Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients

Definitions

• the present invention is related to new salts of the compound alprenolol which is a therapeutically active compound used in treatment of cardiac disorders such as hypertension, angina pectoris and arrhythmias.
• the pharmacological effect of alprenolol is exerted through blockade of beta receptors in the autonomic nerve system.
• alprenolol is used as the hydrochloride.
• alprenolol hydrochloride has a strong local irritating effect. A number of ulcerations in the oesophagus of patients have been reported.
• the object of the invention is to provide alprenolol in a form that avoids the side effects mentioned while maintaining a high absorption of the drug from the gastrointestinal system.
• Alprenolol having the systematic name 1-(2-allylphenoxy)-3-isopropyl- amino-2-propanol, is described in SE-C-2 4 378, GB-C-1 140 508, DE-C-1 294955 and FR-C-1 479614.
• salts were proposed the hydro ⁇ chloride, lactate, sulfate and sulfamate.
• phenoxypropanolamines salts of numerous acids have been proposed in generic and specific terms.
• the present invention provides as new salts the salts of alprenolol with benzoic acid or maleic acid. These salts ' are found to be very well tolerated and they are not causing damages on the oesophagus.
• the absorption of the new salts is about as high as for the hydrochloride.
• Preferred salts are alprenolol benzoate and alprenolol hydrogen aleate. Most preferred is alprenolol benzoate,
• Oral pharmaceutical preparations of the new alprenolol salts are found to provide the greatest advantages over previously known oral alprenolol preparations, and thus such oral preparations constitute a preferred embodiment of the invention. However, the new salts may advantageously be used also in rectal pharmaceutical preparations.
• the new salts of the invention may be formulated into pharmaceutical preparations in a manner known per se. They are suitable also for forming slow-release preparations, as they have a high content of the active compound alprenolol. It is thus possible to produce both products which are rapidly absorbed and products with a prolonged duration.
• the alprenolol salt may be mixed with suitable excipients such as lactose, saccharose, sorbitol, mannitol, starch such as potato starch, corn starch, amylopectin, cellulose derivatives or gelatine, as well as with a lubricating a.gent such as magnesium stearate, calcium stearate, polyethyleneglycol , or the like, and be pressed into tablets.
• suitable excipients such as lactose, saccharose, sorbitol, mannitol, starch such as potato starch, corn starch, amylopectin, cellulose derivatives or gelatine
• a lubricating a.gent such as magnesium stearate, calcium stearate, polyethyleneglycol , or the like
• the above prepared ' core may be coated with a concentrated solution of sugar, which solution may contain e.g. gum arabic, gelatine, talc, titandioxide or
• soft gelatine capsules pearl-shaped, closed capsules
• soft gelatine capsules which consist of gelatine and e.g. glycerine
• the alprenolol salt is mixed with a vegetable oil.
• Hard gelatine capsules may contain the active compound in combination with suitable excipients . such as lactose, saccharose, sorbitol, mannitol, starch (such as e.g. potato starch, corn starch or amylopectin), cellulose derivatives or magnesium stearate.
• Dosage units for rectal administration may be prepared in the form of suppositories, which contain the active substance in a mixture with a neutral fat base, or they may be prepared in the form of gelatine-rectal capsules which contain the active substance in- a mixtur with a vegetable oil or paraffin oil.
• alprenolol salts of the invention may be administered in equal molar amounts as recommended for alprenolol hydrochloride.
• suitable daily dosages of the new salts would be from 0.1 to 1.5 g.
• Dosage units may suitably contain amounts corresponding to 50 to 200 mg alprenolol hydrochloride.
• the salts of the invention may be prepared in a manner known per se by reacting alprenolol base with maleic acid and benzoic acid, respect- ively.
• Alprenolol hydrogenmaleate (128 g, corresponding to 100 g of alprenolol hydrochloride) was mixed with anhydrous lactose (136 g), microcrystall ⁇ ine cellulose (90.7 g) and magnesium stearate (3.3 g). The mixture was compressed into tablets with 10 mm diameter weighing 358 mg. The tablets disintegrated in 37°C water in 3 min. (test according to USP XX)
• Alprenolol benzoate (130 g, corresponding to 100 g alprenolol hydro ⁇ chloride) was mixed with anhydrous lactose, microcrystalline cellulose and magnesium stearate according to Example 3. Tablet weight 360 mg. Disintegration time according to USP XX 3.5 min.
• Tablets were prepared in a manner analogous to Example 3 of a mixture of alprenolol benzoate (260 g), anhydrous lactose (142 g), micro ⁇ crystalline cellulose (181 g), crosslinked polyvinylpyrrolidone (29 g) and magnesium stearate (6 g).
• the tablet weight was 309 mg and the time of disintegration 20 s.
• 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 ethyl cel ulose 10 cps in 71 g of ethanol 95%. The moist mass was dried and milled through a 1.0 mm sieve. Anhydrous lactose (115 g), microcrystalline cellulose (90 g) and magnesium stearate (4.9 g) were added. Tablets weighing 510 mg were made with 12 mm punches. The tablets disintegrated very slowly. The dissolution properties in artificial gastric juice were compared with commercial
• Alprenolol hydrogenmaleate 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!inked polyvinylpyrrolidone (14.5 g) and magnesium stearate (3 g). The mixture was compressed into tablets with 10 mm diameter weighing 308 mg. The disintegration time was about 10 s and the dissolution in artificial gastric juice was complete in 10 min.
• 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), di-sodium hydrophosphate (10 g) were mixed in an intensive mixer. The mixture was moistened with about 35 g of water and was worked until round granules were formed. These were dried and granules greater than 1.0 mm and smaller than 0.5 mm were sieved off. The granules were coated in a fluid-bed coating equipment with a solution consisting of 10 g ethyl cellulose, 2.5 g hydroxypropyl cellulose and 2.5 kg ethanol. After drying the granules were filled into hard gelatine capsules in an amount corresponding to 200 mg of alprenolol hydrochlori.de.
• the capsules thus prepared disintegrate after ingestion and then releas the dosage as a large number of small granules each contained within a coating which causes slow release of the drug. By these means further safety against local damage in the digestive channel is achieved.
• Tablets prepared according to Examples 3 and 4 were compared on oesophagus-irritating effect with tablets containing 100 mg alprenolol hydrochloride (Aptin , AB-Hassle) and tablets containing di-alprenolol fumarate in an amount corresponding to 100 g of the hydrochloride, said tablets being prepared in analogy with Example 3.
• the test was carried out in the anaesthetized pig by lowering the tablets into the oesophagus and fixing with a silk thread according to Olofsson et al., Acta Pharmacol, et Toxicol. 53, 385-391 (1983).
• tablets containing the alprenolol salts of maleic acid and benzoic acid produced substantially less harmful effects than did the marketed alprenolol hydrochloride product.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Medicinal Preparation (AREA)

Applications Claiming Priority (2)

Publications (1)

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• 1984
  • 1984-04-05 SE SE8401907A patent/SE8401907L/sv not_active Application Discontinuation
• 1985
  • 1985-03-14 ZA ZA851934A patent/ZA851934B/xx unknown
  • 1985-03-15 IL IL74611A patent/IL74611A0/xx unknown
  • 1985-03-22 GB GB08507473A patent/GB2153828B/en not_active Expired
  • 1985-03-29 PL PL25266085A patent/PL252660A1/xx unknown
  • 1985-04-01 AP APAP/P/1985/000009A patent/AP8500009A0/en unknown
  • 1985-04-01 MA MA20618A patent/MA20396A1/fr unknown
  • 1985-04-02 ES ES541850A patent/ES8609210A1/es not_active Expired
  • 1985-04-03 GR GR850840A patent/GR850840B/el unknown
  • 1985-04-03 JP JP60501740A patent/JPS61501779A/ja active Pending
  • 1985-04-03 WO PCT/SE1985/000159 patent/WO1985004579A1/en unknown
  • 1985-04-03 EP EP85902182A patent/EP0209520A1/en not_active Withdrawn
  • 1985-04-03 AU AU42311/85A patent/AU4231185A/en not_active Abandoned
  • 1985-04-04 DD DD85274891A patent/DD232488A5/de unknown
  • 1985-04-04 PT PT80232A patent/PT80232B/pt unknown
  • 1985-11-12 NO NO854518A patent/NO854518L/no unknown
  • 1985-12-04 KR KR1019850700365A patent/KR860700008A/ko not_active Application Discontinuation
• 1986
  • 1986-07-24 HK HK555/86A patent/HK55586A/xx unknown
  • 1986-12-30 MY MY650/86A patent/MY8600650A/xx unknown

Non-Patent Citations (1)

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