months months Storage stability tests Esmolol formulation Esmolol formulation without with Contaminants cyclodextrin (example 4) cyclodextrin (example 3a) CONTAMINANT 0 2.56 ± 0.53 0 1.94 ± 1.06 A CONTAMINANT n.d. n.d. n.d. n.d. B CONTAMINANT n.d  n.d. n.d. n.d. C CONTAMINANT n.d. .018 ± 0.01 n.d. n.d. D Unknown 0 0.37 ± 0.04 0 0.38 ± 0.02 contaminants Total 0 3.11 0 2.24

Example 7

Determination of the Osmolarity

(29) The osmolarity/reduction in freezing point vis-a-vis water was determined with a Knauer semi-micro-osmometer. In order to be able to determine the osmolarity with this osmometer the samples are cooled to freezing in the osmometer.

(30) The 5% solution with α-cyclodextrin in accordance with example 3a has an osmolarity of 290 mosmol/l. This corresponds to an isotonic solution as the range of isotonia extends from 281 to 297 mosmol/l. Solutions of >310 mosmol/l would be described as hypertonic and solutions of <270 mosmol/l classified as hypotonic.

Example 8

Production and Stability Testing of Cyclodextrin-Landiolol Complexes

(31) Landiolol was dissolved in purified water at a concentration of 0.25% (m/v). Subsequently α-cyclodextrin (Cyclolab, Budapest), 2-hydroxypropyl-β-cyclodextrin (CTD, Inc., Florida) and γ-cyclodextrin (ISP, Germany) was added in final concentrations of 0%, 0.5%, 1%, 2% and 7% (w/v). The solutions were heated to 70° C. and the stability of landiolol determined in accordance with the HPLC method described in example 5. Landiolol was detected at 220 nm. The retention time of landiolol hydrochloride was on average 10.5 minutes, that of the principal degradation product 1.4 minutes. To determine the degradation the ratio of the principal degradation product to the remaining landiolol hydrochloride was calculated and indicated in percent (“degraded landiolol (%)”). The results of this study are shown in FIG. 5-7. The shown values are mean values of 3 tests±SD. FIG. 5 shows the influence of 0% (.square-solid.), 0.5% (X), 1% (○), 2% (Δ), 4% (.box-tangle-solidup.) and 7% (.Math.) α-cyclodextrin on the stability of landiolol at 70° C.

(32) FIG. 6 shows the influence of 0% (.square-solid.), 0.5% (X), 1% (○), 2% (Δ), 4% (.box-tangle-solidup.) and 7% (.Math.) hydroxypropyl-β-cyclodextrin on the stability of landiolol at 70° C.

(33) FIG. 7 shows the influence of 0% (.diamond-solid.), 0.5% (.Math.), 1% (X), 2% (Δ), 4% (.square-solid.) and 7% (○) γ-cyclodextrin on the stability of landiolol at 70° C.

Example 9

Evaluation of the Influence of the pH Value on the Stability of Landiolol

(34) Landiolol was dissolved in purified water at a concentration of 0.25 (w/v). The pH value was then adjusted to 3; 4; 5; 5.5; 6; 6.5; 7 and 8. The solutions were heated to 70° C. and the stability of landiolol determined with the HPLC method described in examples 5 and 8. The results of these studies are shown in FIG. 8. These show the degradation of landiolol at pH 3.0 (⋄), pH 4.0 (X), pH 5.0 (.Math.), pH 5.5 (Δ), ph 6.0 (.box-tangle-solidup.), pH 6.5 (.diamond-solid.), pH 7.0 (○) and pH 8.0 (.square-solid.). The shown values are mean values of 3 tests±SD.

Example 10

Stability Tests of Cyclodextrin-Landiolol Complexes Produced by Means of Concentrated Suspensions

(35) Landiolol and α-cyclodextrin (Cyclolab, Budapest), 2-hydroxypropyl-β-cyclodextrin (CTD Inc., Florida) or γ-cyclodextrin (ISP, Germany) were suspended in purified water in a concentration of 10% landiolol (w/v) and 80% cyclodextrin (w/v) and stirred for two hours at room temperature. After 5 minutes of ultrasound treatment the suspensions were diluted in stages so that the final concentration of landiolol was 0.25% (w/v). These solutions were incubated at 70° C. and the taken sample were analysed by means of the HPLC method described in examples 5 and 8. The results of this study are set out in FIG. 9. These show the influence of 2% α-cyclodextrin (.box-tangle-solidup.), 2% 2-hydroxypropyl-β-cyclodextrin (Δ) and 2% γ-cyclodextrin (○) on the stability of landiolol at 70° C. The shown values are mean values of 3 tests±SD.

Example 11

Vasoprotective Effect of Cyclodextrin on Intravenously Administered Ultrashort-Effect β-Adrenoceptor Antagonists

(36) Solutions of said β-adrenoreceptor antagonists with or without cyclodextrin were chronically infused into rats via the jugular vein for a longer period. It can be seen that said beta-adreno-receptor antagonists in solutions containing cyclodextrin bring about considerably less endothelial and vascular damage than the use of a conventional solution.