FI78391B - FOERFARANDE FOER TIDSBESTAEMD REGLERING AV FRIGOERING AV VERKNINGSMEDEL UR VERKNINGSMEDELSPREPARAT, SPECIELLT LAEKEMEDELSPREPARAT. - Google Patents

Abstract

1. Process for the time controlled release of active substances from sustained-release active substance preparations, in particular drug preparations, by addition of hydrophilic polymers characterized in that the release rate which is rising as a result of increasing viscosity steps of the hydrophilic polymers added is empirically determined and the desired release characteristic is adjusted using the values determined.

Description

1 78391

Method for controlling the release of active ingredients from active pharmaceutical preparations, in particular pharmaceutical preparations 5 It is known in pharmaceutical technology to mix active ingredients with pharmaceutical preparations so that the active ingredients are released from these preparations at a predetermined rate. In this way, for example, an increase in the duration of action can be achieved, thus avoiding too rapid and / or too strong a flow of the active ingredient and too high peaks in blood or tissue concentrations, thus leading to side effects.

If good solubility, or also good resorption of the active ingredient when administered orally to pharmaceutical products, is the basis for a rapid release flow, then the resorption of such active ingredient can be slowed down by inhibiting the initial dissolution properties. In the simplest case, this is done, for example, with highly soluble substances by mixing in poorly soluble excipients or by coating the substance with excipients which reduce solubility. As a general rule, highly water-soluble excipients must be treated with poorly soluble excipients and poorly water-soluble excipients with highly soluble or highly swellable excipients when good deceleration is required. Often, such preparations are even further coated with diffusion coatings.

It is also known to use hydrophilic polymers for retardation.

From J. Pharm. Sci. 55, p. 974 (1966), for example, it is known that the desired retardation is based solely on the formation of a viscous gel barrier which prevents the penetration of digestive fluids into the interior of the tablet.

In general, hydrophilic polymers have hitherto been used in pharmaceutical technology only as binders in aqueous solution to provide mechanically strong extrudates as well as extrudates with a high swelling capacity, the so-called as disintegrants in solid form to provide rapid disintegration of the tablet.

5 It has hitherto been very difficult for a person skilled in the art to use blowing agents such as guar gum, John's wort core flour, semisynthetic or synthetic polymers such as silicic acid, cellulose acetate phthalate, hydroxypropylcellulose or Car-10 first, quite extensive empirical experiments were needed to develop retardation ratios with a predetermined drug release characteristic.

It is an object of the present invention, by using a hitherto unknown law, to adjust the release properties of the retardation forms to the desired methods by simpler means and thus to minimize the number of empirical experiments in development work.

Surprisingly, it was found that when using hydrophilic polymers, in particular carboxymethylcellulose and methylcellulose, differences in solubility or swelling have - depending on the degree of substitution - only a very small effect on the release of the active ingredient from the delayed drug forms.

One skilled in the art would in fact have expected that when mixing, for example, carboxymethylcellulose with retarder preparations, the degree of substitution would be essential for aberration of the extrudates and associated release, as the solubility and swelling of this excipient would depend on may have a very different release rate due to the strength-35 delta of the drug products. However, it was found that the release of the active ingredient is mainly determined only by the degree of viscosity of the added hydrophilic polymers, which again, surprisingly, high viscosity polymers control the release of the active ingredient less, while low viscosity polymers slow down the release of the active ingredient.

The invention relates to a process for controlling the release of active ingredients from time-delayed active ingredient preparations, in particular pharmaceutical preparations, with the aid of sparingly soluble excipients, by adding hydrophilic polymers.

The process is characterized in that the release rate, which increases as a result of increasing viscosity levels of the added hydrophilic polymers, is determined experimentally and the desired release characteristic is adjusted using well-determined values.

Particularly preferred hydrophilic polymers are carboxymethylcelluloses (sodium carboxymethylcellulose, CMC, Na-cellulose glycolate). There are many of these on the market. They differ on the one hand in their degree of substitution, on the other hand within a certain range of substitution in terms of viscosity, which in turn depends on the degree of polymerization or molecular weight. The viscosity of common commercial products is determined in aqueous solution and is reported by the manufacturer on a quality basis. The readings in this patent application refer to numerical values reported by the manufacturers and are based on the viscosity determination published in Hercu-30 les, Wilmington, Delaware, USA, regarding the technical numerical values, chemical and physical properties of cellulose resin 800-6A / G.

Not only by using hydrophilic monomers with a completely defined viscosity, but also by mixing polymers of different viscosity grades, the rate of release of the active ingredient from solid retarder preparations can now be varied and controlled in a manner hitherto unknown. For example, by using a thorough mixing of the various carboxymethylcelluloses in the viscosity bridge, retarder products are obtained whose release path is between the release paths that the individual components would have had.

Carboxymethylcelluloses are particularly well suited to the process according to the invention because they are commercially available in various viscosities, from about 0.02 Pa.s up to about 40 Pa.s and because, in particular with regard to their stability and 10 their ability to tolerate active substances and other excipients.

The method according to the invention is advantageous for the development of retarder drugs, since a large number of experiments can be avoided. In the past, it was necessary to perform large series of experiments to find compositions that allow the required release of the active ingredient. In this case, the recipes were either chosen arbitrarily and the series of experiments were varied, or according to the researchers' experimental design, certain strongly influencing factors were sought, which had to be varied at different levels in each case. In this case, it was necessary to perform the planned experiments, examine the products obtained and, on the basis of the results, make a selection for the next series of experiments.

When using the method according to the invention, these works are generally not necessary or their scope is substantially reduced; rather, after a preliminary test, it is possible to find, for example, the probably suitable degree of viscosity of carboxymethylcellulose. If the desired release of the active ingredient does not occur, the appropriate release can be adjusted using mixtures of carboxymethylcelluloses of different viscosities.

Once this adjustment has taken place, products are obtained which are in each case similar in qualitative and quantitative composition and differ only in the degree of viscosity of the carboxymethylcellulose 35 used.

Because the products are assembled in the same way, the machining characteristics are also the same. Thus, there is no risk that by varying the release rates, the physical properties, e.g. tabletability, will also change. The stability of the active ingredient of such products is also the same at all viscosity grades and thus no longer needs to be determined separately by long-term stability tests for each modification.

The amounts of polymers added are usually between 0.1 and 10% by weight of the total weight of the drug preparation. When carboxymethylcellulose is used, amounts between 0.5 and 5% by weight are preferred.

10 In principle, the method can also be used for other active substance preparations, such as, for example, animal feeds, fertilizers or herbicides.

Example 1 100 g of hydrogenated castor oil, 150 g of stearic acid-15a and 750 g of lactose were homogeneously mixed with 10 g of carboxymethylcellulose of different viscosity grades and melt granulated in a known manner.

The following viscosity grades were used: a) 0.05 Pa.s 20 b) 0.3 Pa.s c) 0.6 Pa.s d) 3 Pa.s e) 6 Pa.s f) 20 Pa.s 25 g) 40 Pa.s

All mixtures were then compressed on average at the same pressure into round convex tablets with a diameter of 11 mm and a weight of 490 mg. Disintegration of the tablets was examined for weight loss as described in National Formulary XIV on page 985 in artificial gastrointestinal fluid, with the tablet residues dried at 45 ° C for 10 hours and weighed as shown in Figure 1 as the distance from the abscissa.

35 It is clear from Figure 1 that the weight loss of the tablets depends on the viscosity of the added carboxymethylcellulose.

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Example 2

Demonstrate control of the intended protein release within a predetermined definition.

According to Example 1, tablets with a total weight of 300 mg and an active ingredient content of 60 mg (Diltiazem-HCl) are prepared. The determination of the active ingredient took place in the liquid medium at the intervals shown on the abscissa. First, carboxymethylcellulose having a viscosity of 0.3 Pa.s. was added.

The result is shown in Figure 2a.

The release residues according to Figure 2b had been given in advance.

Based on the curve in Figure 1, a tablet prepared using carboxymethylcellulose-15 having a viscosity of 3 Pa.s. The result of the release test is shown in Figure 2c, indicating that the release occurred too rapidly. The use of carboxymethylcellulose having a viscosity of 0.6 Pa.s thus gave a release characteristic within exactly predetermined limits (Figure 2d). The same result was obtained by mixing carboxymethylcellulose having a viscosity of 0.3 Pa.s with one having a viscosity of 3.0 Pa.s. (cf. Figure 2e).

Claims (4)

7 78391 1. A method for controlling the release of active ingredients over time from slow-release active ingredient preparations, in particular pharmaceutical preparations, by the addition of hydrophilic polymers, characterized in that the release rate which increases as a result of the increased viscosity values determined in favor. Process according to Claim 1, characterized in that methylcellulose and / or carboxymethylcellulose are added as hydrophilic polymers. Process according to Claims 1 and 2, characterized in that the viscosity of the hydrophilic polymer is between 0.02 and 40 Pa.s. Process according to Claims 1 to 3, characterized in that the viscosity is adjusted by mixing hydrophilic polymers with different degrees of viscosity in order to obtain a value between these degrees.