HU197201B - Process for producing oral pharmaceutical compositions of controlled solubility of the active components - Google Patents

Abstract

The invention relates to a sustained-release formulation for oral administration, comprising a substance chosen from pindolol and an ester of 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydroxy-2,6-dimethyl- 3,5-pyridinedicarboxylic acid, a pharmaceutically acceptable hydrophilic swelling substance and optionally a pharmaceutically acceptable inert fat.

Description

FIELD OF THE INVENTION The present invention relates to a process for the preparation of a controlled-release pharmaceutical composition for oral administration comprising 1- (1H-indol-4-yloxy) - (1-methylethyl) amino-2-propanol, isopropylmethyl-4 as active ingredient. 5- (2,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate or diethyl 4- (2,1,3-benzoxadiazole) -4-yl) -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate.

Darodipine is chemically known as diethyl 4- (2, 1,3, 10-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate, known as 2,037,766. United Kingdom Patent No. 4,198. Darodipine is used as a free base for medical purposes. 15

Its pharmacological and clinical properties have been thoroughly mapped. Darodipine has a potent calcium antagonistic effect on isolated coronary arteries and other peripheral blood vessels. 20 hemodynamic examinations in a healthy body result in a reduction in total peripheral resistance and arterial blood pressure.

Darodipine can thus be used to treat angina pectoris, hypertension, stroke 25 and cerebral vasculature.

The usual daily dose for oral administration, for example for the treatment of angina pectoris, is 75-300 mg, preferably in three separate doses, and for the treatment of hypertension, 37.5-150 mg, preferably in two to three doses.

The chemical name of Pindolol is 1- (1H-indol-4-yloxy) -3 - ((1-methylethyl) amino) -2-propanol and is known from British Patent No. 1,138,969. patent. For medicinal purposes, Pindolol is generally used in the form of the free base.

Its pharmacological and clinical properties have been extensively studied. Pindolol is a β-adreno- 40 receptor antagonist (β-blocker) and acts on both O1 and O2 adrenoceptors.

It protects the heart against catecholamine over-stimulation during physical and mental stress and rest, and its true intrinsic sympathomiraetic activity (ISA) provides a basic stimulation that is equivalent to that induced by normal resting sympathetic activity. ' Thus, there is no unnecessary reduction in heart rate, contraction, and intracardiac conduction. As a result, the risk of bradycardia or cardiac arrest is low and does not reduce unchanged cardiac output. Pindolol reduces the high vascular resistance due to existing hypertension and thus does not reduce tissue and organizational perfusion.

Pindolol can be used to treat arterial hypertension, angina pectoris (seizure prevention), sinusoe and atrial tachycardia, seizure-like θθ tachycardia, tachycardia in patients with atrial fluttering or fibrillation, digitalis suppressed, supaventricular and ventricular extrasystole, they are usually administered orally.

The oral dose is determined individually for each patient and is generally 10-30 mg / day.

For the treatment of arterial hypertension, a daily dose of 5-15 mg is given, the 20-30 mg dose is divided into two or three divided doses.

For the treatment of angina pectoris and cardiac arrhythmia, the daily dose is 10-30 mg divided into two or three divided doses.

For the treatment of hyperkinetic heart syndrome, the daily dose is 10-20 mg per dose, preferably in prolonged form.

Isradipine is chemically known as isopropylmethyl 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate and is known from 2,037,766. United Kingdom Patent No. 5,198. It is generally used as a free base for medical purposes.

The pharmacological and clinical properties of isradipine have been extensively studied. It is a potential calcium antagonist and acts on the coronary and peripheral arteries. It is commonly used to treat hypertension, angina pectoris and cerebral insufficiency.

The usual oral daily dose is 10-20 mg, preferably 5-10 mg.

Undesirable side effects may occur with the administration of these agents, such as headache with Darodipine, fatigue, dizziness, gastrointestinal disorders (mainly nausea), headaches, sleep disorders (eg vivid dreams) with Pindolol and headache, restlessness, tension, restlessness.

It has been found that keeping the concentration of the active ingredient within the narrow range of the therapeutically active level avoids the rapid release of the active ingredient after administration of the uncontrolled release composition, which results in transiently high blood concentrations and sometimes severe side effects.

Therapy can be achieved by administering small doses twice or three times daily to a total daily dose. However, this solution is troublesome and does not ensure that the blood levels of the active ingredient are kept within narrow limits.

The present invention therefore relates to a process for the preparation of a sustained release controlled release pharmaceutical composition which allows for a reduction in the number of daily doses and for the reduction of certain side effects.

The pharmaceutical composition of the present invention exhibits excellent bioavailability under the conditions of food interaction studies (e.g., Examples 3 and 18).

The composition for oral administration according to the present invention contains Pindolol or Darodipine or Isradipine as active ingredient in addition to a pharmaceutically acceptable hydrophilic, swellable excipient and optionally pharmaceutically acceptable inert fatty acid ester.

The resulting controlled release oral formulation, which contains Pindolol as the active ingredient, exhibits a relative bioavailability of greater than 85% compared to Pindolol oral formulations.

The relative bioavailability of the controlled release oral formulation of Isradipine is greater than 65% relative to the controlled release controlled release formulation of Izradipin.

The bioavailability difference with the controlled release oral preparation of the present invention is at least 20%.

In the case of darodipine, the dosage unit will generally contain from 10 to 200 mg, preferably from 20 to 150 mg, for example 100 mg, of the active ingredient.

In the case of pindolol, the dosage unit will generally contain 10-20 mg, preferably 15-20 mg, of the active ingredient. Pindolol is preferably used in the form of a base, but may also be used in the form of an acid addition salt.

In the case of isradipine, the dosage unit will contain 5-40 mg, preferably 10-20 mg, of the active ingredient.

The swellable excipient is preferably a cellulose derivative which forms a colloid in water.

Suitable hydrophilic swellable excipients are one or more natural, partially or wholly synthetic, anionic or preferably nonionic hydrophilic gums, cellulose derivatives or acidic protein derivatives such as acacia, tragacanth, locust bean gum, guar gum, caraway gum, agar, , soluble and insoluble alginates, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, carboxypolymethylene and gelatin.

Hydrocolloidal celluloses such as methylcellulose, hydroxypropylcellulose, and especially hydroxypropylmethylcellulose and sodium carboxymethylcellulose are preferred.

The weight ratio of Darodipine to swellable excipient is 1: 0.2 to 1: 2, preferably

The weight ratio of Pindolol to the swellable excipient is 1: 5 to 1:20, preferably 1: 8 to 1:15, and the weight ratio of Isradipine to the swellable excipient is 1: 2 to 1:20, preferably 1 : 4 - 1:10.

Pharmaceutically acceptable inert fatty acid esters include glyceryl esters of glycerides such as fatty acids, or glycerol esters of hydrogenated aliphatic acids such as glyceryl monostearate glyceryl distearate, glyceryl ester of hydrogenated castor oil.

In particular, glyceryl palmitate and stearate, cetyl palmitate having a melting point of 45-65 ° C.

The weight ratio of Darodipine to the fat derivative 4 is 10: 0.2 to 10: 5, preferably 10: 0.5 to 10: 1, the weight ratio of Pindolol to the fat derivative is 1: 0.1 to 1: 3, preferably 1: 0.1 1: 2, in particular 1: 0.25 to 1: 1.4 and the weight ratio of Isradipine to fat is 1: 0.3 to 1: 2, preferably

1: 0.5 to 1: 1.5, especially 1: 0.5 to 1: 1.

Particularly preferred is a composition comprising hydroxypropyl methylcellulose as swelling agent and cetyl palmitate as a fat derivative.

The pharmaceutical composition may also comprise one or more soluble or insoluble pharmaceutical carriers, such as calcium sulfate, phosphate, lactose, mannitol, sucrose, sorbitol, colloidal silica gel and magnesium stearate, preferably soluble carriers such as lactose.

When used as carrier, the weight ratio of Darodipine to carrier is 10: 1

1: 2, preferably 5: 1 to 1: 1, the ratio of Pindolol to carrier is 1: 0.2 to 1:10, preferably 1: 0.3 to 1: 5, and the ratio of isradipine to carrier is 1: 2. 4 to 1:15, preferably 1: 5 to 1:10.

The preparation of the compositions is carried out in the usual manner, for example, by mixing the active ingredients, whereby the fat derivative is preferably melted. The resulting powder mixture is compressed into tablets or preferably filled into capsules.

When a melted fat derivative is used, the active ingredient and other carriers such as lactose, silica, calcium sulfate or phosphate are added to the molten fat. The mixture is allowed to solidify and split (granulate). The resulting granulate is preferably mixed with a porous hydrophilic swellable material and other excipients such as magnesium stearate and compressed into tablets or filled into capsules.

Preferably, the active ingredient in the formulation is contained in a fat-derived matrix, wherein the granules are in contact with a hydrophilic swellable material. The swellable material is preferably in a porous form.

The composition according to the invention has excellent stability despite the fact that the active ingredient is sensitive to many chemical reagents. In addition, the formulation has an excellent pharmacodynamic and pharmacokinetic profile.

The bioavailability of the formulation is better in conventional clinical trials than conventional non-controlled release formulations containing the same amount of active ingredient. The composition exerts its therapeutic effect for at least 24 hours, preferably for at least 35 hours, once daily. Darodipine and Isradipine containing formulations are administered in the usual indications in a single daily dose at approximately the same dose as a conventional, controlled release formulation. Studies have shown that the maximum and minimum blood-36 levels are within narrow limits.

Preferably, the Pindolol containing composition is administered in two daily doses.

The compositions of the present invention are well tolerated. Food interaction studies have shown that the formulations may be administered in the same way before or after meals, for example.

The once-daily formulation is prepared in a conventional manner, wherein the capsule or tablet generally contains from 10 to 200 mg of active ingredient. The formulation exhibits a release ratio as determined by in vivo and in vitro dissolution studies, which is approximately 34% for Darodipine, 50-75% for Pindolol and 50-65% for Isradipine over 6 hours in 0.1 N hydrochloric acid (1, 2 Examples 5, 16 and 17).

The following examples illustrate the invention. The excipients used in the examples are: silica, such as Aerosil 200 (Deutsche-Gold und Silberscheideanstalt, Frankfurt, Germany); glycerol ditripalmito stearate such as Precirol Ato 5 (ETS Gattefosse 929100 Boulogne-Brillancourt, France); hydroxypropyl methylcellulose 15 Pa.s. and 4 Pa.s., such as Methocel K15M and Methocel 4EM (Dow Chemical Company, Michigan 48640, USA); cetyl palmitate such as Cutina CPA (Henkel 4000, Düsseldorf, Germany) or (Gattefosse) or (Johan C. Martens and Company A / S, Bergen, Norway); or can be found in H.P. Fiedler: Lexikon hoer Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete (2nd edition, 1981, Edito Cantor, Aulendorf, Germany).

Example 1

Composition of the preparation:

the) Darodipin 100 mg b) lactose (200 mesh) 30 mg c) cetyl palmitate 8 mg d) hydroxypropyl methylcellulose (100 Pa.s.) 60 mg e) magnesium stearate 2 mg 200 mg

To prepare the composition, components a) and b) are sieved and mixed. Component c) is melted at 60 ° C and added to the above mixture at 55 ° C. The mass was homogenized with stirring (at least 2 minutes) and then cooled overnight. The resulting mass was cut and sieved (250 μ). Components d) and e) were sieved (360 μ) and stirred for 10 minutes. The resulting mixture is filled into capsules.

In vitro release:

Time (hours) Release of darodipine

7

14

25

34

97

Example 2

The capsule composition is prepared with the following composition: 1 stone- the) pindolol 15.0 mg b) Lactose (200 mesh) 73.5 mg c) cetyl palmitate 20.0 mg d) hydroxypropylmethyl cellulose (15.Pa.s, 110.0 mg e) Sodium carboxymethyl -cellulose 50.0 mg f) magnesium stearate 1.5 mg. For the preparation of the preparation (6000 cap-

(a) portion (a) and (b) are sieved and mixed. Component c) is melted at 56 ° C (m.p. 54 ° C) and added to the above mixture at 55 ° C. The resulting mass was homogenized with stirring (at least 2 minutes) and cooled overnight. The mass was comminuted and sieved (250 μ). Components d), e), and f) were sieved (360 μ) and stirred for 10 minutes. The resulting mixture is filled into capsules. In Vitro Release in 0.1 N Hydrochloric Acid (Paddle Test, USP XX):

Time for Pindolol release

30 minute 9% 80 minute 19% 180 minute 40% 360 minute 62%

Example 3

Capsules are prepared with the following composition:

the) pindolol 15.0 mg b) dicalcium phosphate 33.5 mg c) cetyl palmitate 10.0 mg d) hydroxypropyl methylcellulose (15.Pa.s.) 150.0 mg e) sodium carboxymethyl methyl -cellulose 60.0 mg f) magnesium stearate 1.5 mg The preparation of the preparation is described in Figure 2. Example

except that dipotassium phosphate is used in place of component b).

In vitro release in 0.1 N hydrochloric acid

Time Pindolol release minutes 60 minutes 180 minutes 360 minutes

7%

15%

35%

52%

In carrier release:

To determine the bioavailability of the Pindolol-containing controlled-release capsule of Example 3, the capsule and the Pindolol non-controlled-release comparator tablet were administered to a fasted patient. The controlled-release capsule is further administered to a normally nourished patient.

The composition of the comparative, controlled release tablet:

Pindolol 5 mg microcrystalline cellulose 84.3 mg 20 starch 10 mg silica 0.2 mg magnesium stearate 0.5 mg.

The studies were performed on 12 healthy male volunteers using an open three-way randomized crossover design. The volunteers were given a single oral dose of

From a Pindolol Controlled Release Compound Tablet (3x5 mg fasting) and a Pindolol Controlled Release Capsule (2x15 mg) from Example 3 for fasting and non-fasting. The interval between the three administrations was so long that plasma concentrations could not be detected after the previous administration. (About a week.)

Blood samples were collected 0-30 hours after dosing and plasma Pindolol concentration was measured by HPLC. The average plasma concentration is plotted in Figure 1, where a

O = 2x15 mg controlled release capsule for fasting, φ = 2x15 mg controlled release capsule for non fasting and

It is known as 3x5 mg tablets of known uncontrolled release.

From the resulting graph, the area under the curve between 0 and 30 hours (AUC 0 ³⁰ ) and the values of C u and T i ax can be calculated. Relative bioavailability is greater than 85% relative to the comparator.

Controlled release capsules (2x15 mg, not for fasting) Controlled release capsules (2x15 mg) for fasting Comparative tablet (3x5 mg) on an empty stomach AUC 0 ³⁰ (ng h / ml) 571.4 624.2 318.6 Ciax (Ng / ml) 58.6 65.3 59.2 T «x (Hours) 6:00 4.74 0.98

Examples 4 and 5 Tendon in vitro release 0.1 n BÓsavban: We set up a capsule live the following 45 Time for Pindolol release equivalent to: Example 4 Example 5 Content Example 4 Example 5 50 30 minute 17% 20% the) pindolol 15.0 mg 15.0 mg 60 minute 26% 31% b) lactose 1.5 mg 47.4 mg 120 minute 38% 43% c) cetyl palmitate 20.0 mg 15.0 mg 360 minute 64% 74% d) hydroxypropylmethylcellulose 55 1440 minute 100% 101% (15.Pa.s.) 160.0 mg 120.0 mg Example 6 e) silica (colloidal) 1.5 mg 1.1 mg We set up a capsule the composition below f) magnesium stearate 2.0 mg 1.5 mg Tell: 200.0 mg 200.0 mg 60 the) isradipine 10 mg b) lactose 97 mg Preparation of the preparation the In Example 2 c) glycerol ditripalmito- written way, with the difference that stearate 10 mg that component e) silicon- dioxide sub- 65 d) bridge for roxypropyl methylcellulose be employed for. (4.Pa.s.) 60 mg

-510

A capsule is prepared with the following composition:

(e) silica

f) mg of magnesium stearate

Example 8

Capsules are prepared with the following composition:

180 mg

To prepare the composition (6,000 capsule portions), components a) and b) are sieved and mixed. Component c) was melted at 56 ° C (m.p. 54 ° C) and added at 55 ° C to the former mixture. The resulting mass was homogenized with stirring (at least 2 minutes) and cooled overnight. The mass was comminuted and sieved (250 μ). Components d), e), and f) were sieved (360 μ) and stirred for 10 minutes. The resulting mixture is filled into capsules.

In vitro release:

Time (hours)

Release (X)

102

Example 7

A capsule is prepared according to the following

set tellel: 35 the) isradipine 10 mg b) microcrystalline cellulose 97 mg c) cetyl palmitate 5 mg d) hydroxypropyl methylcellulose (4.Pa.s.) 45 mg 40 e) silica 1 mg f) magnesium stearate 2 mg 160 mg 45 Preparation of the composition a Example 6 written way. In vitro release: Time (hours) Release (%) 50 1 11 2 20 4 6 36 52 55 24 96

the) b) c) isradipine microcrystalline cellulose cetyl palmitate 10 mg 47 mg 10 mg d) hydroxypropyl methylcellulose (15.Pa.s.) 90 mg e) silica 1 mg f) magnesium stearate 2 mg 160 mg

The preparation was carried out as described in Example 6.

In carrier release:

The bioavailability of the capsule prepared in Example 8 was compared to a controlled release capsule containing Isradipine when administered on an empty stomach. The controlled-release capsule was not administered on an empty stomach.

Controlled release capsules containing isradipine contain:

the! isradipine 10 mg b) lactose 167 mg c) corn starch 128 mg d) Sodium lauryl sulfate 5.5 mg e) silica 1.5 mg f) polyethylene glycol 6000 8.0 mg The tests were nine healthy man we volunteered to open an open

based on an inept crossing plan. The uncontrolled release comparator capsule (10 mg) was administered on a fasting day, and the controlled release capsule (10 mg) of Example 8 was administered on a fasting and non-fasting dose once daily. The interval between the three different dosages should be at least 7 days.

Blood samples were collected from 0 to 48 hours post-dose and plasma Izradipine content was measured by RIA (detection limit 0.1 ng / ml).

The mean plasma concentration is plotted in Figure 2, where = 10 mg controlled-release capsule fasting data, a = 10 mg controlled-release capsule non-fasting data, and = = 10 mg controlled-release comparator capsule.

The graph shows the area under the curve between 0 and 48 hours (AUC 0 * ⁸ ) and the Cmax and Teax values.

-612

Controlled release tablets on an empty stomach Controlled release capsule for fasting comparative capsule on an empty stomach AUC0 * ⁸ (ng h / ml) 34.73 34.67 49.65 CAAX (Ng / ml) 3.70 1.77 14:22 Tux (Hours) 8:55 9 1.89

Studies have shown that the composition according to the invention has a relative bioavailability of more than 65%.

Example 9

A tablet is prepared having the following composition:

the) b) c) pindolol lactose eetil palmitate 20.0 mg 68.5 mg 20.0 mg d) hydroxypropyl methylcellulose (LOO.Pa.s.) 110.0 mg e) cellulose 50.0 mg f) magnesium stearate 1.5 mg 270.0 mg

To prepare the composition, component (c) is melted and added to the mixture of components (a) and (b). Components d), e) and f) are added to the granulated mass of components a), b) and c) and the resulting mixture is compressed into tablets.

In vitro release:

Time (hours) Active ingredient release (%)

18

31

42

47

54

88

Example 10

A fat-free capsule is prepared with the following composition:

isradipine 10 mg microcrystalline cellulose 57 mg hydroxypropyl methylcellulose (4.Pa.s.) 90 mg silica 1 mg magnesium stearate 2 mg

160 mg

Example 11

A talc without fat adjuvant is prepared with the following composition:

Isradipine 10 mg lactose 287 mg hydroxypropyl methylcellulose (15.Pa.s) 30 mg hydroxypropylmethylcellulose (4,000 cps) 45 mg polyvinylpyrrolidone 20 mg silica 4 mg magnesium stearate 4 mg

400 mg

Claims (32)

PATENT CLAIMS 1. A method for oral administration fron ₃₅ is formalized a sustained release pharmaceutical preparation, characterized in that they contain as' diethyl-4- (2,1,3-4-yl) -1,4-dihydro-2,6-dimethyl- 3,5-Pyridine dicarboxylate40 ^tot ' b) isopropylmethyl 4- (2,1,3-benzodiazol-4-yl) -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate; or c) particles containing 1- (1H-indol-4-yloxy) - (1-methylethyl) amino-2-propanol, optionally after dispersing, cooling and granulating in a melt of an inert fatty acid ester, wherein: weight ratio of active ingredient to fatty acid ester 50: 1: 0.02-1: 3, with a swellable hydrophilic excipient and optionally a pharmaceutical excipient, wherein the weight ratio of active ingredient to hydrophilic excipient is from 1: 0.2 to 1:20, and the mixture is known per se. 55 encapsulated or tableted. (Priority 19/09/1986) 2. The process of claim 1 wherein the hydrophilic excipient is cellulose hydrocolloid. (Priority 60: September 19, 1986) 3. The process according to claim 1 or 2, wherein the hydrophilic excipient is hydroxypropyl methylcellulose. (Priority: September 19, 1986) -714 The process according to any one of claims 1-3, wherein the fatty acid ester is cetyl palmitate. (Priority: September 19, 1986) 5. A process according to any one of claims 1 to 4, wherein the hydrophilic excipient is hydroxypropylmethylcellulose and the fatty acid ester is cetyl palmitate. (Priority: September 19, 1986) 6. A process according to any one of claims 1 to 3, wherein 10 to 20 mg of 1- (1H-indol-4-yloxy) - (1-methylethyl) amino-2-propanol per unit dose are used. (Priority: September 19, 1986) 7. Process according to any one of claims 1 to 5, characterized in that the weight ratio of 1- (1H-indol-4-yloxy) - (1-methylethyl) amino-2-propanol to the hydrophilic excipient is 1: 5 to 1: 20th (Priority: September 19, 1986) 8. Process according to any one of claims 1 to 3, characterized in that the weight ratio of 1- (1H-indol-4-yloxy) - (1-methylethyl) -amino) -2-propanol to fatty acid ester is 1: 0.1 -1: 3rd (Priority: September 19, 1986) 9. A process according to any one of claims 1 to 3, wherein 5 to 40 mg of isopropylmethyl-4- (2,3,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-3,5 pyridine dicarboxylate. (Priority: September 19, 1986) 10. A process according to any one of claims 1 to 9 or 9, wherein the isopropylmethyl-4- (2,3,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-3,5-pyridine weight ratio of dicarboxylate to hydrophilic excipient is 1: 2 to 1:20. (Priority: September 19, 1986) 11. A process according to any one of claims 1 to 4, wherein the isopropylmethyl 4- (2,3,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate and the weight ratio of the fatty acid ester is 1: 0.3 to 1: 2. (Priority: September 19, 1986) 12. A process for the preparation of a controlled release pharmaceutical formulation for oral administration comprising administration of particles containing 1- (1H-indol-4-yloxy) - (1-methylethyl / amino) -2-propanol as an active ingredient. after dispersing, cooling and granulating in a molten inert fatty acid ester, wherein the weight ratio of active ingredient to fatty acid ester is 1: 0.02-1: 3, with a swellable hydrophilic excipient and optionally a pharmaceutical excipient, wherein the active ingredient and the hydrophilic the weight ratio of the excipient is from 1: 0.2 to 1:20, and the mixture is encapsulated or tableted in a manner known per se. (Priority: December 20, 1985) 13. The process of claim 12 wherein the hydrophilic excipient is cellulose hydrocolloid. (Priority: December 20, 1985) The process according to claim 12 or 13, wherein the hydrophilic excipient is hydroxypropyl methylcellulose. (Priority: December 20, 1985) 15. A 12-14. The process according to any one of claims 1 to 3, wherein the fatty acid ester is cetyl palmitate. (Priority: December 20, 1985) 16. A process according to any one of claims 1 to 4, wherein the hydrophilic excipient is hydroxypropylmethylcellulose and the fatty acid ester is cetyl palmitate. (Priority: December 20, 1985) 17. A 12-16. A process according to any one of claims 1 to 3, wherein 10 to 20 mg of 1- (1H-indol-4-yloxy) - (1-methylethyl) amino-2-propanol per unit dose are used. (Priority: December 20, 1985) 18. A 12-17. Process according to any one of claims 1 to 5, characterized in that the weight ratio of 1- (1H-indol-4-yloxy) - (1-methylethyl) -amino) -2-propanol to the hydrophilic excipient is from 1: 5 to 1: 20th (Priority: December 20, 1985) 19. Process according to any one of claims 1 to 3, characterized in that the weight ratio of 1-1H-indol-4-yloxy) - ((1-methylethyl) amino) -2-propanol to fatty acid ester is 1: 0.1- 1: 3rd (Priority: December 20, 1985) 20. A process for the preparation of a controlled release pharmaceutical formulation for oral administration, wherein the active ingredient is isopropylmethyl 4- (2,1,3-benzodiazol-4-yl) -1,4-dihydro-2,6-dimethyl-3. The particles containing 5-pyridine di-carboxylate are optionally after dispersion in a melt of an inhaled fatty acid ester, wherein the weight ratio of active ingredient to fatty acid ester is 1: 0.02 to 1: 3, with swellable hydrophilic excipient and optionally pharmaceutical with an excipient, wherein the weight ratio of active ingredient to hydrophilic excipient is from 1: 0.2 to 1:20, and the mixture is encapsulated or tableted in a manner known per se. (Priority: 07/10/1985) 21. The process of claim 20 wherein the hydrophilic excipient is cellulose hydrocolloid. (Priority: 07/10/1985) 22. A process according to claim 20 or 21 wherein the hydrophilic excipient is hydroxypropyl methylcellulose. (Priority: 07/10/1985) 23. A 20-22. The process according to any one of claims 1 to 3, wherein the fatty acid ester is cetyl palmitate. (Priority: 07/10/1985) 24. A 20-23. A process according to any one of claims 1 to 4, wherein the hydrophilic excipient is hydroxypropylmethylcellulose and the fatty acid ester is cetyl palmitate. (Priority: 07/10/1985) 25. A 20-24. A process according to any one of claims 1 to 4, wherein 5 to 40 mg of isopropylmethyl-4- (2,3,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-di -816 methyl-3,5-pyridinedicarboxylate was used. (Priority: 07/10/1985) 26. A 20-25. A process according to any one of claims 1 to 3, wherein the isopropylmethyl-4- (2,3,3-benzoxadiazol-4-yl) -5-1,4-dihydro-2,6-dimethyl-3,5-pyridine the weight ratio of dicarboxylate to hydrophilic excipient is 1: 2 to 1:20. (Priority: 07/10/1985) 27. A 20-26. A process according to any one of claims 1 to 3, wherein the isopropylmethyl 4- (2,3,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate and the weight ratio of the fatty acid ester is 1: 0.3 to 1: 2. (Priority: 07/10/1985) 28. A process for the manufacture of a controlled-release pharmaceutical composition for oral administration comprising diethyl 4- (2,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-3,5 as the active ingredient. particles containing pyridine dicarboxylate after optionally dispersing, cooling and granulating in a melt of an inert fatty acid ester, wherein the weight ratio of the active ingredient to the fatty acid ester 1: 0.02 to 1: 3, with a swellable hydrophilic excipient and optionally a pharmaceutical excipient, wherein the weight ratio of active ingredient to hydrophilic excipient is from 1: 0.2 to 1:20, and the mixture is encapsulated or tableted in a manner known per se. (Priority: 10.10.1985) 29. The method of claim 28 wherein the hydrophilic excipient is cellulose hydrocolloid. (Priority: 10.10.1985) 30. The process according to claim 28 or 29, wherein the hydrophilic compound is hydrophilic hydroxypropyl methylcellulose is used as auxiliary material. (Priority: 10/01/1985) 31. A 28-30. The process according to any one of claims 1 to 3, wherein the fatty acid ester is cetyl palmitate. (Priority: 10/01/1985) 32. A 28-31. A process according to any one of claims 1 to 4, wherein the hydrophilic excipient is hydroxypropyl methylcellulose and the fatty acid ester is cetyl palmitate. (Priority: 10/01/1985)