DK143095B - PROCEDURE FOR THE PREPARATION OF SOLID MEDICINALS CONTAINING SUBSTITUTED XANTHINES WITH EXTENDED RELEASE OF THERAPEUTICALLY EFFECTIVE COMPOUNDS - Google Patents

Description

143095

The invention relates to a process for the preparation of solid drugs containing substituted xanthines with extended release of therapeutically effective compounds.

5 It is known to produce orally useful drugs with delayed release of active substance, providing active substances such as granules or press bodies with one or more of such enclosures - each of which may also contain active substances - which are not or only partially soluble in the gastric juice, e.g. with keratin, heavily soluble fatty acid esters, gelatin capsules, lacquers, e.g. those of acrylate resins. Also known are compositions containing several layers of active substances, without these layers forming complete envelopes.

It is also known to achieve a time-delaying effect by mixing the active substance with high molecular weight, swellable, but indigestible, insoluble carriers such as polyethylene, polyvinylpyrrolidone and polyvinyl chloride. By means of these carriers, the release of the active substance is greatly inhibited. Resorption in the gastrointestinal tract may also be delayed by using ion exchange resins.

From the disclosure of GB Patent No. 815,969 and the disclosure to U.S. Patent No. 2,953,493, it is known that mixtures of 25-hexyl-3,7-dimethylxanthine and nicotinic acid prepared by mixing in conventional manner have therapeutic effect. .

Further, from the specification of US Patent No. 2,446,916, it is known to prepare mixtures of a hexanitrate of a hexavalent alcohol, a desensitizer, a xanthine and nicotinic acid or a salt thereof by grinding the ingredients to obtain homogeneous mixtures.

2 U3095

However, in the methods known from the aforementioned patent specifications, there is no preparation of sustained release mixtures of the therapeutically effective compounds.

In the known methods for the preparation of solid drugs with prolonged release of therapeutically active compounds, it is necessary to use one or more adjuvants which cause the delay. However, this is not desirable in all cases, as apparatus for dosing these substances and for applying envelopes or layers is required.

It has now been found that solid drugs containing substituted xanthines and with extended release of therapeutically active compounds can be prepared, and the process of the invention is characterized by mixing at least two therapeutically effective compounds at elevated temperature. which are absorbed faster than the other in the human or animal body, under such conditions that at least one of the compounds melts, while the others are distributed homogeneously therein, and of which one is a xanthine which is or the 7-position is substituted by a) an aliphatic hydrocarbon group of 3 to 20, preferably 5 to 15 C atoms, or b) a hydroxyalkyl or oxoalkyl group of 6 to 20, preferably 7 to 15 C atoms, or c) a benzyl group, and in both of the other positions mentioned is substituted by an alkyl group of 1 or 2 C atoms, which substituents 30 a) - c) are bonded to the xanthine backbone by acyclic C atoms , after which the mixture thus obtained is solidified. Conveniently, the solidified mixture is brought over a granulation in the form of a solid drug. Of course, three or even more pharmaceutically active substances can also be distributed to each other by the method according to the invention.

143095 3

By means of the distribution in the second substance it is possible to delay the effect of a substance / whose effect otherwise expresses rapidly, ie. the release of this active substance takes place over a long period of time. This is particularly desirable when e.g. for therapeutic reasons, a prolonged action of one or more active substances must be obtained, or, by the delay of the resorption of one or more active substances, undesirable side effects of individual constituents of the preparation, e.g.

10 gastrointestinal tract irritations, the appearance of unwanted sudden changes in blood pressure and sensations of heat.

It is the release of the compound which is homogeneously distributed in the second compound which is delayed, and this may apply to both the initially faster and the initially slower active compound.

According to the invention, it is particularly advantageous to use nicotinic acid (pyridine-3-carboxylic acid) and / or its therapeutically equivalent equivalents, such as nicotinic salts, nicotinic esters or amides as the other therapeutically active compound.

According to the invention, it is particularly advantageous to use a combination of 1-hexyl-3,7-dimethylxanthine and nicotinic acid and / or its therapeutically effective derivatives. Since, in this combination, 1-hexyl-3,7-dimethylxanthine has the lower melting point, a particularly favorable processing is possible in excess of this component. Furthermore, such a ratio of proportions has the advantage of having a particularly good therapeutic effect.

The drugs 30 obtained by the method of the invention are especially intended for oral administration, but a different mode of administration, e.g. The rectal is also possible.

The mutual distribution takes place by distributing in one melt of one active substance the other active substance (s). Mixture of the active compounds may e.g. be done by processing on friction rollers or in a worm press. This pressure, together with the rubbing, causes the melting of at least one component and then the possibility of an intimate mutual distribution.

The choice of the component into which the other components are to be incorporated depends on the melting points and the mutual volume ratio. As a rule, the higher melting components will be incorporated into the lower melting, whereby the higher melting can be incorporated into the lower melting in solid or liquid form. This is especially advantageous when the lower melting components are present in the greatest amount. However, it is also possible to distribute a three-component system, e.g. by melting component 15 with the middle melting point and incorporating the other two components, especially when the lowest melting substance is present only in relatively small amounts.

Conveniently, the mixture present in homogeneous distribution is solidified under cooling, e.g. by means of 20 cooling bands or cooling rollers, to achieve a fast and thus uniform solidification.

Although not necessary, the products prepared by the process of the invention can be processed with therapeutically inactive processing aids. As processing means, e.g. lactose, mannitol, talc or even swelling agents, e.g. milk protein, starch, gelatin, cellulose or derivatives thereof, such as methyl cellulose, hydroxyethyl cellulose, or suitable swelling or non-swelling copolymericates. By means of such auxiliaries which may be added in greater or lesser amounts, the decay of the solid drug and thus the release of the active substance may be further influenced. Thus, a further deposit effect can be obtained. Such an effect can also be achieved by further coating the solid drug obtained according to the invention, e.g. granules, with a physiologically acceptable envelope, e.g. with a lacquer such as a lacquer made from a polymerization or condensation resin.

On the other hand, the usual additives such as colloidal silicic acid, starch, interface actives, e.g. glycerol fatty acid esters, long chain alcohols, e.g. cetyl alcohol, or wax, which prevents premature sedimentation by solidifying the molten mixture.

It is also possible to mix a granulate with at least one additional therapeutically active substance which is not treated according to the invention and which may already be present in the granulate as a component. Thus, the temporal effect of the drug may vary such that the one part of this component is fast acting, while the other part's effect is first delayed.

The granulation can be done in a manner known per se. The granulate may be administered as such or processed into other pharmaceutical forms, e.g. capsules, tablets and dragees.

In the processing of capsules and, optionally, tablets or dragees, a further delay effect may be obtained, e.g. by the use of capsules or by providing the tablets or dragees with an additional sheath. It is also possible to squeeze the granulate into tablets and drag them.

By the method according to the invention, control of the time for delivery of active substance is possible within wide limits. Eg. the delivery can be extended for up to 12 hours. In this way, the end 30 of the release of active substance can also be regulated.

The following are described comparative tests with tablets (A) prepared from the granulate of Example 1 below containing 1-hexyl-3,7-dimethylxanthine and nicotinic acid and tablets (B) prepared in the usual way by dry mixing and pressing the same two ingredients.

2 tablets (A) containing 400 mg of 1-hexyl-3,7-dimethyl-xanthine and 100 mg of nicotinic acid are administered to two men who have not taken caffeine in the last three days prior to administration of the tablets. For the next 24 hours, total urinary excretion is collected for each person for periods of 3 hours. After a further 3 days without caffeine intake, 2 tablets (B) containing 10 400 mg of 1-hexyl-3,7-dimethylxanthine and 100 mg of nicotinic acid are administered.

The urine is collected for the same period of time as above and at the same intervals. The individual urine samples are analyzed as follows:

The secreted 1-hexyl-3,7-dimethylxanthine and its degradation products are isolated from the urine samples collected for the 3 hour periods. These portions are adjusted to pH 1-2 by the addition of 2N sulfuric acid and then extracted with 10 x 20 ml of freshly distilled chloroform. The mixed chloroform extracts are washed with 5 ml of 0.1 N sodium-20 hydroxide solution and with water. After this treatment, the chloroform phase contains the original dimethylxanthine and the metabolic products I, II and III listed below. The extracts are concentrated in vacuo and then dissolved in chloroform. A portion of the solutions is etherified with bis-trimethylsilyl acetamide. Both solutions are subjected to gas chromatography using a "Varian 1520 B" gas chromatograph. An isotherm of 185 ° C, an injector temperature of 280 ° C and a detector temperature of 315 ° C are used. The column has a length of 30 180 cm and a diameter of 3.2 mm. The stationary phase is 2% KE 60, the carrier material is "Aeropak 30" with a particle size of 100-200 mesh. The detector used is a flame ionization detector.

The analysis shows that the extract contains unreacted 1-hexyl-3,7-dimethylxanthine and the following metabolic products: 1- (5'-oxohexyl) -3,7-dimethylxanthine (I), 1- (5 '' hydroxyhexyl) - 3,7-dimethylxanthine (II) and 1- (4 ', 5'-dihydroxyhexyl) -3,7-dimethylxanthine (III).

The quantities of these products found are added and the total amount corresponds to 400 mg of the original 1-hexyl-3.7-5 dimethylxanthine. In tablet (A), 26.9 mg of the original dimethylxanthine is in the form of metabolic products, and in the case of tablet (B), 28.0 mg of the 1-hexyl-3,7-dimethylxanthine is in the form of metabolic products. By graphically depicting the test results, it appears that the excretion of the metabolic products originating from (B) is completed after 24 hours; In contrast, metabolic products derived from tablet (A) can still be detected after 49 hours. Furthermore, in the latter case, the amount of secreted weight is more uniform.

In depicting the amount of metabolism products in% of the original 1-hexyl-3,7-dimethylxanthine as a function of time in hours, it appears that within 6 hours after administration of tablet (B), about 68% of the original xanthine compound is secreted. In contrast, during the same period only approx. 17% of the original xanthine compound from tablet (A). Only after 18 hours is approx. 68% of the original xanthine compound in tablet (A) is secreted.

It is clear from the above comparison experiments that the tablets prepared using the method of the invention have a substantially longer release of active substance relative to the comparative compound.

The process of the invention is further illustrated in the following examples.

Example 1 200 g of 1-hexyl-3,7-dimethylxanthine are melted and maintained at a temperature of 90 ° C. In this melt, 50 g of nicotinic acid (3-pyridinecarboxylic acid) is homogeneously distributed by means of a suitable stirrer, cast over the solidification point into blocks or a thin layer and granulate after solidification in a manner known per se. The granules can be administered as is, or can be encapsulated. However, it can also be molded into press bodies, e.g. tablets, as follows: 250 g of granules are over-powdered with 25 g of starch and 25 g of a mixture of talc, colloidal silicic acid and magnesium stearate and pressed into round biconvex press bodies having a diameter of 10 mm and a weight of 300 mg. Above all, these press bodies release the nicotinic acid slowly over a few hours, thus with a significantly delayed effect.

Example 2 200 g of 1-hexyl-3,7-dimethylxanthine are clearly melted and therein distributed 20 g of 3-dimethylamino-1-phenyl-1- (p-) tolylpropane hydrochloride and 50 g of nicotinic acid homogeneously at a temperature of about 80 -90 ° C. Then proceed as in Example 1.

A granulate is also obtained which delivers the active substances with delay.

Example 3 200 g of 1-hexyl-3,7-dimethylxanthine and 50 g of nicotinic acid are mixed homogeneously and fed to a friction roller which is heated to melt at least one blend component. A scaly product is obtained which has the same properties as the product of Example 1. The powder mixture can also be fed to a screw press. Thereby the heat of friction causes the 1-hexyl-3,7-dimethylxanthine to melt or soften, whereupon the nicotinic acid is distributed homogeneously. A pressurized kneading apparatus which can be heated to melt at least one blending component and is provided with sigma blades also provides a delayed action product.

Example 4 In a clear melt of 150 g of 1-isoamyl-3,7-dimethylxanthine, 50 g of nicotinic acid are distributed at 110-120 ° C. It is then followed as in Example 1. The obtained product is further processed into granules or to press bodies which deliver the active substances with delay.

Example 5 50 g of 1-hexyl-3,7-dimethylxanthine are clearly melted and 50 g of calcium nicotinate are distributed therein. This results in a high viscous suspension which is allowed to cool. After solidification, the mixture is granulated. The granulate is then pressed with 100 g of 1-hexyl-3,7-dimethylxanthine and tablet auxiliaries such as corn starch, talc, magnesium stearate for 250 mg tablets. These tablets release the active substances with delay.

EXAMPLE 6 500 g of an analog of Example 1 are melt mixed with 50 g of one or more swellable compounds such as hydroxyethyl cellulose; 15 g of a lubricant such as talc is added and pressed into tablets or drum cores. Binders such as gelatin, polyacrylates, polyethylene glycol 20 and polyvinylpyrrolidone may also be added to the pulp. The molds obtained produce the active substances with considerable delay.

Example 7 200 g of 1-hexyl-3,7-dimethylxanthine are melted with 50 g of cetyl alcohol at ca. 90 ° C. In the melt, 50 g of nicotinic acid is suspended; the pulp is solidified and therefrom made a granulate which is processed into drug formulations using usual tableting auxiliaries or filled into capsules.

The active substances are released from the obtained drug form bodies over 8-10 hours. Here too, the release of active substance can be further delayed by the addition of swellable substances.