DD232488A5 - PROCESS FOR PRODUCING PHENOXYPROPANOLAMINE SALTS - Google Patents

Abstract

New salts of alprenolol useful in the treatment of heart disease or disorders are the salts with benzoic acid and maleic acid. The invention relates to a process for the preparation of Phenoxypropanolaminsalzen, which can be processed for use in human or veterinary medicine for therapeutic purposes to preparations. By the method according to the invention, salts of alprenolol base are prepared with benzoic acid and / or maleic acid.

Description

in which A "

or / Q) -COO

means.

A pharmaceutical preparation for the administration of alprenolol via the gastrointestinal system, wherein alprenolol is in the form of a salt with benzoic acid or maleic acid, is another aspect of the invention.

Oral pharmaceutical preparations of the novel alprenolol salts provide the greatest advantages over heretofore known oral ingestible alprenolol preparations, and thus such orally administered preparations represent a preferred embodiment of the invention. However, the novel salts may be used to advantage in rectally-administered pharmaceutical preparations.

The new salts according to the invention can be incorporated into pharmaceutical preparations in a manner known per se. They are also suitable for obtaining slow-release preparations because they have a high content of the active compound alprenolol. It is thus possible to produce both products that are absorbed quickly and products with a prolonged duration of action.

In the preparation of pharmaceutical preparations containing a salt of the present invention in the form of dosage units for oral administration, the alprenolol salt may be treated with suitable excipients such as lactose, sucrose, sorbitol, mannitol, starch such as potato starch, corn starch or amylopectin, cellulose derivatives or Gelatin, as well as with a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol or the like, are mixed and pressed into tablets. When coated tablets are desired, the core prepared as above may be coated with a <oncentrated sugar solution, and this solution may contain, for example, gum, arabic, gelatin, talc, titanium dioxide or the like. In addition, the tablets with a polymer in an organic or aqueous solution can be given a film coating.

In the preparation of soft gelatin capsules (beaded closed capsules) consisting of gelatin and, for example, glycerol, or in the preparation of similar closed capsules, the alprenolol salt is mixed with a vegetable oil. Hard gelatin capsules may contain the active compound in combination with suitable binders such as lactose, sucrose, sorbitol, mannitol, starch (eg potato starch, corn starch or amylopectin), cellulose derivatives or magnesium stearate.

Dosage units for rectal administration may be prepared in the form of suppositories containing the active substance in admixture with a neutral fat base, or they may be prepared in the form of gelatin rectal capsules containing the active substance in admixture with a vegetable or paraffin oil , The alpraenolol salts of the invention may be administered in equal molar amounts as recommended for alprenolol hydrochloride. For example, suitable daily doses of the new salts would be 0.1 to 1.5 g. Dosage units may conveniently contain amounts corresponding to 50 to 200 mg of alprenolol hydrochloride.

The salts according to the invention can be prepared in a manner known per se by reacting alprenolol base with maleic acid or benzoic acid.

Exemplary embodiments Example 1

31.2 g of a 40% solution of alprenolol base (50.1 mmol) in acetone was evaporated and 35 ml of isopropyl alcohol were added. After evaporation, the residue was dissolved in 18.7 g of isopropyl alcohol and heated to 50 ° C. 5.8 g (50.1 mmol) of maleic acid were dissolved in 60 ml of isopropyl alcohol with stirring. The maleic acid solution was mixed with the Alprenolollösung at 5O ⁰ C. 15.3 g of alprenolol hydrogen maleate (1: 1 salt) was obtained as a white crystalline powder after crystallization and drying. Yield 83.6%, mp = 111 ^° C.

Example 2

31,2g of a 40% solution of Alprenololbase (50.1 mmol) in acetone and 25 mL of acetone were heated to 50 ⁰ C. 6.1 g (50.1 mmol) of Bezonesäure were dissolved in 70 ml of acetone. The benzoic acid solution was added to the alprenolol solution and heated to 50 ^° C. 16.7 g of alprenolol benzoate was obtained as thick white crystals after crystallization and drying. Yield 89.8%, mp = 119 ° C.

Example 3

Alprenolol hydrogen maleate (128g equivalent to 100g alprenol hydrochloride) was mixed with anhydrous lactose (136g), microcrystalline cellulose (90.7g) and magnesium stearate (3.3g). The mixture was compressed into 10mm diameter tablets weighing 358mg. The tablets melted away in water at 37 ⁰ C in 3 min (test according to USP XX).

Example 4

Alprenolol benzoate (130 g corresponding to 100 g alprenolol hydrochloride) was mixed with anhydrous lactose, microcrystalline cellulose and magnesium stearate according to Example 3. The tablet weight was 360 mg. The time to melt according to USP XX was 3.5 minutes.

Example 5

Tablets were crosslinked in a manner analogous to Example 3 from a mixture of alprenolol benzoate (260 g), anhydrous lactose (142 g), microcrystalline cellulose (181 g)! Polyvinylpyrrolidone (29g) and magnesium stearate (6g). The tablet weight was 309 mg and the time to dissolve 20 seconds.

Example 6

Slow release tablets were prepared by mixing alprenolol benzoate (260 g) with magnesium stearate (26 g). The mixture was moistened with a solution of 12.6 g of ethyl cellulose from 10 cps in 71 g of 95% ethanol. The wet mass was dried and ground through a 1.0mm sieve. Anhydrous lactose (115g), microcrystalline cellulose (90g) and magnesium stearate (4.9g) were added. Tablets weighing 510 mg were made with 12 mm press punches. The tablets zergincen very slowly. Dissolution properties in artificial gastric juice were compared to commercial slow release drug alprenolol hydrochloride tablets (Aptin® Durules® Ab Hässle). The test was carried out with a 50 rpm stirring paddle method according to USP XX.

, 1h 2h 4h 6h

Tablets, Example 6 40% 58% 77% 88%

25Aptin ^(RI Durules ^(R1, 45%, 63%, 83%, 94%)

Example 7

Alprenolol hydromaleate (64 g) was granulated with ethanol (17 g). After drying, the granules were sieved through a 0.7 mm sieve and mixed with anhydrous lactose (136 g), microcrystalline cellulose (91 g), cross-linked polyvinylpyrrolidone (14.5) and magnesium stearate (3 g). The mixture was compressed into 10mm diameter tablets weighing 308mg. The time to melt was about 10 seconds, and the dissolution in artificial gastric juice was complete in 10 minutes.

Example 8

A slow-release preparation based on a large number of individually coated small pellets was prepared in the following manner:

Alprenolol benzoate (74 g), microcrystalline cellulose (16 g) and disodium hydrogen phosphate (10 g) were mixed together in an intensive mixer. The mixture was moistened with about 35 g of water and processed until round granules had formed. These were dried and granules larger than 1.0 mm and smaller than 0.5 mm were sieved.

The granules were coated in a fluidized bed coater with a solution consisting of 10 g of ethyl cellulose, 2.5 g of hydroxypropyl cellulose and 2.5 kg of ethanol. After drying, the granules were filled into hard gelatin capsules in an amount equivalent to 200 mg of alprenolol hydrochloride.

The capsules thus prepared slipped after ingestion and then released the dosage as a large number of small granules, each contained in a coating which caused slow release of the active ingredient. With this agent, a further security against local damage to the revenue channel is achieved.

The release of the active substance from this product, tested in artificial gastric juice (USP XX) with Annex II according to (USP XX), was as follows:

0.5 h 1 h 2h 3h 4h

21% 41% 72% 85% 90%

Biological Experiments Esophageal Stimulation

Tablets prepared according to Examples 3 and 4 were given for esophageal irritation with tablets containing 100 mg alprenolol hydrochloride (Aptin® ^R , AB Hassle) and tablets containing dialprenolol fumarate in an amount corresponding to 100 g of the hydrochloride, these tablets being analogous to Example 3 were prepared compared. The test in the anesthetized pig by introducing the tablets into the esophagus and fixation with a silk thread according to Olofsson et al. Acta Pharmacol, et Toxicol. 53, pages 385 to 391 to 391 (1983). After 5 hours, the tablets were withdrawn and the esophagus was rinsed with 50 ml of water. The mucosa was photographed by a fiber optic. The results are summarized in the following table:

Reaction in the preparation pig no esophagus

Tablet, Example 3 1 no reaction

2 no reaction

Tablet, Example 4 3 Erythema

4 no reaction

Alprenolol hydrochloride 5 heavy

tablet ulceration

6 ulceration

Alprenololfumarate 7 no reaction

tablet 8 ulceration

Thus, the alprenolol salts of maleic acid and benzoic acid-containing tablets produced significantly less adverse effects than the commercial alprenolol hydrochloride product.

In vivo absorption

The absorption of tablets prepared according to example 5 and alprenolol hydrochloride tablets (aptin ^(R1 ) with 100 mg were examined in 6 healthy subjects after fasting during one night, plasma samples were taken for 25 hours and the alprenolol content was determined by gas chromatography In the accompanying diagram, where alprenolol HCl (aptin "" tablets) with 100 mg (n = 6) and alprenolol benzoate tablets with 130 mg (n = 6), the absorption from the benzoate tablet was as fast and complete as from the reference tablet Absorbance of alprenolol from tablets prepared according to Example 7 was tested and compared to tablets containing 50 mg alprenolol hydrochloride (aptin ^fR1 , 50 mg) by orally administering two tablets to a fasting dog on various occasions: blood samples were repeated for 5 ^hours The plasma concentrations are found in the following Ta belle.

Alprenolol Hydro tablets

Chloride tablets Example 7

Time (h) (nmol / l) (nMoi / l)

<5

54 457 690 398 315 206 126

64 Both tablets were rapidly absorbed to about the same extent.

0.25 27 0.5 221 0.75 401 1 590 1.5 432 2 367 3 164 4 62 5 19

Claims (2)

Invention claim: 1. A process for preparing a Phenoxypropanolaminsalzes, characterized in that reacting alprenolol base with benzoic acid and / or maleic acid. 2. The method according to item 1, characterized in that reacting the alprenolol to the benzoate or hydrogen maleate. For this 1 page drawing Field of application of the invention The phenoxypropanolamine salts prepared by the process of this invention may be processed for use in human and veterinary medicine for the treatment of cardiac disorders. Characteristic of the known technical solutions Alprenolol with the systematic name 1- (2-allylphenoxy) -3-isoproylamino-2-propanol is described in SE-C-214378, GB-C-1 140508, DE-C-I 294955 and FR-C-1 479614. As salts, the hydrochloride, the lactate, the sulfate and the sulfamate have been proposed. For other substituted phenoxypropanolamines, salts of many acids have been generally and specifically suggested. To reduce the gastrointestinal side effect of locally irritating compounds, slow release preparations are used. Thus, potassium chloride is successfully used in preparations called Slow-K and Potassium Duretter (®). However, preparations of this type containing alprenolol hydrochloride do not reduce the risk of deleterious effects on the esophagus. On the contrary, most of the reported lesions stem from slow release preparations. Complex formation with carrageenan to reduce esophageal damage by emepronium, doxycycline and propranolol has been proposed in EP-AI-0091409. Such complexes are sparingly soluble in water but release the active ingredient in the acidic environment of the stomach. The active ingredient content in these complexes is lower than in the original salts. This can cause problems in cases where high dosage tablets are desired. The pharmacological action of alprenolol is caused by the blockage of beta-receptors in the autonomic nervous system. In pharmaceutical preparations for oral administration, alprenolol is used as the hydrochloride. Alprenolol hydrochloride, however, has a strong local irritant effect. A number of ulcerations in the esophagus of patients have been reported. Attempts to eliminate these side effects by using coated tablets have not yet been successful. Object of the invention The aim of the invention is the preparation of new better compounds for the treatment of heart diseases such as high blood pressure, angina pectoris or arrhythmias. Explanation of the essence of the invention The object of the invention is a process for the preparation of compounds by means of which alprenolol can be administered in a form which avoids local irritation and its sequelae while maintaining high absorption of the drug from the gastrointestinal system. These compounds are salts of alprenolol with benzoic acid or maleic acid. These salts proved to be very well tolerated and did not cause damage to the esophagus. In addition, the absorption of the new salts is about as high as that of the hydrochlorides. Preferred salts are alprenolol benzoate and alprenoiol hydrogen maleate. Most preferred is alprenolol benzoate. The preferred salts according to the invention are represented by the formula