DE3433678A1 - DOBUTAMINE CONTAINING PREPARATION FOR ORAL APPLICATION - Google Patents

Description

"Preparation containing dobutamine for oral administration"

The invention relates to new preparations of dobutamine, i.e. (4- [2- [[3- (p-hydroxyphenyl) -1-methylpropyl] amino] ethyl] catechol, or its acid addition salts for oral administration.

Epinephrine, norepinephrine, isoproterenol, dopamine and dobutamine belong to the group of cetecholamines and are selected according to the nature of their mode of action. These drugs play an important role in increasing the myocardial contractile force in heart failure. Among the above However, epinephrine and norepinephrine are not used in the treatment of heart failure. Epinephrine should not be used in the treatment of heart failure despite its strong cardiac effects. because it simultaneously increases myocardial oxygen consumption and thus the myocardial workload, without any improvements bring about. Also isoproterenol, which is also available as a preparation under the trademarks Protanol ^ - ^ and Sooner * ^ positive-inotropic effect is allowed in the treatment of heart failure caused by recent myocardial infarction cannot be used because it is simultaneous sharply accelerates the sinus rhythm; see Mashino et al., Rinshoyakuri & Yakubutsuryohogaku /

30 Clinical Pharmacology & Pharmacotherapy (1980), 298.

For the reasons mentioned above, more recently norepinephrine, dopamine or dobutamine have been used to improve the Force of contraction used in heart failure. However, one was of the opinion that these active ingredients show no effect when administered orally. The reasons for this false assumption are the following:

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■ · - - ⁴ - ^ 3A33678 ^Π

First was when studying the metabolism of ■ epinephrine and norepinephrine found both compounds to contribute , _- "" Oral application show no effect because they are in the digestive organs and - the liver is inactivated (Ito, Yakuri-gaku (Pharmacology) (1976), 225). Second, it was believed that oral administration of both dopamine and even dobutamine could not have any effect because it by the same mechanism as the known catecholamines and, moreover, with a short half-life (both ^ for example within 5 minutes in the case of intravenous infusion).

Surprisingly, there was now a positive inotropic effect of dobutamine found after oral administration. 15th

The invention thus relates to that characterized in the claims Object.

When dobutamine or its salts with acids are administered orally to adult patients in a single dose of 50 mg or more, preferably from 100 mg or more and especially within a range from about 200 to about 400 mg The preparations according to the invention show the same thing as dobutamine

positive inotropic efficiency like the injection preparations. 25th

Figure 1 shows a curve of the dobutamine plasma level and a Curve of changes in cardiac index after oral administration of dobutamine hydrochloride, where the ordinate is the plasma level of the

Dobutamine (ng / ml) or the changes in cardiac index

(1 / min / m ² ), and the abscissa show the time in hours after the pursuit; the solid curve shows the DBX plasma level, the dashed line shows the changes in the heart index.

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Figures 2, 3 and 4 show the dissolution rate in the first and second liquids (defined in the Japanese Pharmacopoeia, 10th edition) examined using the corresponding preparations as described in Examples 1, 2 and 3 ben are; where the ordinate indicates the rate of dissolution in percent and the abscissa the time in minutes; the The solid curve and the dashed line show the resolution properties in the first and second liquid, respectively.

Dobutamine hydrochloride was recently developed as an agent analogous to dopamine and used as an infusion preparation. ^ ~ _ ~ ^ ~~~ -. ". ^ ... w-. "W" "w- put on the market. It

with strong positive inotropic effectiveness calls a special slight peripheral vasoconstriction and shows in comparison lower side effects with other catecholamines, such as acceleration of the heart rate, arrhythmia, Arrhythmogenesis and related side reactions. Accordingly, it is a very good positive inotropic agent.

In the early stages of the animal screening tests, it was confirmed that the half-life of free dobutamine (hereinafter referred to as DBX) is very short when administered intravenously - namely only 1 to 2 minutes and so the effect is lost in a short time. For this reason, the application was limited to an intravenous drip infusion. In addition comes that the DBX level in the plasma when administered orally to test animals! could hardly be increased; it became the It was concluded that oral administration of dobutamine was ineffective.

It has now been found that even with oral administration, DBX reaches a sufficiently high level in the plasma because the rate of metabolism is much slower at high doses, this result is surprising.

The present invention has been made based on these findings.

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Recently, acute myocardial infarction in Japan is showing one upward trend; however, the aforementioned potent agents have made a remarkable advance in the successful acute treatment of this disease and resulted in successful rehabilitation of the patient.

The reintegration into society as it is on Attempts in various ways have recently become a major problem; rehabilitation and exercise therapy for patients with myocardial infarction are generally accepted procedures in medicine. As from the under- ' Research by Nobutaka Doba in Clinica, Vol. 10 (6) (1983), 496, results in the forced rest regimens the follow-up treatment after the acute stage many disadvantages, so that an early termination of the rest cure and a possible early start of rehabilitation was identified as necessary.

According to the most recent therapeutic methods, a catecholamine, such as dobutamine, is continued even after the acute one is complete Administered at the stage in order to avoid complications until the patient relapses his fear of relapse loses. Due to the shortness of its duration of action, it is necessary to take the catecholamine continuously through an intravenous route To be administered as a continuous drip infusion. It follows that the patient is forced to recline for a long period of time is; he is unable to get out of bed and start rehabilitation at an early stage.

The preparations according to the invention enable the patient to take the dobutamine orally and thus to get out of it at an early stage Bed to come; these clinical benefits are very valuable to the patient, who will assist them earlier with rehabilitation can start and leave the hospital. Since the invention Preparations for the patient also on an outpatient basis, i.e. 35

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outside of the hospital, they are a very useful tool in outpatient treatment of patients with otherwise treatment-refractory or chronic myocardial infarction or with bradycardia

5 infarct as well as infarct prophylaxis.

As mentioned above, the preparations of the invention have been developed for hospitalizing myocardial infarction patients leave and return to their environment and patients with refractory myocardial infarction outside of the Hospital can be treated.

It has been shown that the dobutamine is released by the action of the Catechol-O-methy! Transferase (hereinafter referred to as COMT) converted into 3-0-methyl-dobutamine (hereinafter referred to as MDBX), that coupled with glucuronic acid and excreted as the conjugate 3-0-methyl-dobutamine (hereinafter referred to as CMDBX) will. It is recognized that CMDBX. Is in fact ineffective since its clinical effect is about 1/10 or less compared to free dobutamine.

In consideration of the above findings, the inventors have now searched for the absorption site of the dobutamine (see Experiment 1) and came to the conclusion that dobutamine mainly is absorbed in the small intestine, slightly in the large intestine, but hardly in the stomach.

The "_Dobutamine hydrochloride was taken in powder form on rats administered in such a way that the dosage varied and the rats in some groups without before administration Food remained in others were fed in order to clarify how the DBX plasma level depends on the conditions of the application is influenced (experiment 2). As it turned out surprisingly

the active ingredient does not give the expected plasma level for DBX according to the dosage and it could be for the invention

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Should preparations be necessary, the active ingredient in high concentrations to be released in the small intestine as the main absorption site. As mentioned at the beginning, it was to be expected that the plasma level of DBX reached a relatively high level because the dobutamine is at the main absorption site in such a high amount was absorbed that the metabolic route was saturated.

On the basis of the above conclusions and results of the experiments serving as a basis, such as the experiment on acute Toxicity, clinical trials have been conducted on catecholamine-dependent Patients undertook apparently the inventive Require preparation (experiment 3). The clinical trials confirm that the preparation contains the plasma a sufficient DBX level supplied, with the oral ^ - '"single dose to achieve the desired clinical effect, such as improving the heart index and decreasing the filling pressure of the left ventricle (pulmonary capillary pressure; Wedge pressure) with a single oral dose of 200 to 300 mg.

It goes without saying "that the amount to be administered Single dose and the daily dose of dobutamine should be carefully determined depending on the patient's condition must, since the single dose also depends on age, body weight, nutritional situation, the state of liver function, etc. Generally, the dobutamine preparation is administered orally in a dose of at least about 50 mg, preferably at least about 100 mg, especially from about 200 mg to about 400 mg

30 dobutamine applied one to five times a day.

The preparations of the invention are used for myocardial enhancement Contraction force used, for example in patients in the rehabilitation phase after myocardial infarction, as well as for the treatment or prophylaxis of a chronic

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see heart failure and related ailments. The preparations are suitable for patients who have to discontinue intravenous infusion of catecholamines, especially dobutamine, Causes difficulties; They are suitable for patients with chronic heart failure who are not up Cardiotonics such as digitalis or diuretics respond; they are also suitable for patients with bradycardiac heart failure.

As stated above, it is necessary that the patients after surviving the acute phase of a myocardial infectious disease Begin rehabilitation without delay and get out of bed as early as possible. The preparations according to the invention make this possible and the patients can leave their bed under stable conditions early and into their familiar surroundings to return. Since the patients can supply themselves with the drug outside of the hospital, they will be able to continue treatment during their normal life, especially when treating refractory or chronic heart failure or in their prophylaxis. The result is both psychological how the physical suffering of the patient formerly due to long bed rest is reduced and his economic suffering Load reduced.

Another advantage is that the preparations of the invention enable emergency admissions and early treatment of new patients in the hospitals through the beds that become available.
30th

The preparations of the invention can also be administered through a nasogastric tube to patients who are difficult to inject and in emergencies if the clinic does not have any free beds available for inpatients. Furthermore this form of administration does not cause adverse reactions as would otherwise occur at the site of an injection, such as an injury or pain on the inner wall of the vein.

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The preparations of the invention are generally in the form of powders, fine granules, granules or tablets, or in the form of easily soluble push-fit capsules are used. If necessary, they can be used in any dosing unit, for example in soft capsules as suspensions in oils or fats or as liquid preparations such as syrups, emulsions and Suspensions, as long as their shelf life under the usual preservation conditions is guaranteed.

In accordance with the invention, the dobutamine is generally in the form its acid addition salts are used. In the case of using dobutamine hydrochloride, this can be in the form of a powder the connection . or, if desired, in the form of a powder mixed with suitable additives, or used as granules , which is made from the powder in the usual way, or as easily soluble push-fit capsules with the powder or granules are filled.

Examples of suitable additives are sugars, such as lactose, cane sugar, glucose, D-mannitol, sorbitol, inositol and xylose, Starches such as wheat starch, corn starch and dextrin and crystalline cellulose. These additives can be the active ingredient added alone or in a mixture in pharmaceutically suitable amounts and processed into medicinal products. If necessary, a lubricant such as magnesium stearate, talc or Carplex ^ = can also be added.

When making up the acid addition salts of dobutamine, in particular of dobutamine hydrochloride, must not

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disregard the fact that this turns slightly brown under the action of water; it is therefore advisable to to carry out the packaging by dry granulation, pressing or similar packaging methods.

The addition of carrier materials is preferred for packaging, for example sugar, such as lactose, cane sugar,

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Glucose, D-mannitol, sorbitol, inositol and xylose, starches such as wheat starch, corn starch and dextrin and crystalline cellulose, disintegrants, _w h _e carboxymethyl cellulose potassium (CMC-Ca), and sodium starch (CMS-Na), lubricating agents such as Magnesium stearate, potassium stearate and talc and binders such as methyl cellulose (MC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), potato starch and gelatin; All of the above additives are found in the appropriate amount for the production of fine granules, granulates, tablets, etc.

10 turn.

The following experiments and examples illustrate the invention.

¹⁵ ~ attempt 1

To the place of absorption of dobutamine in the gastrointestinal tract found in rats, SD strain male rats weighing 200 to 250 g were grouped from 3 to 4 rats anesthetized with urethane. . Both ends of the The stomach, small intestine, or large intestine were in the appropriate Groups tied, these previously with an isotonic solution of dobutamine hydrochloride (5 mg / ml dobutamine hydrochloride) was added in doses of 40 mg / kg

²⁵ ren.

. The values given in the tables below are Average values of three to four rats examined.

Method of quantitative analysis:

a) DBX remaining in the gastrointestinal tract:

The digestive organs of the rats are removed and DBX out

extracted them twice with 20 ml of methanol. The extract is diluted accordingly with methanol and the DBX with the help of the

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High pressure liquid chromatography (HPLC) analyzed quantitatively. The conditions of the applied HPLC are below specified.

5 column: Nucleosil -] o ^C 18 * ^{4 mm X 30} °

(Chemco Co., Ltd.)
Mobile phase: Methanol ": PICV ^ B ₇ (Waters Associates)

= 50:. 50

Flow rate: 1.3 ml / min 10

The compound to be examined was determined at 278 nm with an ultraviolet absorption detector.

b) DBX and MDBX plasma levels

DBX concentrations were determined as follows: A mixture of approximately 30 mg of activated clay and a sample (1 ml) of the plasma is added 5 ml of purified water and the mixture is separated by centrifugation. The protruding Solution is removed. The clay is washed with an additional 5 ml of purified water and three times with 1 ml of a mixture eluted by methanol and acetic acid in a ratio of 11: 3, with DBX being obtained as the eluate. The eluate will evaporated and the residue dissolved in 200 µl of the mobile phase for high pressure liquid chromatography and subjected to HPLC.

The MDBX concentration is determined as follows:

A 1 ml sample of the plasma is adsorbed on a filled SEP-PAK C _{1 o} (Waters Associates) column, the column was washed twice with 5 ml of purified water and eluted with 5 ml of methanol; the methanol is removed by evaporation. The residue is measured in the same manner as described above. The high pressure liquid chromatography was

³⁵ de carried out under the following conditions:

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1 column: Nucleosil -iqC, .., (4 now x 300 mm) Mobile phase: tetrahydrofuran - acetonitrile:

0.1 M potassium dihydrogen phosphate buffer

(pH 3.0) EDTA 250 mg / 1) = 5 2: 14.5: 83.5

Flow rate: 1_ ^ 5 ml / min.

The active fraction is determined in a voltmeter (loaded with 800 mV).

c) CMDBX plasma level:

0.3 ml of concentrated hydrochloric acid are added to 0.5 ml of the plasma and the mixture is left to stand for hydrolysis ^{at 100 ° C. for 2 hours.} The mixture is then brought to a pH value of 10 by adding 0.5 ml 6 η sodium hydroxide solution and then mixed with 2 ml 1 M borate buffer solution (pH 10.0). 6 ml of dichloromethane are added to the mixture and the mixture is shaken for 15 minutes to extract the active ingredient into the dichloromethane layer. After separating in the centrifuge, 5 ml of the organic layer are removed and evaporated; the residue is dissolved in 200 μl of the mobile phase as indicated below and subjected to high pressure liquid chromatography. conditions

25 of the HPLC:

Column: Nucleosol -i ₀ ^c ₁₈

Mobile phase: tetrahydrofuran: PIC B. = 11:89

Flow rate: 1.5 ml / min. 30th

The eluate was in an ultraviolet absorption detector examined at 278 ran.

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1 results:

Table I.

Remaining DobutanurrW "in the respective area 30 minutes later of administration and plasma level (ng / ml)

Leftovers (%) Plasma mirror MDBX (ng / ml) ßereicn Dobutamine
at the respective
area DBX 14.1 CMDBX stomach 86.7 25.2 412.2 119 Slim
colon 43.7 3113.9 278.3 2349 Thick
colon 61.7 1531.6 1007

The values summarized in Table I confirm that Dobutamine is absorbed best in the small intestine, well in the large intestine, but insufficiently in the stomach.

Attempt 2

Determination of DBX, MDBX or CMDBX plasma levels different dosages.

In this experiment, dobutamine hydrochloride was in powder form administered to rats as described below.

Determination method and results:

About 30 mg of talc are poured into a polyethylene tube in such a way that a 1 mm thick layer is at its end is obtained, on which the powdery dobutamine hydrochloride is

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will give. The hose end is connected to the upper end of a gastric tube and the drug with 0.5 ml of purified water to egg NEN Ve rsuchsort spent in the gastrointestinal tract.

1) Dobutamine hydrochloride was given orally to fasted rats

administered in a dosage of 8 mg / kg and the plasma levels determined in the manner described in experiment 1b) or c); the results are summarized in Table II.

Table II

Time after
application Plasma game MDBX (ng / ml) istdf.) DBX 23.3 CMDBX 0.25 ND ¹ ) 12.3 897 0.50 N.D. 10.3 1178 1.00 N.D. 0.7 1010 3.00 N.D. 381

1) N.D .: The presence of active ingredient could indeed can be detected, but not quantitatively due to the extremely low level.

2) Dubutamine hydrochloride is used in rats without a fasting period administered at a dose of 60 mg / kg; the plasma levels are determined in the same way as mentioned under 1); the results are summarized in Table III.

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- 16 Table III

10

Time after Plasma mirror MDBX (ng / ml) the application
(Hours.) DBX 107.7
37.4
11.9
13.2 0.25
0.50
1.00
3.00 154.0
70.4
13.2
5.8 CMDBX 1536
1835
2466
2112

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3) Dobutamine hydrochloride is administered to fasted rats

administered at a dosage of 60 mg / kg; the plasma mirror are determined in the manner mentioned under 1) above; the results are summarized in Table IV.

Table IV

25 30 35

Time after
application Plasma level (ng / ml) MDBX CMDBX (Hours.) DBX 78.1 798 0.25 234.4 138.1 .2130 0.50 152.2 148.1 1931 1.00 216.9 23.9 1547 3.00 34.1

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" ¹⁷ ~""~ 343367a

1 results

The values given in Tables III and IV confirm that that the DBX plasma levels of rats ^ which had been fed are unexpectedly lower than at the same dose the values in fasted rats. This leaves the To the conclusion that in this case the dobutamine was diluted with the meal and slowly moved to the main area of absorption the small intestine, at a low concentration for a long period of time. On the other hand, provided Dobutamine is an orally administrable agent that, depending on its dosage, influences the plasma level the DBX plasma levels in Table ΪΙ correspond approximately proportionally to the values in Table IV; the values in the table

15 Ie, however, speak against this assumption.

The results of the experiments lead to the conclusion that the preparations of the invention only produce desirable DBX plasma levels when the active ingredient is in the range of the main Absorption, namely the small intestine, has arrived in relatively high concentrations.

Attempt 3

Dobutamine capsules for oral administration were produced as described in Example 1, containing 100 mg of the active ingredient Contained dobutamine per capsule, and administered to nine heart failure patients.

5 men and 4 women aged 19 to 78 years with a body surface area of 1.34 to 1.75 m ² took part in the experiment, four of whom suffered from congestive heart failure and five from myocardial infarction. The severity of the disease state was determined according to the classification according to NYHA (New York Heart Association) (K. Nanba et al, Junkanki-byo no chiryokeikaku, Guide for Treatment of Cardiovascular Disease, 84 (1969)).

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■ " ¹⁸ " ..- 343367a The capsules containing dobutamine described above were orally administered to each fasted patient in single doses of 2 to 3 capsules (200 to 300 mg of dobutamine). The effects were hemodynamically too fixed

5 times determined.

Result ".-

The effects after taking dobutamine are shown as average values in Table V below, as they each obtained from nine patients.

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Table V

Time after Before 0.5 1.0 2.0 3.0 79.6 4.0 .7 Application (hours) 2.08 2.37 2.56 2.63 2.35 2.39 Heart index ± 0.08 ± 0.25 ± 0.22 ± 0.21 ± 0.12 5.3 ± 0.11 1 / min / m ¹ 82.3 80.7 86.2 81.4 18.0 81 19.1 middle Blood pressure ± 4.8 ± 7.0 ± 4.4 ± 4.5 + ± 1.6 mmHg 20.1 17.5 17.3 17.4 ± 2.1 17.6 diastolic 15.8 Pulmonary artery ± 1.4 t 2.1 ± 2.2 ± 2.0 ± 1.5 pressure
mmHq 19.4 17.6 16.2 17.3 ± 1.9 7.4 pulmonary capillary 6.8 pressure ± 1.1 ± 1.8 ± 2.1 ± 1.9 ± 1.3 mmHg 7.8 6.9 6.1 6.5 ± 1.3 83.3 Pressure in the right 88.1 ± 8.5 Forecourt ± 1.1 ± L.2 ± 1.2 ± 1.3 ± 7.3 mmHg 77.0 85.1 86.9 88.1 Heart rate ± 5.4 ± 7.2 ± 5.0 ± 5.7 r

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Ί The DBX plasma level that was given in six patients Time could be determined are in the following

_'.- summarized in Table VI. The procedures and conditions for the determination of the plasma level takes place according to the method described in experiment 1-b).

10 15 20 25

Table VI

DBX plasma mirror

Time after
application
(Hours) 3 0.5 1.0 2.0 3.0 4th 5.4 262.2 * 44.2 '4.5! 5 0 80.2 5.7 2.0 Patient 6th 34.1 44.0 15.3 1.7 7th 9.6 3.9 0 0 9 3.7. 34.0 5.6 3.3 Average
value 29.6 97.4 2.4 8.1 ' 13.7 ± 5.9 87.0 ± 37.6 12.2 ± 6.7 3.3 = 1.1
i

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When dobutamine was administered orally at a dose of 200 to 300 mg, the mean value for the heart index increased after 1 hour and 2 hours by 0.48 l / min. / M ² and 0.55 l / min. / m ² : The increase at the time of maximum effect (2 hours after application) was 26.4%. As for the other hemodynamic effects, the average increase in heart rate was 14.7%, the

mean decrease in left ventricular filling pressure at 18.7%, while there was practically no change in the mean blood pressure

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25 30 35

were observed. Table VII below gives an overview of the clinical efficacy in each patient The numbers given relate to those given in the other tables of the experiments.

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Table VII

•Patient Ge * 2
bad age Body upper
area (mM illness Degree at
NYHA. Dose of
Dobutamine, clinical;
VJeffectiveness Adjoining
kungen. J * 3 •1
1 M. 19th 1.67 Heart failure IV 250 mg Well.- 2 W. 70 1.34 III · -IV 200 mg ■
I. ■ "ι 3 M. 50 1.60 » in· ί
300 mg » 4th W. 55 1.45 111 ° -IV 200 mg 5 W. 75 1.43 ·· IV 200 mg I.
Λ "'
A! 6th M. 67 1.63 ·· 111 ° 200 mg 7th W. 78 1.63 : iv 200 mg 8th M. 75 1.56 » IV 300 mg » 9 M. 66 1.75 . IV 200 mg »

* 1 dobutamine was given to patient 1 at a dose of 3 capsules, each of which was 50 mg of dobutamine

contained.

* 2 M: male, W: female
* 3 palpitations 2-3 hours after ingestion

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1. Results

FIG. 1 shows the DBX plasma level and the time-dependent changes in the heart index. In this figure, the solid line shows the DBX plasma level. (ng / ml) and the dashed line the increase in the heart index (l / min / m ² ). In this context, the increase in the heart index means the difference between the values before and after the application shown in Table V.
10

The plasma levels are shown as average values of six patients and the changes in the heart index as the mean values of "9 patients. As can be seen from the figure, dobutamine showed suitable DBX plasma values for oral applications

-15 tion, which were accompanied by a marked increase in Heart index within 3 hours. In particular, 2 hours after application - at the maximum effects were observed the desired hemodynamic effects were observed; i.e. the cardiac index increased by 26.4% and the left ventricular index Filling pressure decreased by 18.7%. These results indicate that the preparations of the invention show satisfactory clinical effects.

Example 1 25

Capsules

7.847 g of dobutamine hydrochloride and 7.00 g of D-mannitol will be thoroughly mixed and filled into push-fit capsules No. 1 (70 capsules in total).

The preparation contains 112.1 mg of dobutamine hydrochloride, accordingly 100 mg dobutamine per capsule and showed in the dissolution test with the first liquid (described in Japanese Pharmacopoeia 10th Edition - hereinafter referred to as JPX -) the

35 desired solution property (see Figure 2).

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The dissolution test was carried out according to the second method (shovel method) at 100 r.p.m. with the same device

^ leads. 900 ml of the first or second liquid, as defined in the dissolution test by JPX, were used as the test medium. This method was used for all of the dissolution tests in the following examples.

Example 2

10 tablets

A mixture of 2 g of dobutamine hydrochloride, 0.4 g of CMC-Ca and 0.02 g of magnesium stearate were compressed into tablets (121 mg per tablet) (diameter 7 mm) in a tablet machine (Kikusui Press No. 4: Kikusui Seisaku-sho Ltd.).

'The preparation contains 100 mg of dobutamine per tablet and showed the desired dissolution property (see Figure 3) both in the first as well as in the second liquid of the dissolution test.

Example 3

granules

A mixture of 2 g of dobutamine hydrochloride and 0.4 g of CMC-Ca is mixed with 1.3 g of 10 percent HPC-SL and then ground in a mortar. The mixture worked through was granulated by passing it through a sieve with a diameter of 1.2 mm under pressure and ^{drying it with aeration at 60 °} C. within 3 hours in a drying cabinet.

The granules are passed through a 1.4 mm and then 0.84 mm sieve to remove dust. There are 2 g of granules obtained in a particle size of 1.4 to 0.84 mm.

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1 The granules contain 0.79 g dobutamine hydrochloride / g

and shows sufficient dissolution properties in both the first and the second liquid in the dissolution test (see Figure ~ 4ή ~.

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Claims (7)

VOSSIUS. VOSSIUS. TAUCHTET * '■ H EHEMANN -RAUH PATENTANWALTS- SIEBERTSTRASSE 4.6OOO MUNICH 86 ■ PHONE: (O89) 47 4O76 CABLE: BENZOLPATENT MÖNCHEN -TELEX 5-29453 VOPAT D and 2nd: T 252 13 Sep. 1984 Case: F 4861-TS SHIONOGI & CO., LTD. Osaka, Japan 10 11 Preparation for oral administration containing dobutamine "Patent claims 15 1. Preparations containing dobutamine or its salts with acids with positive inotropic effect for oral application. 2. Preparation according to claim 1, containing as active ingredient substance a unit dose of at least 50 mg of dobutamine. 3. Preparation according to claim 1, containing as active ingredient Dojbutamine hydrochloride .. 4. Preparation according to claim 1 to 3 in the administration form of powders, fine granules, granules, tablets, Capsules or liquid preparations. 5. Use of the preparations according to claim 1 to 4 for loading treatment of heart failure. 6. Use according to claim 5, wherein the therapeutic Amount of the dobutamine about 1 mg / kg to about 10 mg / kg per Gift is. 35 7. Use according to claim 5, wherein the therapeutic amount of the dobutamine is about 50 mg to about 400 mg per Administration in an adult patient. 10 20 25 30 35 L ^': j