NO157204B - PROCEDURE FOR THE PREPARATION OF GALENIC PREPARATION WITH CONSTANT EFFECTIVENESS. - Google Patents

Abstract

1. A pharmaceutical composition which contains a calcium-antagonistic active compound, with or without additional active compounds, is intended for oral administration to produce a sustained action for continuous therapy and contains only the sustaining dose of active compound, bound to pharmaceutical auxiliaries, wherein the calcium-antagonistic active compound is Gallopamil or Verapamil and wherein, at the sustaining dose, the ratio of the constituents with rapid release of active compound to those with sustained release of active compound is from 1 : 0.6 to 1 : 6.

Description

The present invention relates to a method for producing a galenic preparation which contains a calcium antagonist, and possibly other active compounds.

In drug therapy, the use of oral galenic drugs with prolonged release of the active ingredients is common and partly necessary in order to extend the effective

the duration of drugs, especially those with short biological half-lives. Oral drugs with prolonged release of the active ingredient are significantly more favorable for the patient, as the reduced dosing frequency compared to ordinary preparations without prolonged release of the active ingredient gives the therapy greater safety. When using oral drugs with prolonged active substance f-release, it is also often prevented that the drug gives unwanted concentration peaks in plasma.

Retard drugs must have an initial phase with rapid release of the active substance, followed by a maintenance

phase to achieve a prolongation of the therapeutically desired plasma concentration. The initial phase is absolutely necessary, so that the required plasma concentration is achieved as quickly as possible. This form of retard medication is described as ideal,

(see in this connection Thieme Verlag, Stuttgart,

Pharmazeutische Technologie 1978, p. 487). Retard medications are also often used, especially long-term therapeutics, which have no initial dose, but only the maintenance dose. The maintenance dose is released evenly and protractedly.

With repeated intake of a drug, depending on the biological half-life, an equilibrium (steady state) is established between the elimination of the active substance and its uptake in plasma.

In order to achieve a sufficiently high therapeutic steady-state concentration for a substance with a short half-life, frequent administration is necessary. However, this is undesirable from the patient's point of view.

A similar situation exists with substances with longer half-lives, where a predominant proportion is metabolized before the substance reaches the portal circulation (first-pass effect in the intestine and/or liver). In general, therefore, retard medications with substances with a pronounced first-pass effect are considered very high

critical (Der Internist 1_9 , 333 ( 1 978), Pharm. Ind. £0,

37.4 (1 978), especially page 381, left column).

A pronounced first-pass effect can be found among a number of beta-receptor blockers, e.g. propranolol, or calcium antagonists, such as Verapamil and Gallopamil.

U.S. Patent 4,248,858 describes a new retard drug of propranolol. According to this, 160 mg of propranolol is available in the form of a tablet where the release of the active substance is retarded through encapsulation in a gel

formers and insoluble polymers. The tablet core is surrounded by

an outer coating layer containing a further 20 mg.

propranolol with a greater release rate for the active substance, and is separated from this by a gastric juice-resistant film that will prevent the active substance in the retarded part of the tablet from being released already in the stomach.

This form is only suitable for btoff such as propranolol, which

on the first liver passage forms 4-hydroxypropranolol,

which has a similar effect to propranolol itself (Brit. J. Pharmacy,. (1971) 4_3, 222).

The present invention relates to a method for producing a galenic preparation containing a calcium-antagonistic active substance and possibly other active substances, for

prolonged-acting oral administration for long-term therapy,

and which only contain the maintenance dose of the calcium-antagonistic active substance bound to galenic excipients. The method is characterized by the fact that gallopamil or verapamil is used as the calcium-antagonistic active ingredient, and two mixtures are produced:

a) mixture with rapid active ingredient release where the active ingredient is crushed with sugar, cellulose, a binder and water and pressed through a sieve, the granules thus obtained are dried, sieved and cellulose and a lubricant are added, b) mixture with slow active ingredient release where the active ingredient is mixed with sodium alginate, a binder and cellulose, carefully crushed with water and pressed through a sieve, and the granules thus obtained are dried, sieved and cellulose and a lubricant are added, and the final mixtures prepared according to a) and b) are mixed in the ratio a:b = 1:0.6 to 1:6, based on the active ingredient content, and incorporated into coated tablets, layered tablets or capsules. . Verapamil (X=H) and Gallopamil (X=OHCH2) have the following formula:

As medicine, the compounds are preferably used as hydrochlorides.

In addition to these compounds, the preparations produced according to the invention may also contain additional active substances such as diuretics, psychotropic drugs and antihypertensives. These additional components are present, depending on their biological half-life, in the phase with faster and/or slower release of action.

The ratio between the active substance forms with fast and slow release of Verapamil, resp. Gallopamil, in the galenic preparation, lies between 1:0.6 and 1:6, preferably between 1:1 and 1:4, and especially between 1:1.2 and 1:3.

When dosed in the right amount, this ratio ensures that wide-ranging, constant and therapeutically appropriate plasma levels are maintained, as the active substances are released during the gastrointestinal transit time (usually 3 to 5 hours).

The preparation of the galenic preparations can take place according to known methods. Coated and layered tablets, where a layer, resp.

the tablet core, consists of retarded granules and a further layer, resp. the encasing tablet part of the jacketed tablet consists of a granule where the active ingredient is released quickly, or retard dragees, where the retarded core is coated with a sugar layer containing the active ingredient with rapid release, can thus be produced according to well-known techniques.

A mixture with rapid active ingredient release is obtained by granulating the active ingredient with sugar, cellulose, starch and binder while adding separation agents and regulating substances to the granulate. The active ingredient proportions can be varied considerably in the granulate. Preferably they are at 40-80%. When using such granules as encasing material for coated tablets or when incorporating them into two-layer tablets, it has been shown that the release rate for the active ingredient is essentially independent of the pressure during tablet pressing.

Granules with prolonged active ingredient release are obtained using sodium alginate as a gel-former that does not dissolve in the digestive tract, but forms swollen particles from which the active ingredients diffuse slowly into the digestive fluids.

Particularly suitable sodium alginates are those in which 10% aqueous solutions have a viscosity of 100 to 300 cp. at 20°C. When using low-viscosity sodium alginates, the addition of natural substances that are insoluble in water, such as cellulose or starch, is recommended, while the addition of soluble substances such as lactose or low-molecular polyethylene glycols is recommended for high-viscosity sodium alginates. Also by using polyacrylic acid and polymethacrylic acid derivatives, very advantageous release rates can be achieved. The pressure during tablet pressing can also affect the release of the active substance in granules with a prolonged effect.

It is also possible to fill the active substance in granules or pellets with prolonged active substance release, together with the free or non-retarded active substances in a therapeutic unit, e.g. slip-on caps.

Through the invention, it is possible to produce preparation forms that contain Verapamil or Gallopamil and which provide a constant and effective active ingredient level over a long period of time.

The new retard preparations are perfectly suitable for use

as a long-term therapeutic, where relatively narrow and therapeutically effective plasma levels are achieved over the entire treatment period. With regular intake, there is thus no danger of the plasma level falling to the subtherapeutic range. Furthermore, the new retard form reduces the application frequency

to 1-2 times a day, whereby patient friendliness is clearly improved. Drug safety is also improved. The new preparations can also be prepared very easily using common methods.

Example 1

A. Production of the starting granules

a) Granules with rapid active ingredient release.

10.6 kg Verapamil, 4 kg cellulose powder, 0.6 kg

Kollidon VA 64 and 4 kg of lactose were carefully mixed and then moistened by stirring in 6 liters of water. By vigorous mechanical stirring and kneading, the mixture was processed into a moist dough which was converted into a granule by pressing through a sieve. After drying, the granulate was sieved again. After mixing in 9.7 kg of cellulose powder and 0.1 kg of magnesium stearate, a pressable granule was obtained.

b) Granules with slow active ingredient release

14 kg Verapamil, 25 kg sodium alginate, 4 kg Kollidon 30

(chain-shaped PVP, M=30,000) and 5 kg of cellulose powder were carefully mixed, moistened while stirring with 17 kg of water and mechanically processed by vigorous stirring and kneading into a moist dough, which, after pressing through a sieve, was processed into a granule. After drying the granulate, it was sieved again. By mixing 1.75 kg of cellulose powder and 0.25 kg of magnesium stearate, a pressable granule was obtained

B. Preparation of finished tablets.

Tablets with the following composition were pressed on a tablet press for the production of two-layer tablets:

Inner layer: 1.90 mg granules Aa (100 mg Verapamil)

Outer layer: 500 mg granules Ab (140 mg Verapamil)

For taste camouflage, tablets thus obtained were coated with a film varnish of cellulose derivatives and common plasticizers and dyes.

Example 2

Aa) Analogous to example 1 Aa, granules with rapid active ingredient release were produced by granulating sugars, celluloses and starches with the active ingredient and a binder. Separating agents and regulating substances were then added to the granules. Granules with the following composition were thereby obtained:

B. From the granules listed in tables 1-3, tablets were prepared analogously to example 1B. Among them, the free active substance amounts ranged from 60 to 150 mg, and the bound amounts between 80 and 190 mg Verapamil. The corresponding Gallopamil values were 30-80 resp. 40-100 mg.

Example 3

.From the granulate obtained according to Example 1 Ab, pressed cores with 140 mg of Verapamil were produced. These were coated in a press coater with a layer of granules from example 1 Aa (120 mg Verapamil) and then coated with a film varnish analogous to example 1 B.

Example 4

The granulate obtained according to example 1 Ab was pressed into press cores with 150 mg Verapamil resp. 75 mg Gallopamil. The granulate was then provided with a coating with a composition as indicated in table 4, so that the coatings contained 90 mg of Verapamil resp. 45 mg Gallopamil.

However, this method is laborious as the water must be removed. It is also difficult to achieve even distribution of the active ingredient in the coating layer. The best results were achieved with coatings that contained a low active substance content. After polishing with a 70% aqueous sugar solution (approx. 20-40 g sugar solution per 10 kg coating portion) they were coated with a film layer as described above. -

1 the examples mean:

Kollidon V 64: Mixed polymer of PVP and polyvinyl acetate in the ratio 6:4

Kollidon 30: Chain-shaped PVP, M 49,000

Kollidon 90: Chain-shaped PVP, M 1,100,000

Eudragit RL.: Polyacrylic and polymethacrylic acid derivatives Aerosil: Highly dispersed silicon dioxide

Claims (1)

Process for the production of a galenic preparation containing a calcium-antagonistic active substance and possibly other active substances, for oral administration with prolonged action for long-term therapy, and which only contains the maintenance dose of the calcium-antagonistic active substance bound to galenic excipients, characterized in that the gallopamil or verapamil is used as calcium-antagonistic active ingredient, and two mixtures are produced: a) mixture with rapid active ingredient release where the active ingredient is crushed with sugar, cellulose, a binding agent and water and pressed through a sieve, and the granules thus obtained are dried, sieved and cellulose and a lubricant are added, b) mixture with slow active ingredient release where the active ingredient is mixed with sodium alginate, a binder and cellulose, carefully crushed with water and pressed through a sieve, and the granules thus obtained are dried, sieved and cellulose and a lubricant are added , and the final mixtures prepared according to a) and b) are mixed in the ratio a:b = 1:0.6 to 1:6, based on the active substance content, and incorporated into coated tablets, layered tablets or capsules.