DE2805165A1 - MEDICINAL PRODUCT CONTAINING GITOXIN AND THE METHOD OF MANUFACTURING IT - Google Patents

Description

VON KREISLER SCHONWALD Mb'fER tlSHOLD FUES FROM KREiSLER KELLER SELTING

^ 2605165

PATENT LAWYERS Dr.-Ing. by Kreisler + 1973

Dr.-Ing. K. Schönwald, Cologne Dr.-Ing. Th. Meyer, Cologne Dr.-Ing. K. W. Eishold, Bad Soden Dr. J. F. Fues, Cologne Dipl.-Chem. Alek von Kreisler, Cologne Dipl.-Chem. Carola Keller, Cologne Dipl.-Ing. G. Selting, Cologne

5 COLOGNE 1

DEICHMANNHAUS AT THE MAIN RAILWAY STATION

February 7, 1978 AvK / IM

A. Christiaens S.A.

Rue de l'Etuve 6o, Brussels / Belgium

Medicinal product containing gitoxin and process for its manufacture

609832/0948

Telephone: (02 21) 2345 41-4 · Telex: 8882307 dopa d ■ Telegram: Dompatent Cologne

2605165

The invention relates to new pharmaceutical compositions containing gitoxin as an active ingredient, and relates to especially gitoxin-containing pharmaceutical agents for oral applications.

Gitoxin is a glucoside known for its good potential properties, which is used to treat congestive disorders Heart disorders, atrial fibrillation, flutter, supraventricular Tachycardia and extrasystoles is applied. The resorption mixed with the usual pharmaceutical excipients and gitoxin administered in tablet or other solid form, however, leaves much to be desired; in the dog, in vivo absorption is limited to approximately 15 to 1850 of the administered dose. Bioavailability The amount of gitoxin taken in the previously known forms is therefore very limited.

This limited bio-availability of gitoxin is a big disadvantage. During treatment with a cardiotonic, it is essential to keep the dosage within certain limits to keep, because too high a dose of the same can have a cardiotoxic effect, while too low a dose Dosages the effectiveness of the remedy is reduced too much., \ As with serious heart diseases dire consequences may have.

The applicant has now found that the resorption of gitoxin occurs in the previously known forms of use was limited to 15 to 18%, to 95 to 100% of the

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administered active ingredient dose improved, if this Glucoside in the form of a liquid solution all in one organic solvents, or in a mixture of organic solvents, or in the form of a solid Solution in solid aids from the range of saponins is administered.

With respect to the previously known gitoxin-containing pharmaceutical compositions in solid form the improved bioavailability of the in an inventive Application form administered Gitoxins in a ratio of approximately 1: 5 to 1: 6.

This strong improvement in gitoxin absorption is all the more so more surprising than the administration of another known glucoside, digoxin, in its liquid form Degree of absorption only about doubled.

This unpredictable improvement in the bioavailability of the gitoxin in the form of a liquid or according to the invention solid solution has a considerable expansion of the application possibilities of this potential cardiotonic result.

It was also found that the gitoxin administered in a form according to the invention was only about 21% is excreted via the urinary tract, whereas the excretion of digoxin in this way is approximately 7096 running.

If you now consider that in patients with Heart ailments also often affect kidney function, stemming from the more limited Excretion of gitoxin via the urinary tract significantly reduces the risk of toxic effects.

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Another not insignificant advantage of gitoxin compared to digoxin is the shortened half-life, which is only about 24 hours, whereas digoxin takes about 35 hours. Thanks to the faster breakdown of the The active ingredient according to the invention is the risk of it being caused by its accumulation in the patient's body Intoxication also significantly reduced.

The invention is therefore a cardiotonic pharmaceutical composition in the form of a liquid or solid solution containing gitoxin as an active ingredient.

The liquid gitoxin solutions according to the invention are preferably solutions in a physiologically permissible range organic solvents such as ethanol, dimethylformamide (dimethylformic acid amide), dimethylazetamide (dimethyl acetic acid amide) and N-methyl-2-pyrrolidone, with the organic solvent optionally a certain Amount of water can be added.

The amount of water added, if any, should be as small as possible and not exceed the amount which is necessary to dissolve the gitoxin in the solvent-water mixture. Usually organic Solvent and water in a weight ratio of 2: 1 used up to 1: 1.

The liquid gitoxin solutions according to the invention contain furthermore advantageously a liquid glycol or a mixture of liquid glycols in the form of monomers or polymers, such as propylene glycol (glycerine) and / or a polyethylene glycol such as the commercially available one Polyethylene glycol 400.

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The gitoxin-containing solutions according to the invention can also contain sweeteners, for example sugar, and / or aromatics.

The pharmaceutical compositions according to the invention containing gitoxin in liquid solution can in any form applicable to oral applications such as a solution, syrup, etc., or in the form of Solutions for intravenous injections are available.

Cardiotonic compositions in the form of a solid gitoxin solution are made with the help of solid saponins prepared.

Among the saponins used as auxiliaries are in particular digitonin, escin and the sodium salt of It's preferred.

A particular embodiment of an inventive The pharmaceutical composition therefore consists of a homogeneous mixture of gitoxin and a saponin in the form of a solid solution to which conventional pharmaceutical auxiliaries are added.

In such solid solutions of gitoxin and saponin, the weight ratios of the two components vary within wide limits, that is to say between approximately 1: 3 and 1: 100 and preferably between approximately 1: 4 and 1:10.

The compositions according to the invention containing gitoxin in the form of a solid solution can be in any one of them in the form that can be used for oral applications, for example in the form of tablets, dragees, lozenges, Pills, granules, powders, in soft or hard capsules

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drawn up, or as a suspension, emulsion, etc.

In addition to gitoxin and saponin, the preparations according to the invention can contain other customary pharmaceuticals Auxiliaries such as fillers, binders, lubricants, neutralizers, sweeteners, colorants, coating agents and coating agents, etc. included.

The preparations according to the invention can furthermore in the form of a suspension of a solid solution of gitoxin and saponin in a lipophilic or hydrophilic Liquid.

The invention also relates to a process for the preparation of the new gitoxin containing in solid solution pharmaceutical compositions.

In this two-stage process, the first process stage comprises the preparation of a gitoxin solution in an organic solvent or in a mixture of such solvents and the preparation of a Saponin solution in the same or a different solvent or solvent mixture, as well as simultaneous precipitation the two components by mixing the two solutions and separating the solvent or solvent mixture, whereupon the mixed precipitate obtained is dried. Various organic solvents, optionally in mixtures, are used, especially lower alkanols such as methyl or ethyl alcohol, chloroform and dichloromethane, as well their mixtures such as a mixture of 8 parts by volume of chloroform with 2 parts by volume of methyl alcohol.

The second process stage of the process according to the invention

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includes. the manufacture of a pharmaceutical composition by admixing conventional pharmaceuticals Aids to the solid gitoxin-saponin solution produced in the first process stage and forming the desired application form, for example tablets, capsules, suspensions, etc.

The gitoxin is in the form of approximately 0.1 to 3 milligrams to administer containing regular doses, whereby the one or twice a day of the prescribing dose general health of the patient depends.

The invention is further illustrated by the following examples explained, examples 1 to 4 referring to the preparations of liquid, examples 5 to 7 referring to the Manufacture of solid gitoxin solutions; the remaining examples are intended to have various uses describe the compositions of the invention.

example 1

Preparation of a liquid solution of gitoxin in an aqueous Athano1-Propylene Glyko1 mixture

Such solutions preferably contain at least 35 percent by weight ethyl alcohol and at most 30 percent by weight Water.

Such a solution can be composed, for example, as follows:

Gitoxin 0.025 wt.? £

Ethyl alcohol 35 "

Propylene glycol 35 "

V / ater 30 "

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Example 2

Preparation of a liquid solution of gitoxin in an aqueous ethanol-glycerine mixture

Such solutions preferably contain at least percent by weight. Glycerine and a maximum of 30 percent by weight Water.

Such a solution can be composed as follows, for example. :

Gitoxin 0.025 wt .- #

Ethyl alcohol 50 »

Glycerine 20 "

Water 30 "

Example 3

Preparation of a liquid solution of gitoxin in dimethylazetamide

Such solutions preferably contain at least percent by weight of dimethyl acetic acid amide and at most 20-6 Water.

Such a solution can contain, for example, the following ingredients:

Gitoxin 0.025 wt. 96

Dimethylazetamide 40 "

Fropylene Glycol 40 "

Water 20 »

Example 4

Preparation of a liquid solution of gitoxin in N-methyl-2-pyrrolidone ■

Such solutions preferably contain at least

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Percentage by weight of N-methylpyrrolidone and a maximum of $ 30 Water.

Such a solution can be composed, for example, as follows:

Gitoxin 0.025 wt. 96

N-methyl-2-pyrrolidone 35 "

Prcpylene Glycol 35 "

Water 30 ".

Example 5

Manufacture of solid gitoxin-digitonin solutions

(1) 1Q0 mg gitoxin and 1 g digitonin be mL in 40 of a chloride of orm-Mg thy lalkohol mixture (mixing ratio of 8: 2), and the solution obtained is evaporated in a rotary evaporator at 40 ⁰ C under vacuum to dryness, whereupon the solid solution is dried under vacuum in a drying oven (code number 770629).

(2) With the procedure described under (1) a number of liquid solutions are made with different weight ratios between the components. The composition of the mixed precipitates and their code numbers are listed in Table I below.

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TABLE I KodpnummpT * Weight ratio Git oxin-Dig it on in 770629 1:10 770730 1: 4 770719 1: 4 770726 1: 3 770713 1: 2 770715 1: 1 770714 10: 1

Example 6

Manufacture of solid gitoxin-escin solutions

(1) On the one hand, 100 mg of gitoxin are dissolved in 40 ml of a chloroform-methyl alcohol mixture with a mixing ratio of 8: 2, and. on the other hand, 900 mg of escin in 20 ml of methanol. The two solutions are combined and the mixture in a rotary evaporator under vacuum at 50 ⁰ C and evaporated to dryness. The solid evaporation residue is then dried in a drying oven under vacuum.

(2) Using the methods described under (1) The procedure is a series of such solid solutions with different weight ratios between the two Components manufactured. The weight ratios and the assigned code numbers can be found in Table II see.

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TABLE II

Weight ratio code number

Gitoxin-Esc: m

1: 9 770913

1: 4 770920

1: 3 771005

1: 2 771004

1: 1,770926

Example 7

Manufacture of solid solutions of gitoxin in escin sodium salt.

500 mg gitoxin and 2 g of sodium salt of escin is dissolved in 100 ml of an 8: 2 mixture of chloroform and Kethy1 alcohol dissolved, the mixture is evaporated in a rotary evaporator under vacuum "at 40 ⁰ C to dryness and the evaporation residue obtained under vacuum in the Drying oven «

Example 8

Gitoxin tablets with an active ingredient content of 200 μg (code number 770831)

Solid gitoxin-digitonin solution 2.2 mg (No. 770629)

Lactose

Potato starch 20.8 mg

Colloidal silica 1 mg

Magnesium stearate 1 mg.

Example 9

Gitoxin tablets with an active ingredient content of 200 μg (code number 770927)

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Solid gitoxin-escin solution (No. 770920) 1 mg

Lactose 77 mg

Potato starch 20 mg

Colloidal silica 1 mg

Magnesium stearate 1 mg.

Example 10

Gitoxin tablets with an active ingredient content of 200 μg (code number 77 K 07)

Solid gitoxin-escin sodium salt solution (Kr, 771025) 1.1 mg

Milk sugar 76.9 mg

Potato starch 20 mg

Colloidal silica 1 mg

Magnesium stearate 1 mg.

Example 11

Gitoxin suspension with an active ingredient content of O, O4? O

Liquid gitoxin solution 200 mg

Paraffin 10 mg

Lecithin 200 mg

Peanut oil ad 100 g.

To study the pharmacokinetic and pharmacodynamic Properties of Gitoxin in Humans A solution of the following composition was used Gitoxin 1.5 mg

Ethyl alcohol 5 ml

Glycerine 2 ml

Aqua de st. ad 10 ml,

which was administered orally and intravenously to four healthy subjects.

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The patients had a normal electrocardiogram (EKG) and the following biometric data; Patient Age Weight Height Gender

P.T. 49 76 177 P.H. 23 55 160 V.L. 20th 112 193 J.W. 23 50 167

The patient J.W. became 1.2 mg, the remaining 1.5 mg Gitoxin administered orally and intravenously at four week intervals.

For each application, an ECG and a carotidogram were recorded after 0 hours (reference diagram), 3 hours, 6 hours, 12 hours, 24 hours and 72 hours using these diagrams was the left ventricular Blood expulsion time index (LVETI or "left ventricular (blood) ejection time index ") is calculated as follows: LVETI (in msec.) = LVET + 1.6 ν, where ν is the pulse frequency and LVET represents left ventricular blood ejection time.

Furthermore, blood was taken from each patient at certain intervals and the urine was checked for one week collected quantitatively.

The gitoxin content in the blood plasma and in the urine was determined by X-ray immunology determined with the help of the "Gitoxi-Test" ^; the principle of this method is based on a comparative one Determination of the cardiotonic compound and a dosed amount of a likewise specific with the one for the cardiotonic specific antibody to be determined reacting reference substance.

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The cardiotonic antibody formed by incubation

Complex becomes by absorbing the uncomplexed Antibody fraction through an activated charcoal-dextran mixture separated from the same and after centrifugation the supernatant liquid is ± in a scintillation counter analyzed (Lesne and Dolphen, Arch. Int. Physiol. Biochem., 83 (1975), pp. 136-138).

FIGS. 1 to 4 of the accompanying drawings graphically illustrate the effect of gitoxin when administered orally ( ^c ) and intravenously (A) on the LVETI of the four test subjects identified by their initials (abscissa: time in hours; ordinate: Δ LVETI in msec.) .

The course of the gitoxin levels in the blood plasma (in mg / ml) of the four test subjects in relation to time (ordinate, in days) is graphically represented by FIGS. 5 to 8, the same in the urine (in ng) represented by FIGS. 9 to 12.

It is clear from FIGS. 1 to 4 that this was administered orally or intravenously in liquid form Gitoxin significantly increases the LVETI and is therefore a very effective cardiotonic. The cardiotonic one The effect is most pronounced 6 to 12 hours after administration and then rapidly decreases.

FIGS. 5 to 8 show that the orally administered gitoxin enters the bloodstream very quickly and the blood level is very high for about six hours. The figure's slightly lower blood level

7 is due to the fact that the patient was not fasted at the time of administration. Figures 5 to

8 furthermore show that the absorption of the orally administered gitoxin is practically quantitative. These

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Plague is in complete contrast to the previous one published work in this area and according to which the gitoxin administered orally is not absorbed

Figures 9 to 12 prove that the Gitoxin-

Excretion via the urinary tract less than 20% of the administered Dose is.

The following conclusions can be drawn from the results of the tests carried out:

1. Gitoxin administered orally in the form of a liquid solution is quickly and completely absorbed.

2. The maximum value of the gitoxin content in the blood plasma

occurs about six hours after administration.

3. A single dose of gitoxin of 1.5 mg shows one remarkable cardiotonic efficacy (strong codification of LVETI between the 3rd and 24th hour after administration).

4. Only a small fraction (around 2050 of the administered Gitoxins is found unchanged in the urine; this statement proves that, contrary to others Glucosides of the digitalis series, the excretion of gitoxin is less kidney-dependent.

5. The half-life of the gitoxin is around hours.

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The greater solubility and the resulting better bioavailability of the in the form of the invention Gitoxins used in solid solutions was based on Levy and Hayes (New England J. Ked., 262 (1960), 1053; Finholt, P. and Solvang, S., J. Pharm. Sci., 57 (1968), 1322) demonstrated tests carried out, with 250 ml of 0.1N hydrochloric acid containing 12.5 mg as the test medium (0.05 $ 0 Tween 80, and 1 mg each of gitoxin were used.

The results of these tests are shown in Tables III to VI.

From Table III, in which the solution speed of gitoxin from solid solutions with different proportions between gitoxin and digitonin (such as described in Example 5), it is clear that the gitoxin from solid solutions with. a gitoxin-digitonin ratio under 1: 3 goes into solution quickly and practically quantitatively in the test medium. Table IV relates to the experiments with solid gitoxin-escin solutions (as described in Example 6). The results show that in gitoxin-escin conditions the percentage of gitoxin dissolved in the test medium drops sharply above 1: 3.

From Table V, which relates to the tests with solid gitoxin-escin sodium salt solutions with a weight ratio of 1: 4, it is clear that more than 85% of the gitoxin is dissolved in the first 30 minutes and the solution of the same in the test medium after 80 minutes Minutes is complete.

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StO

TABLE III Gitoxin Solubility (%)

Gitoxin
Digitonin
Identical relationship 15th V er
30th search
(Minutes)
45 there
60 97.2 uer
90 120 1:10 93.4 98.3 101.3 101.7 97.6 101.5 100.8 1: 4 95.3 99.2 ■ 98.6 80.3 98.3 101.4 1: 4 91.9 95.1 96.8 68.1 99.4 99.5 1: 3 79.0 79.3 79.8 32.9 82.9 87.8 1: 2 58.4 61.8 65.3 20.9 70.9 73.0 1: 1 27.4 29.2 30.4 35.5 38.1 10; 1 13.8 18.4 19.5 23.9 33.0

TABET J .F- TV Gitoxin solubility (%)

Gitoxin
Esein—
Quantity ratio 15th V er
30th suchsd
(Minutes)
45 60 104.4 except
90 120 1: 9 87.9 94.3 100.2 104.6 105.4 104.9 1: 4 76.8 96.8 104.0 90.7 107.9 110.0 1: 3 76.1 85.0 86.7 54.7 90.0 94.1 1: 2 44.4 50.1 52.4 21.8 55.7 54.1 1: 1 17.1 18.2 20.0 27.6 31.2

TABLE V

Gitoxin Solubility (%)

Solid 1: 4 gitoxin-escin sodium salt solution In the test medium after 15 30 45 60 dissolved gitoxin (%) 76.9 90.0 96.0 99.0 98.0

120 min, 98.0

Further attempts were made with git oxine-containing pharmaceuticals

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Compositions in tablet form, especially those in the use forms described in Examples 8, 9 and 10 carried out. Analog tablets were used for comparison the following compilation (lot 770608): 200 μg gitoxin; 20 mg potato starch; 59.8 mg of milk sugar; 18 mg talc and 2 mg silicone talc are used, their ingredients however, were mixed by simply grinding and in which the gitoxin was not in the form of a solid solution.

The results presented in Table VI demonstrate the unexpected improvement in the in vitro dissolution of the in Gitoxins present in the form of a solid solution in a saponin.

TABLE VI Gitoxin Solubility (%) from Tablets

Tablets 15th verse u c h s d a u e r (Minutes) Code number 83.2 30th 45 60 90 120 770831 71.7 84.9 84.6 88.2 91.8 93.5 770927 85.0 80.1 86.9 92.1 96.6 95.7 77 K 07 14.2 92.1 94.2 95.8 97.2 97.8 770608 23.2 28.6 35.7 45.2 50.9

The excellent bio-availability of the gitoxin administered in the form of solid gitoxin-saponin solutions was achieved by the results of in vivo tests in the dog confirmed.

In these experiments with a group of six male Beagle dogs with a mean live weight of 16 kg, each animal was given 40 μg at intervals of one week Gitoxin per kg live weight orally under one of the following

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«A.

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Forms administered:

- contained in a hard gelatin capsule Mixture of gitoxin and lactose;

- tablet according to example 8;

- Tablet according to Example 9>

- Tablet according to example 10.

The Gitoxingehalt in the blood plasma was determined by the above-described X-ray-immunological I ^v fethode (Gitoxitest in the extracted for 48 hours in certain time intervals blood samples.

The results of the blood analyzes are summarized in Table VII (gitoxin contents in ng / ml; mean values for the six dogs).

TABLE VII

j blood sample intra 1 * 4, 4th Oral gitoxin route of administration in in 4 * 11 ,8th in Escin- in ¹ ben— venous 4 * 5, 1 Digitonin Escin 1 * 10 , 4 Sodium Lactose ! withdrawal
inach (h) 1 * 2, 6th 5 * 9, 0 . salt ί 0.5 80, 0 * 3, 1 19.2 * 8.6 26, 5 ^ 5, 2 32.2 * 10.5 0.2 * 0.2 1 72, 9 * 4, 2 44.6 * 8.7 55, 4 * 5, 2 48.2 * 10.6 1.1 * 0.5 : 2
ι 58 2 * 2, 1 53.6 * 5.7 58 1 * 3, 0 53.9 * 10.1 3.5 * 1.0 I.
3 55, 8 * 2, 4th 49.8 * 5.7 45, 9 * 2, 2 50.7 * 7.1 4.3 * 1.4 I 4 49, 8 * 2, 4th 43.5 * 4.7 0 * 1, 8th 43.8 * 6.1 4.6 * 1, .6 6th 37, 3 ± 2, 6th 34.0 * 3.5 23, 1 * 0, 7th 34.5 * 3.0 4.6 * 1.8 8th 29 2 * 1, 25.0 * 2.7 21 5 * 0, 2 i 28.4 * 4.2 4.2 * 1.6 24 11 9.6 * 1.9 9, 9.8 * 1.2 3.6 * 0, δ 32 17, 6.2 * 1.0 5, 4.8 * 0.6 3.0 * 0.6 48 1.6 * 0.5 1, 1.3 * 0.3 1.3 * 0.4

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Te'05185

The comparison of the blood plasma levels in one according to the invention solid citoxin-saponin solution, oral drug administration was carried out with the at the same time intervals levels achieved when using a previously customary Compilation (gitoxin-milk sugar mixture) proves that the gitoxin absorption from the solid solutions is essential occurs faster and results in much higher blood levels leads.

It is also evident from Table VII that the half-life of the gitoxin is about 10 hours, whereas for another well-known glucoside, digoxin, this value is approximately 35 hours. This shorter one Half life is very beneficial as it reduces the risk of the active ingredient building up in humans Body possibly caused symptoms of poisoning.

In Table VIII, on the one hand, the calculated diagram surfaces, expressed in ng.h.ml and limited by the blood concentration curves, and, on the other hand, the calculated bioavailability of the gitoxin expressed in % by comparing these surfaces with the bioavailability of the gitoxin obtained after intravenous administration are listed.

With a sensitivity threshold value P = 0.05, the Surface differences when the compositions of Examples 8, 9 and 10 are administered orally as statistical irrelevant (above).

In summary, it can be said that gitoxin is administered in the form of a solid gitoxin-saponin solution, is absorbed quickly and by more than 80%, whereas absorption des in the form of a gitoxin-milk sugar mixture in hard capsules

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entered Gitoxins is only 20% .

The results of the in vivo tests on dogs show that that :

- Orally administered in one of the solid gitoxin-saponin solutions according to the invention Gitoxin is absorbed faster and more completely;

- the maximum blood level is reached in the first six hours after administration is ;

- the half-life (absorption phase) is 10 hours.

TABLE VIII

Gitoxin Diagram Bio Conversation

Application surface availability area shape (ng.h. ml-Ό (%) difference

in Digitonin 708 - 77 82.2 - 10.6 oB

in Escin 650 - 62 75.8 ± 8.4 oB

in Escin-Na in milk sugar

733 i 96 86.6 - 13.5 oB

153 - 21 18.4 ^ 3.6 significant

The pharmacokinetic and pharmacodynamic properties of gitoxin in humans were studied using the following compositions :

(1) Liquid solution with a gitoxin content of 1.5

* "in 5 ml ethyl alcohol, 2 ml glycerine, with aqua destillata brought to 10 ml. Gitoxin is well absorbed from this solution and serves as a basis for comparison.

(2) Tablets with a gitoxin content of 0.2 mg, active ingredient mixed with the other ingredients by simple grinding (lot 770608).

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(3) tablets with a gitoxin content of 0.2 mg in
Escin sodium salt, as described in Example 10 (77 K 07).

A group of five healthy people stood for the "experiments Available to people with a normal EKG who had the following biometric information:

Patient Age Weight Height Gender

F.B. 25th 58 163 9 S.B. 57 55 176 O* OH. 34 72 181 Cf M.L. 28 70 185 Cf CU. 34 69 174 Cf

With the exception of patient F.B., who took the tablets (2) administered, each patient received 1.5 mg gitoxin orally at four week intervals.

Table IX gives the blood plasma titoxin levels (in ng / ml) a number of other patients to the one in the table indicated time after oral administration of the drinkable solution (1).

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TABLE IX

TIME PATIENT PATIENT PATIENT PATIENT PATIEiJT

(h) BR BU. HA LO UR

0.25 63.9 47.3 82.5 2.9 69.7 0.5 73.8 64.9 76.3 27.7 64.0 1 71.7 56.8 80.3 76.6 65.9 1.5 67.7 58.8 65.2 67.7 65.4 2 64.8 54.1 60.6 50.9 47.8 2.5 72.8 54.7 59.4 49.7 72.2 3 65.8 49.7 52.7 43.6 49.0 4th 65.8 48.6 48.6 35.5 49.0 6th 54.8 40.9 49.4 37.3 38.3 12th 39.6 24.2 47.7 30.2 31.3 24 23.9 7.7 25.6 17.9 15.8 48 8.9 6.2 11.9 9.4 6.3 72 3.8 3.5 6.6 4.1 3.4 96 2.3 2.4 3.5 2.7 1.8

Table X relates to the blood plasmagitoxin levels thereof Patients after oral administration of 1.5 mg gitoxin in the tablet form not according to the invention (2).

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TABLE X

DURATION PATIENT PATIENT PATIENT PATISHT (H) BU. HA LO UR 0.25 4.3 i, 3 1.8 7.4 - 0.5 5.6 3.8 3.8 8.4 1 9.8 6.5 13.0 10.3 1.5 12.3 12.6 8.1 10.6 2 13.3 13.3 13.9 10.8 2.5 • 15.5 15.7 17.5 10.5 3 14.0 18.5 17.3 10.0 4th 12.0 22.5 16.8 10.2 6th 11.7 20.0 15.7 8.0 12th 9.4 24.2 17.1 9.3 24 7.4 14.2 9.6 8.2 48 6.5 10.7 10.6 4.1 12th 4.8 5.7 4.7 1.6 96 3.1 2.7 2.3 1.1
i

In Table XI, the data relate to the gitoxin blood plasma level after oral administration of 1.5 mg gitoxin in the tablet form containing a solid gitoxin-escin sodium salt solution (3).

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TABLE XI

Tables IX, X and XI clearly show that when the gitoxin is administered orally in a solid solution according to the invention, absorption takes place very quickly and that higher blood level values can be achieved than with the previously customary forms of use. As a rule, the gitoxin levels are relatively high for about 6 hours. In addition, administration of the present invention provides oral
Application forms an almost quantitative absorption of the gitoxin, and this in contrast to the earlier literature, according to which the orally administered gitoxin should not be absorbable.

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DURATION PATIESiT PATIENT PATIENT PATIENT PATIENT (H) BR BU HA LO UR 0.25 3.5 - 56.2 30.2 115.9 0.5 20.0 11.7 84.2 87.7 105.9 0.75 58.7 2S, 7 99.5 83.5 • 90.4 1 64.1 43.6 121.4 82.7 89.0 1.5 60, p 44.0 103.3 75.4 78.2 2 63.0 42.4 104.2 96.8 80.5 3 68.8 44.3 -91.6 79.3 78.2 j 4th 53.7 38.3 81.1 71.9 63.5 6th 61.9 25.2 75.6 61.2 48.6 9 44.0 22.9 64.3 48.4 43.9 12th 38.0 18.3 57.9 40.3 33.4 24 21.4 7.9 33.0 24.2 16.7 48 9.1 3.3 13.8 8.9 3.9 72 6.1 2.8 5.0 4.8 - 96 2.7 - 3.1 3.3

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The comparison of the data in the following Table XII, in which the degree of absorption of the under the
Gitoxins administered in various forms described above was calculated from the diagram surfaces limited by the blood plasma content, proves that with the tablets (2) not according to the invention the average absorption value is 55.9%, with those according to the invention
Administration forms (1) and (3), however, between 100 and 103.5%.

TABLE XII

patient Solution (1) Resorp-
ions
Degree(%) Tablets "(3) Resorp-
ions
Degree(%) Tablets (2) Resorp-
ions
Degree F.B. Upper '
area
(ng.T / ml) 100% Upper
area
(ng, T / ml) 97.16% Upper
area
(ng.T / mi; S.B. 72.41 100% 70.36 65.4% 62.50% OH. 46.86 100% 30.63 125.4% 29.32 57.31% M. L. 80.53 100% 100.99 131.9% 46 _S 18 64 ₈ 66% CU. 59.20 100% 78.14 97.8% 38.28 39.0% Average 54.76 100% 53.54 103.5% 21.37 55.86% 62.75 66.73 33.78

The data given in Table XIII relate to the course of the LVETI in relation to the time after administration of 1.5 mg gitoxin by oral intake of 7.5 tablets to 0.2 mg gitoxin in solid escin sodium salt solution and prove the positive inotropic effect of the active ingredient.

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TABLE XIII

after PATIENT
BR PATIENT
BU PATIENT
HA PATIENT
LO PATIENT
UR LVETI 0 h
(msec.) 418 383 398 414 405 ALVETI 2 h 27 7th 11 18th 9 ALVETI 6 h 27 18th 11 25th 17th ALVETI 9 h 39 16 12th 22nd 32 ALVETI 12 h 18th 14th 20th 16 12th ALVETI 24 h 0 5 6th 0 2

As stated above, this is gitoxin only grasps excreted via the urinary tract and represents consequently a particularly beneficial cardiotonicura for the treatment of heart problems in patients who also have renal insufficiency.

This fact has been confirmed by clinical trials with a group of 7 patients with impaired kidney function (but without heart problems) who were given intravenous injection Administration of 1.5 mg of gitoxin in a consisting of 5 ml of ethyl alcohol, 2 ml of glycerin and 3 ml of water Solution the half-life of gitoxin in the blood plasma was investigated with the help of creatinine excretion. the Results of these tests are given in Table XIV.

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TABLE XIV

patient i Business age weight Creatinine Blood plasma ^: FE real Show Half-life -. . YES manure duration (h) LA 9 48 65 5 33.0 (29.4-37.6) CR 49 67.8 23.5 33.5 (26.6-45.3) \ RU of 22nd 58.6 7.5 30.8 (29.1-32.6) DI of 48 69 6.5 29.5 (27.9-31.3) GO of 50 63 5 32.7 (29.6-36.7) σ 25th 70 15th 27.4 (24.7-30.6) of 68 66 15th 31.9 (2S, 6-36.0)

The fact that, even if the kidney function is inadequate, is only slightly influenced by administration of gitoxin, confirms that the active substance is for the most part excreted via other veggies .

The normal half-life of gitoxin in humans is given as 26 i 3.6 hours.

For purposes of comparison, the degree of binding to the blood plasma proteins was also determined in the case of those customary in therapy Concentrations for gitoxin (86 #), for digoxin (23%) and investigated for digitoxin (97? 0.

Table XV shows the values found.

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2605165

TABSLIE XV
Biological half life (in hours)

at normal at more pronounced

working kidneys renal failure

Digoxin 33-36 * 85 * Gitoxin 26th 31 Digitoxin 110-120 * 144-160 *

χ values taken from literature

This information shows that in the case of very severe kidney insufficiency, the half-life of digoxin is 2.5 times is longer than normal kidney function and the risk of iatrogenic poisoning by a bad chosen dosage is large. With Gitoxin, on the other hand, the half-life is only reduced in this case with one in the medical practice not taken into account multiplied by a factor of 1.2.

In addition, the gitoxin is excreted significantly faster than the digitoxin and the risk of an iatrogenic Poisoning through the accumulation of the active ingredient in the human body is practically impossible.

In the attached FIG. 13, the course of the daily breakdown (ordinate, in %) of gitoxin, digoxin and digitoxin in relation to the creatinine excretion (abscissa, in ml.min ") in renal insufficiency was shown graphically.

The results of the tests carried out by the applicant show that the gitoxin on the one hand the digoxin is superior because the effectiveness of Gitoxin is practically not influenced by renal insufficiency, and

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on the other hand also the digitoxin, because the relative rapid excretion of the gitoxin, there is a risk of the active substance accumulating in the human organism excludes.

Furthermore, in a liquid according to the invention or solid solution as opposed to orally administered gitoxin from previous work quickly and completely absorbed.

- Claims 809832/0946

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Claims (14)

Claims 1. Cardiotonic containing gitoxin as an active ingredient Composite, characterized in that the same the Active ingredient in the form of a liquid solution in an organic solvent or in the form of a solid solution in one Contains saponin, as well as other pharmaceutical auxiliaries and / or carriers. 2. Cardiotonic composition according to .Anspruch 1, thereby characterized in that the gitoxin is in the form of a solution in an optionally aqueous organic solvent is present. 3. Cardiotonic composition according to claim 2, characterized in that the organic solvent Ethyl alcohol, dimethylformamide, dimethylazetamide or N-methyl-2-pyrrolidone is used. 4. Cardiotonic composition according to any one of the claims 2 and 3, characterized in that the amount by weight of water is less than the amount by weight of organic Solvent. 5. Cardiotonic composition according to any one of claims 2 to 4, characterized in that the same further a liquid glycol in monomeric or polymeric form contains it. 6. Cardiotonic composition according to claim 5, characterized characterized in that the additional glycol is glycerine. 7- cardiotonic composition according to claim 5, characterized characterized in that the additional glycol is a liquid 809832/094 $ ORIGINAL INSPECTED - 31 - Polyethylene Glyko1 is. 8. Cardiotonic composition according to claim 1, characterized in that the gitoxin as a solid solution in one Saponin, among others in digitonin, escin, escinnatriun salt, etc., is present. 9 · Cardiotonic composition according to claim 8, characterized characterized in that the gitoxin-saponin weight ratios are between 1: 3 and 1: 100. 10. Cardiotonic composition according to claim 9, characterized in that the weight ratios gitoxin-saponin between 1: 4 and 1:10. 11. Method of making a cardiotonic, gitoxin in the form of a solid solution in a composition containing saponin, characterized in that the in an organic solvent or gitoxin dissolved in a mixture of organic solvents to form a solution of a saponin in the same or a different solvent or solvent mixture is added to this mixture is evaporated to dryness by separating the solvent or the solvent mixture and that by Mixed precipitation product obtained dried and then the desired pharmaceutical auxiliaries and / or Carriers is added. 12. The method according to claim 11, characterized in that the saponin is digitonin, escin or escin sodium salt is used. 13. The method according to any one of claims 11 and 12, characterized - 32 -609832/0946 characterized in that the organic solvent is methyl alcohol, ethyl alcohol, chloroform and / or dichloromethane is used. 14. Cardiotonic composition prepared according to the method according to any one of claims 11 to 13. 809832/0946