NL8602370A - PHARMACEUTICAL PREPARATIONS WITH REGULAR DELIVERY OF THE ACTIVE MATERIAL. - Google Patents

Description

f '. - v -¾

Reg. No. 125.698 Schut / CN - 1 -

Pharmaceutical preparations with a controlled release of the active material.

This invention relates to controlled-release pharmaceutical preparations of active materials that affect blood circulation, including the heart, and are selected from the group of Pindolol and a 5- (2,1,3-benzoxadiazol-4-yl) - 1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarhoxylate ester, in particular Darodipine and Isradipine.

Darodipine is the common name of diethy1-4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-3,5-oyridine diethyl acrylate. This compound is described in British Patent GB 2.Q37766 B. For pharmaceutical use, Darodipine is used as the free base.

The pharmacological and clinical properties have been thoroughly investigated. Darodipine is a powerful calcium antagonist on isolated coronary arteries and other periphere blood vessels. Hemodynamic investigations on sin. Adults show a decrease in total periphere resistance and arterial blood pressure.

Darodipine is indicated for the treatment of angina, hypertension, cerebral haemorrhage and cerebral vaso spasms.

For example, conventional oral daily doses have been administered for the treatment of angina pectoris 75-300 mg, preferably in separated doses, and for the treatment of hypertension, 37.5-150 mg-v administered in 2 or 3 separate doses.

Pindolol is the common name for 1- (ltt-indol-4-yloxy) ~ 3- / 1-methyl-ethyl-amino-7-2-propano-1 and is described in British Patent No. 1,138,969.

For pharmaceutical use, Pindolol is preferably used in the form of the free base. The pharmacological and clinical properties have been extensively investigated.

Pindolol is an 8-adreno cep to rantagonis t (g-blocker).

863237 $ $ _ £ - 2 -

The compound works both: on Bj and ^ renoceptors. It protects the heart against excessive stimulation by catecholamines during physical and mental stress and also at rest; however, its intrinsic sympathomimetric action (ISA) 5 provides the heart with a basal stimulation similar to that induced by sympathomimetric action through normal rest. The heart rate and the contraction capacity at rest. and the intracardiac conduction is thus not very suppressed. As a result, the risk of bradycardia or heart blockage is low, and non-increased cardiac output is not decreased. The high vascular resistance of an established hypertensi® is lowered by Eihdölol'enr aidüs nd does not damage the tissue and organ perfusion.

Pindolol is; indicated for the treatment of, inter alia: - arterial hypertension, - angina pectoris (dyeing attack) - sinus and arthral tachycardia, paroxymal tachycardia, tachycardia in patients with arterial flutter or fibrillation.

20 supraventricular and ventricular extrasystoles, drug-induced extrasystoles (digitalis) and hyperkinetic cardiac syndrome and is normally administered orally.

The oral dosage is adapted to the needs of the individual patient and is usually between 10 and 30 mg per day.

For arterial hypertension, 5-15 mg are given as a single daily dose in the morning. It is also possible to divide 2Q - 30 mg into 2 or 3 doses per day.

3Q For angina and cardiac arrhythmias, the daily dose of IQ - 3Q mg is generally divided into 2 or 3 single doses.

For hyperkinetic heart syndrome, the dose is 10-20 mg, usually once a day, preferably in a delayed-release form.

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Israpidine is the common name of isopropylmethyl-4- (2,1,3-benzoxadiazo-4-yl) -1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarhoxylate. This hindrance is generally administered as a free base and is described in British Patent 5 2,037,766 B.

The pharmacological and clinical properties of israpidine have been extensively investigated. The compound is a potent calcium channel blocker, particularly affecting the coronary and peripheral veins. The drug is in particular indicated for the treatment of, for example, hypertension, angina pectoris and cerebral insufficiency. Usual oral, daily doses are between 10 and 20 mg, preferably divided into smaller doses of 5 to 10 mg administered twice a day.

The administration of the aforementioned active materials can sometimes be accompanied by adverse side effects, for example headaches in the case of Darodipine, fatigue, dizziness, gastrointestinal disturbances (usually vomiting), headache, sleep disturbances (eg exciting dreams), if 2Q Pindolol and headache, blood flow to the brain, palpitations and tachyeardia when Isradipine is administered.

It has now been found that it is preferable to maintain the concentration of the active material between narrow limits at a therapeutically active level, and the usual drug explosion that after the immediate administration of preparations from which the active material becomes at an uncontrolled rate - fatty, which leads to temporarily high blood levels and to relatively powerful adverse effects.

3Q Therapy can be improved by administering smaller doses two or three times a day, the sum of these doses being equal to the total daily dose. However, this method is cumbersome and does not meet the requirement to provide blood levels of the active material within only narrow limits. The present invention provides a composition of controlled release and prolonged-action active materials of 8602370-4 * 1 * to reduce the number of times the active material has to be administered each day and certain reduce adverse reactions.

In addition, the present compositions provide excellent bioavailability in food interaction studies under test conditions, as described, for example, in Examples 3 and 18 below.

The present invention consequently provides a controlled release IQ preparation for oral administration that contains an active material selected from the group of Pindolol and a 4- (2,1,3-henzoxadiazol-4-yl) -1,4-dihydro- 2,6-dimethyl-3,5-pyridinedicarboxylate ester, - a pharmaceutically acceptable, hydrophilic swellable material, and optionally - a pharmaceutically acceptable, inert, fatty material.

Another aspect of the present invention provides a controlled release oral formulation containing 2% Pindolol and a relative bioavailability of more than 85% relative to an oral Pindolol non-controlled release formulation when administered to a person who is fasted has-has ...

Yet another aspect of the present invention provides a controlled-release formulation oral administration containing Isradipine and a relative availability of greater than 65% relative to a non-controlled release oral Isradipine formulation when administered to a subject which has fasted, In another aspect of the present invention there is provided a controlled release formulation for oral administration, which preparation comprises an active material selected from the group of Pindolol and a 4- (2,1,3-benzoxadiazole) -4-yl) -1,4-dihydro-2,6,6-dimethyl-3,5-pyridinedicarhoxylates, with bioavailability differences when administered to a person who has fasted 8802370-5 - * * and to a person who has not fasted up to 20

Recommended amounts of Darodipine in unit dosage form are between 10 and 200 mg, especially between 2 and 150 mg, for example 100 mg.

Recommended amounts of Pindolol in unit dosage form are between 10 and 20 mg, especially between 15 and 20 mg. Preferably Pindolol is in the base form, but an acid addition salt is also possible.

Recommended amounts of Isradipine in unit dosage form are between 5 and 40 mg, especially between 10 and 200 mg.

A recommended swellable material is a cellulose compound, which turns into a colloid in water.

Preferred hydrophilic, swelling-up materials include one or a number of natural, partial or totally synthetic, anionic or, preferably, nonionic, hydrophilic gums »modified cellulosic or proteinaceous materials such as, for example, acacia, gum tragacanth, guar gum , karaya gum, agar, peptin, carrageenan, soluble and insoluble alginates, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxypolymethylene, gelatin.

Recommendation is made of cellulose hydocolloids, which include methyl cellulose, hydroxypropyl cellulose and in particular hydroxypropyl methyl cellulose and sodium carboxymethyl cellulose.

Preferably, the weight ratio of Darodipine to the swelling material is between 1: 0.2 to 1: 2, especially from 1: 0.5 to 1, of Pindolol to swellable material from 1: 5 to J: 2Q, in especially from 1: 8 to 1:15 and from Isradipine to the swelling material from 1: 2 to 1:20, especially from 1: 4 to 1:10.

Suitable pharmaceutically acceptable inert fatty materials include beeswax, fatty acids, higher alcohols with a βδ-12370 + * - 6 - long chain, such as, for example, cetyl alcohol, myristyl alcohol, stearyl alcohol, esters, for example glycerides, such as glyceryl esters of fatty acids or hydrogenated aliphatic acids, such as, for example, glyceryl monostearate, glyceryl distearate, glyceryl esters of hydrogenated castor oil, etc., oils such as mineral oil, etc. The fatty materials preferably have a melting point between 30 and 90 ° C.

It is especially recommended that the fatty materials have a melting point between 45 and 65 ° C, including glycerides such as glyceryl palmitates and stearates and fatty acids such as hydrogenated castor oil and fatty acid esters such as cetyl palmitate.

Preferably, the weight ratio of Darodipine to the fatty material is between 10: 10.2 to 10: 5, especially J5 between 10: 0.5 to 10: 1, of Pindolol to the fatty material between 1: 0.1 to 1: 3, in particular 1: 0.1 and 1: 2, in particular 1: 0., 25 to 1: 1.4 and from Isradipine to the fatty material between 1: 0.3 to 1: 2, in particular 1: 0.5 to 1: 1.5, in particular from 1: 0.5 to 1: 1.

2Q The compositions preferably contain hydroxypropylmethylcellulose as a swelling hair material such as cetyl palmitate as the fatty material.

It is also suitable to include in the composition at least one soluble or insoluble pharmaceutical excipient, such as calcium sulfate, calcium phosphate, lactose, mannitol, sucrose, sorbitol, colloidal silicon dioxide and magnesium stearate. A soluble excipient, in particular lactose, is preferably present.

If these other excipients are present, a 3Q weight ratio of Darodipine to the other excipients suitably ranges from 10: 1 to 1: 2, especially between 5: 1 and 1: 1, from Pindalol to the other excipients between 1: 0, 2 to 1:10, in particular 1: 0.3 to 1: 5 and from Isradipine to the other excipients from 1: 4 to 1: J5, in particular 1: 5 to 1:10.

8602370 J »% - 7 -

The preparation can be prepared or prepared in a conventional manner by mixing the ingredients together, preferably by melting a fatty material. The resulting mixture is a powder. This powder can be compressed into a tablet, preferably a capsule is filled with it.

When the fatty acid material is melted, the drug and additional excipients, such as lactose, silicon dioxide, calcium sulfate or calcium phosphate, can be incorporated into the melted fatty acid material. The mixture is then allowed to solidify and then divided into small particles (granules).

The resulting granular product can be mixed with a preferably porous, hydrophilic, swellable material and other excipients, for example magnesium stearate, and the mixture can be compressed into a tablet or preferably filled with capsules.

Thus, according to a recommended aspect of the present invention, there is provided a composition containing the active material in a granular matrix of a fat-like material, the granular particles in contact with a hydrophilic swelling material.

The swelling material is preferably present in a porous polymer.

It has now surprisingly been found that the compositions have excellent stability, despite the fact that the active materials are sensitive to many chemical reagents. In addition, the compositions have a satisfactory pharmacodynamic and pharmacokinetic profile.

In general, the preparations have a comparable bioavailability according to standard clinical studies compared to conventional non-sustained release preparations containing the same amounts of active material.

The compositions of the invention, even when administered once a day for 35 days, can provide a therapeutic effect for at least 24 hours or 8602370 7 * - 8 hours. The formulation for Darodipine and Isradipine can be administered only once daily in the known indications of the active materials in approximately the same daily doses as used in the conventional non-sustained release forms.

Equilibrium tests exhibit a narrow range between the maximum and minimum levels of the active material in the blood.

The preparation for Pindolol can be administered twice a day.

The compositions of the present invention are well-worn.

In addition, the present compositions may have similar activity profiles in studies of food interactions. for example, before eating after a breakfast, with people who have fasted.

The formulations to be administered once daily may be formulated in a conventional manner, for example 20 to a capsule or tablet, and may contain 10-200 mg of active material. Preferably they have the release profile as determined by the in vivo or in vitro dissolution assay, for example a release of about 34% Darodipine, 50 to 75% Pindolol and 50 "to 65% Isradipine, for 6 hours. In 0.1 N 25 hydrochloric acid, for example under the experimental conditions of Examples 1, 2 - 5, 16 and 17.

In the following examples, all temperatures given in degrees Celsius are uncorrected.

Further information regarding the properties, etc., of the pharmaceutical excipients listed below may be obtained from the manufacturers listed below, brochures from manufacturers and other sources, in particular H.P.

Fiedler Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und β an boundende Gehiete, 2 edition 1981, Edito Cantor, Aulendorf, 35 West Germany.

8602370 * * --9-

Silicon dioxide (silica) is, for example, Aerosil 200 available from Deutsche-Gold und Silherscheideanstalt,

Frankfort, West Germany.

For example, glycerol ditripalmitostearate is Precirol 5 Ato 5 available from ETS Gattefosse 929100 Boulogae-Brillancourt, France.

Hydroxypropy lmethylcellulose 15000 cps. and 4000 cps. for example, Methocel K15M and Methocel 4EM from Dow Chemical Company, Michigan 48640 United States of America.

For example, IQ Cetyl Palmitate is Cutina CPA available from Henkel 4Q0Q, Düsseldorf, West Germany or can be obtained from Gattefosse or from A / S Johan C. Martens and Company, Bergen, Norway.

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Example 1:

Components mg a) Darodlpine 100 b) lactose (200 mesh) 30 5 c) cetyl palmitate 8 d) hydroxypropylmethylcellulose (1QQ.QQQ cps) 60 e) Mgstearate 2 200 J ° Manufacture

Components a) and b) are sieved and mixed. Component c) is melted by heating at 60 ° C and added to the mixture heated at 55 ° C. The mass is stirred for two minutes or until homogeneous and cooled overnight. The solidified mass is crushed and sieved (through a sieve with 250 micron openings). Components d) and e) are sieved (through a 360 micron aperture sieve) and mixed for 10 min.

The mixture is then encapsulated.

In vitro release time (hours) Darodipine release 1 7 2 14 4 25 25 6 34 24 97

Example 2:

3Q

Composition of each capsule

Ingredients mg

ai Pindolol 15, Q

b) Lactose (2Q0 meshl 73.5 35 8602370 * ♦ - 11 - c) edyl palmitate 20.0 d) hydroxypropylmethylcellulose (I500Q cps) 110.0 e) sodium carboxymethylcellulose 50.0 f) magnesium stearate 1.5 5

Yery fabrication (charge of 6000 capsules).

Components a) and b) are sieved and mixed. Component cl is melted by heating at 56 ° C (melting point: 54 ° C) and added to the mixture heated at 55 ° C.

The mass is stirred for 2 min or until homogeneous and cooled overnight. The solidified mass is crushed and sieved (through a sieve with 250 micron openings).

Components d), e) and f) are sieved (through a sieve with 36 micron openings) and mixed for 10 min.

The mixture is then encapsulated.

In vitro release in 0.1 n HCl (x determined by the Paddle method described in USP "XX.) 2Q time * release of Pindolol 3Q min 9%

80 min 19 Z

I8Q minus 40 Z

360 min 62 Z

25

Example 3:

Composition of each capsule 30 components mg a) Pindolol 15.0 b) dicalcium phosphate 33.5

c) cetyl palmitate 10, Q

d) HydroxypropyImethylcellu- 150.0 35 lose (15000 cps) 8602370 * * - 12 -

tbsp sodium carhoxymathyl cellulose 60, Q

f). magnesium stearate J, 5 yy.

5

The components are mixed in an analogous manner as described in Example 2, except that component bl is replaced by dicalcium phosphate.

10 In vitro release in Q, J 'n'HCl time release of Pindolol

30 min 7 Z

60 min 15% 180. min 35% 15 360 min 52%

Delivery in viyo

According to a study to evaluate the availability of the capsule of Example 3 containing Pindolol in a sustained release form, this capsule and a reference tahlet containing Pindolol in a non-sustained release form were administered to persons who had fasted .

The long-acting capsule was additionally administered to 25 persons who had not yast.

The composition of the usual reference tablet containing Pindolol in a non-sustained release form was as follows:

Pindolol, 5 mg 30 microcrystalline cellulose 84.3 starch 10.

silicon dioxide Q, 2 magnesium stearate 0.5

For the study, an "open-label three-way rando-mized crossover" schedule in 12 healthy male volunteers was 8602370 * -13-.

applied. It was given to the persons. single, oral dose of either reference tablets containing Pindolol in a non-sustained release form (3x5 mg in a fasted state 1) or capsules containing Pindolol in a sustained-release form according to Example 3 (2x15mg] in a fasted state and in a non-fasted state The time periods between the three administrations were so long that no plasma level effect of an earlier dose (approximately one week) could be found.

Blood samples were collected from Q to 30 hours after each dose and the plasma was analyzed for Pindolol by HPLG.

The mean transient plasma concentration values are plotted in Figure 1, wherein 15 O 2 x 2 X 5 mg sustained release capsules in a fasting state φ 2 x 15 mg sustained release capsules in a 2Q unfasted state H = 3x5 mg of conventional tablets from which the active ingredient was normally released.

25 Plasma concentration in nanograms / ml vs. time in hours.

The following values were calculated from the curves:

Long-term Capsules with Referenced-release long-term affinity ta- (2xl5mgl in a donation (2xl5mgl in a bllet state in which a condition (3x5mg) was not fasted in which a fast was applied in a state of fastening '571, 4 624.2 318.6 in ng h / ml ................................

35 8602370 w * - 14 - C 58.6 65.3 59.2 max * in ng / ml_ T 6.00 4.74 0.98 max (in hours) _ 5 Geometric mean for n = 12 people.

30 AUGq _ = area under the curve from 0 to 30 hours.

Compared to the reference form, relative bioavailability is greater than 85% 10 The foreseen 4 and 5

Composition of each capsule:

Ingredients: Example 4 Example 5 15 a) Pindolol 15.0 mg 15.0 mg hl lactose 1.5 mg 47.4 mg c) cetyl palmitate 20.0 mg 15.0 mg dl hydroxypropyl methylcellulose 160.0 mg 120.0 mg ( 15000.cpsl 2Q el Silica (colloidall 1.5mg 1.1mg fl magnesium stearate 2.0mg 1.5mg 20Q, 0mg 20Q, 0mg

Manufacture 25

The components are mixed in an analogous manner as described in Example 2, except that component e) in Example 2 is omitted and replaced with silicon dioxide.

30 In vitro release in 0.1 n hydrochloric acid.

Time Release of Pindolol example 4 example 5 30 min 17% 20% 35 60 min 26% 31% 8602370 - 15 - 120 min 38% 43 "% 360 min 64% 74% 1440 min 100% 101% 5 Example 16: Capsule

Ingredients mg al Isradipine 10 b} lactose 97 10 c} glycerol ditripalmitostearate 10 dl hydroxypropylmethylcellulose 400Q cps 60 tbsp Silica 1 fl magnesium stearate 2 15 180

Manufacture (load of 6000 capsulesl

The components a and b) are sieved and mixed.

Component c) is melted by heating the bet at 56 ° C (melting point: 54 ° Cl and added to the mixture heated at 55 ° G. The mass is stirred for 2 min or until a homogeneous mixture is obtained and chilled overnight The solidified mass is crushed and sieved (through a 250 micron-sized sieve. Ingredients dl, el and fl are sieved (through a 36 micron-sized sieve and mixed for 10 min. The mixture is then encapsulated.

30 In vitro release

Time (hoursl Issue% 1 11 2 19 35 4 43 8602 370 - 16 - 6 64 24 102

Example J 7: Capsule 5

Ingredients mg a) Xsradipine 10 b) microcrystalline cellulose 97 c) cetyl palmitate 5 JO dj hydroxypr opylmethyl cellulose 40QQ 45 cps, e) Silica 1 f 1 magnesii imstearate 2 160 15

Manufacture.

In an analogous manner as described in example 16. 1 '.

20 In vitro release

Time (hours). Delivery%

1 YY

2 20 4 36 25 6 52 24 '96

Example 18: Capsule Ingredients mg 3Q al Isradipine 10 µl microcrystallyne cellulose 47 cl Cetyl palmitate 10 parts hydraxypropylmathyl cellulose 15000 cps 90 e) Silica 1 8602370 - 17 - £) magnesium tearate 2 160

In a clinical trial, a very good sustained-release profile 5 and a relative bioavailability of the preparation of Example 18 was found in both fasted and fasted subjects, versus capsules containing the same amount of isradipine, but with a non-delayed release.

10

Manufacture.

In an analogous manner as described in example 16.

15 In vivo delivery.

In a study to determine the bioavailability of the capsule of Example 18, this capsule and a reference capsule containing isradipine in a non-extended release form were administered to subjects who had fasted. The extended-release capsule was additionally administered to subjects who had not fasted.

The composition of the usual reference capsule containing isradipine in a non-sustained release form was;

Ingredients mg a) Isradipine 10 b) Lactose 167 cl Corn starch 128 30 d) Sodium lauryl sulfate 5.5 è) Silica 1.5 f] polyethylene glycol 6000 8.0

The study used an "open-label three-way 35 randomized crossover" scheme in 9 healthy male volunteers. Subjects were given a single oral dose of either a sustained release reference capsule ¢ 10 mg) in a fasted state, or an extended release capsule according to Example 18 (10 mgl in both a fasted state). as in which no fasting was administered The time periods between the three different administration periods was at least 7 days.

Blood samples from each volunteer were taken 0-48 hours after each dose and the plasma was analyzed for 10 Xsradipine using a RIA technique (detection limit 0.1 nanogram / ml).

The mean transient plasma concentration values are graphically plotted in Figure 2, wherein 15 = 10 mg sustained release capsule in a fasted state

O = 10 mg capsule with long-term release in a non-fasted state 2Q

A = 10 mg conventional capsule where the active material has not been released for a long time

Plasma concentration in nanograms / ml v.s. time.

From the curves, the following values were calculated: capsule (10 mg): with capsule (10 mg) Beferen-a sustained release with a long-duration tablet in a state where release ((X) mg) was not fasted where was an applied position where 30 was fasted ATjf 34.73 34.67 49.65 in ng h / ml C 3.70 1.77 14.22 max in ng / ml__ 35 i1) 2370 - 19 - T 8.55 9 1.89 max (in hours) _ ._

Geometric, mean for n = 9 people 48 AUCq = area under the curve from 0 to 48 hours 5

Compared to: de: .ri £ è'rentievürmcxs ^ de ': rèlatievê- "bioavailability more than" 65%, yporheeld 19: Tablet 10

Ingredients mg a) Pindolol 20.0 b) Lactose 68.5 c) Cetyl palmitate 20.0 15 d) Bydroxypropylmetbyl cellulose 110.0 100,000 cps e] Cellulose * 50.0 f) Magnesium stearate 1.5

270, Q 2Q

Component c) is melted and added to a mixture of a) and h].

The components d1, e} and f} are added to the granulated mass of a), b) and c), after which the resulting mixture is pressed into a tablet.

In vitro release time (hours release% 1 18 3Q 2 31 3 42 4 47 6 54 24 88 35 3 802 - 20 -

Example 20: Capsule (without fatty acid material)

Components: mg

Isradipine 10 5 cellulose (microcrystalline) 57 bydroxyp ropy lmethyl cellulose 90.

4Q0Q cps

Silica 1 magnes i.umst arate 2

10 16Q

Example 21: Tablet (without fatty acid material).

Components mg 15 Isradipine 10 lactose 287 bydroxyprapylmethylcellulose 30 15000 cps bydroxypropylmetbylcellulose 45 20 4Q.QQ. cps

Polyvinylpyrrolidone 20

Silica 4 magnesium stearate 4 -4Q0 25 5 6 0 2 3 7 0

Claims (25)

A controlled release formulation of active material, comprising - Pindolol and / or a 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl- 3,5-pyridinedicarboxylate ester, and 5 - contains a pharmaceutically acceptable hydrophilic swellable material *. A composition according to claim 1, additionally containing a pharmaceutically acceptable, inert, fat-like material. 3. A composition according to claim 2, characterized in that the active material is Pindolol. Preparation according to claim 2, characterized in that the active material is Isradipine. 5. A composition according to any one of the preceding claims, characterized in that the swellable material is a cellulose hydrocolloid. Preparation according to any one of the preceding claims, characterized in that the swellable material is hydroxypropyl 1-methylcellulose, 7. Preparation according to any one of the preceding claims 2-6, characterized in that the fat-like material is a hydrophobic material with a melting point between 30 and 90 ° C. Preparation according to any one of the preceding claims 2-7, characterized in that the fat-like material is a fatty acid ester. 9. Preparation according to any one of the preceding claims 2-8, characterized in that the fatty material is cetyl palmitate. 10. A composition according to any one of the preceding claims, characterized in that it contains 10-20 mg of Pindolol per unit dosage form. Λ Preparation according to any one of claims 1 to 9, characterized in that it contains 5-40 mg of Isradipine. 12. A composition according to any one of the preceding claims * 1 - 10, characterized in that the weight ratio of 8502370 <e '- 22-Pindolol to the swellable material is between 1: 5 and 1:20. Preparation according to any one of claims 1 to 9 and 11, characterized in that the weight ratio of 5 Isradipine to the swollen material is between 1: 2 and 1:20. J4. Preparation according to any one of claims 1 to 10 and 12, characterized in that the weight ratio of Pindolol to the fatty material is between 1: 0.1 and 10 1: 3. Preparation according to any one of claims 1 to 9 and 13, characterized in that the weight ratio of Isradipine to the fatty material is between 1: 0.3 and 1: 2. Preparation according to any one of the preceding claims 2 to 15, characterized in that it contains hydroxypropylmethylcellulose as swelling agent and ethyl palmitate as fat-like material. 17. The composition of claim 1 substantially as described above with respect to any of the examples. 18. A composition according to any one of the preceding claims 2-16, characterized in that it contains the active material in a granular matrix of a fat-like material, the granular particles in contact with a hydrophilic swelling material. 19. A method of treating circulatory disorders, including the heart, characterized in that a patient-appropriate treatment requires administration of a therapeutically effective amount of repair agent according to one of the preconditions. A composition according to any one of the preceding claims relating to Pindolol, for use in the treatment or prevention according to the method of claim 35 19, ift unit dosage form: die. Contains 10-20 mg of Pindolol. 8602370 # «* r - 23 - 21. A composition according to any one of the preceding claims 1-19 related to Isradipine, for use in the Treatment or prevention according to the method of claim 19, in a unit dosage form comprising 5 - 40 mg 5 Isradipine Contains. 22. Process for the preparation or manufacture of a controlled-release preparation for oral administration according to claims 1-18, characterized in that one or a number of active materials are mixed with the hydrophilic, swellable material and, if desired, the fatty material. 23. Process according to claim 22, characterized in that the one or more active materials are mixed with the molten fat-like material, the resulting mixture is allowed to solidify and granulate and the granular particles are mixed with the porous, swellable material. 24. A controlled-release formulation for oral administration according to claim 1 containing Pindolol and having a relative Bioavailability of more than 85% compared to a non-controlled-release oral Pindolol formulation when administered to a fasted patient. A controlled-release formulation for oral administration according to claim 1 containing Isradipine and having a relative Bioavailability of more than 65% compared to an Oral-Controlled-Release Isradipine formulation when administered to a fasted patient. 26. Controlled-release formulation for oral administration this an Active Ingredient selected from the group of Pindolol and a 4- (2,1,3-Benzoxadiazol-4-ylj-1,4-dihydro-2,6-3Q dimethyl-3 5-pyridine dicarboxylate ester, which has Biohazardness Differences When administered to a fasted patient and to a nonfasted patient of not more than 2%. 27. Preparation and a method as described in the s * yjf 35 Description and / or examples. / 7 86C 2 37 C