WO2005034918A1

WO2005034918A1 - Pellets containing a pharmaceutical ingredient

Info

Publication number: WO2005034918A1
Application number: PCT/HU2004/000094
Authority: WO
Inventors: Pál FEKETE; Tibor KORBÉLY; Ágnes BOZSÓ; Eszter MÓRICZ
Original assignee: EGIS Gyógyszergyár Rt.
Priority date: 2003-10-10
Filing date: 2004-10-08
Publication date: 2005-04-21
Also published as: HU227115B1; HU0303383D0; HUP0303383A2; HUP0303383A3

Abstract

The invention relates to pellets containing a pharmaceutical ingredient, namely 5-chloro-4-[{3-({2-(3,4-dimethoxyphenyl)ethyl}methylamino)-propyl}amino]-3 (2H)-pyridazinone (E)-2-butene-dioate (1 : 1) (CAS: 190333-92-7), and a process for the preparation thereof. The pellets according to the invention are nearly spherical in shape and contain, in addition to the active ingredient, 10 to 60 % by weight of sodium chloride and/or potassium chloride, 10 to 60 % by weight of micro-crystalline cellulose and optionally other pharmaceutically acceptable excipients and/or pelletization promoting additives. Said pellets are particularly suitable to be coated with a layer ensuring a controlled release of the active ingredient.

Description

PELLETS CONTAINING A PHARMACEUTICAL INGREDIENT

Field of the invention

The invention relates to pellets containing a pharmaceutical ingredient, namely 5-chloro-4- [ {3- ({2- (3,4-dimethoxyphenyl) ethyl } methyl ami no) - propyl }amino] -3 (2H) -pyridazinone (E) -2-butenedioate (1:1) of the formula (I) (CAS: 190333-92-7),

(I)

and a process for the preparation thereof.

Technical background of the invention

5-Chloro- -[{3-({2-(3,4-dimethoxyphenyl) ethyl } - methylamino) propyl } -amino] -3 (2H) -pyridazinone (E) -2-butenedioate (1:1) is a pharmaceutical ingredient having antiarrhytmic activity. In the course of the therapeutic application of this ingredient extended release pharmaceutical dosage forms are much more effective than immediate release dosage forms , as they provide a uniform therapeutic effect and enable a decrease in the number of both the side-effects and the drug administrations.

The most advantageous forms of sustained release pharmaceutical dosage forms are pharmaceuticals containing drug-loaded pellets. Pellets are spherical agglomerates 0,2-2 mm in diameter, which may be coated with one or more layer (s) regulating the release of the active agent and filled into hard gelatine capsules or tabletted. When administering these compositions to patients, in the stomach the capsules or tablets are disintegrated or distributed into individual pellets, which are then thoroughly mixed with the content of the stomach, and the discharge of the pellets from the stomach becomes more uniform. In this way a high active agent concentration cannot develop during the release of the active ingredient from the pellets, thus the plasma concentration becomes more even. Thus plasma concentration also becomes more even, the therapeutic activity of the composition becomes more favourable and the likelihood of the occurrence of side-effects considerably decreases .

From the beginning of the 1970s a special equipment is available for the preparation of pellets. This equipment serves basically for the purpose of extrusion-spheronization, centrifugal granulation, fluidization rotogranulation and high-shear mixing processes. By applying said equipment pellets can be produced directly, within only a few hours from a suitable powder mixture. Recently especially the application of fluidization rotary granulators and high-shear pelletizing machines combined with vacuo or microwave drying has become frequent, because by using such an equipment the production of pellets can be performed in a single apparatus (Isaac Ghebre-Sellassie: Pharmaceutical Pelletization Technology, Marcel Dekker, Inc. , New York, Basel, 1989).

Pellets can be prepared according to a number of methods, which all can be based on the following tree principles: 1. layering 2. extrusion-spherofonization 3. build-up granulation

By the layering method a mixture of the particles of the active ingredient and/or the auxiliary agents of small particle size is applied in layers onto a nearly lsodiametric seed material of larger particle size than the particles of said active ingredient and/or the auxiliary agents. The application can be performed in a conventional coating drum, in a centrifugal granulating equipment or fluidization spraying apparatus. In certain cases in the fluidization machines the active ingredient can be sprayed onto the surface of the inert granules from a solution. However, according to Hungarian patent specification No. 199,677 the high solubility (exceeding 600 mg/ml) of the active ingredient is disadvantageous from the viewpoint of the layering pelletization as well.

In case of the extrusion-spheronization process the active ingredient is mixed with the auxiliary agents and a liquid, the wet mass is fed into an extruder having holes of about 1 mm in diameter, and the extrudate is formed into uniform, nearly spherical particles in a rotary spheronization machine.

According to the build-up granulation process a mixture of the active ingredient and the auxiliary agents is mixed in a mixer or in a centrifugal or fluidization granulator, while a liquid is fed into the machine. During this process the particles of the powder mixture adhere to each other and become spherical upon the effect of shear forces and abrasive orces .

The last step of all pelletization processes is drying of the particles and separation of the fraction having a particle size suitable for further processing. The quality of the pelletization technology can be characterized by the product fraction, that is by the ratio of the mass of the pellets having the desired particle size to the total mass of the pellets. The pellets of unsuitable size are namely recycled to the manufacturing process and processed repeatedly, which results in an increase of the production time, costs of material and energy and the intensity of the labour involved in the procedure. In case of pellets filled into capsules the preferable particle size varies between 0.5 mm and 1.0 mm, in case of pellets compressed into tablets between 0.3 mm and 0.6 mm. In case of active ingredients readily soluble in water it is expedient to use pellets of bigger particle size, such as 0.8 - 1.6 mm or 1.0 - 2.0 mm, in order to decrease the amount of the coating material necessary for the coating modifying the release of the active ingredient.

In addition to the active ingredient pharmaceutically acceptable excipients are also applied for the pelletization, which promote the formation of pellets of appropriate shape and surface. Such excipipents may be fillers, lubricants, antiadhesives , disintegrants or drug release promoting additives, buffers, surfactants, surface-active substances, pelletization promoting additives or glidants (Isaac Ghebre-Sellassie: Pharmaceutical Pelletization Technology, Marcel Dekker, Inc., New York, Basel, 1989) .

As fillers which can be used for the pelletization e.g. calcium sul ate, calcium hydrophosphate , lactose, mannitol, szaccharose, starch and microcrystalline cellulose are mentioned. Suitable binders are e.g. gelatine, hydroxypropyl cellulose, hydroxypropyl-methyl cellulose, methylcellulose, polyvinyl pyrrolidone, szaccharose and starch. As lubricant calcium stearate, hydrogenated vegetable oil, magnesium stearate, mineral oil, polyethylene glycol , glycerine and propylene glycol may be applied.

The pellets may also contain antiadhesives, such as kaolin, talk or silicon dioxide, furthermore disintegrants or drug release promoting agents, e.g. alginates, sodium carboxymethyl cellulose, crospovidon, starch, pre-gelatinized starch, sodium carboxymethyl starch, or e.g. ethyl- cellulose, carnauba vax, shellac. Buffers (such as citrate, phosphate, carbonate and hydro- carbonate salts) , surface-active additives (such as polysorbate, sodium laurylsulfate) and substances promoting spheronization (e.g. micro- crystalline cellulose or a mixture of micro- crystalline cellulose and sodium carboxymethyl cellulose) may also be used for the pellets. Glidants applied during pelletization include e.g. colloidal silicon dioxide, magnesium stearate, talc and starch. In the conventional pelletization methods the ratio of the product fraction is about 60% by weight. That is why every technical solution resulting in an increase in the product fraction in addition to the maintenance of other important characteristics of the pellets - such as a nearly spherical shape and a suitable quality of the surface - is of high importance.

Several methods aiming at increasing the product fraction have been published. According to the European patent specification No. 288,732 during extrusion-spheronization process organic acids (such as citric, tartaric, maleic, fumaπc, succinic acid) applied in the composition in an amount of 5 to 50% by weight improve the plasticity of the wet mass and thus enable the preparation of harder pellets with particles of a narrow size range. At the same time this method cannot be used for the formulation of acid-sensitive active ingredients.

According to a publication of G.A. Hileman et al . (Drug Dev. and Ind. Pharmacy, 19(4), 483- 491, 1993) in case of the preparation of pellets with high active agent content the application of microcrystalline cellulose containing a slight amount of sodium carboxymethyl cellulose promote the formation of high-quality pellets.

In the process disclosed in the International patent application No. WO 94/08567 0.03% by weight of polysorbate is applied in order to increase the ratio of product fraction.

According to the process disclosed in Hungarian patent specification No. 198,396 a coating powder containing 5 to 98% by weight of low- substituted hydroxypropyl cellulose (containing 4 to 20% of hydroxypropyl group) is applied during the pelletization.

On the basis of the above facts it can be established that pelletization is a complicated pharmaceutical operation requiring a special equipment and intensive labour.

In order to achieve a prolonged release of the active ingredient the pellets are optionally supplied with a water-insoluble film coating. In case of such dosage forms the dissolution of the active ingredient occurs by diffusion through the coating. The dissolution rate is determined by the diffusion coefficient of the active ingredient, the thickness of the coating and the concentration gradient of the active ingredient. Considering that the solubility of certain active ingredients depends on the pH of the dissolution mixture, in such cases the composition of the pellets should be independent of the pH of the releasing medium.

The known 5-chloro-4- [ { 3- ( {2- (3, 4-dimethoxy- phenyl) ethyl }methylamino) propyl }amino] -3 (2H) - pyridazinone (E) -2-butenedioate (1:1), an antiarrhytmic ingredient, belongs to the group of the active ingredients problematical from the viewpoint of the preparation of prolonged release pellets . The release of the active ingredient in an aqueous medium from pellets prepared according to methods known from the prior art and containing said compound in an amount of 10% by weight fluctuates considerably in the physiological pH interval , and at a pH value of 6.8 characteristic of the bowels the release of the active ingredient does not meet the requirements specified in the European Pharmacopoeia (Edition 4, Directorate for the Quality of Medicines of the Council of Europe, Strasbourg, 2003) . According to said requirements the amount of the active ingredient released within 45 minutes should be as high as at least 70% related to the total amount of the active ingredient.

The aim of the invention was to elaborate a pharmaceutical composition comprising as active ingredient 5-chloro-4- [ {3- ({2- (3, 4-dιmethoxy- phenyl) ethyl }methylamιno) -propyl }amιno] -3 (2H) - pyridazinone (E) -2-butene-dιoate (1:1), furthermore a process for the preparation thereof, which process is suitable for the preparation of pellets in up-to-date fluidization roto- granulators and high-shear mixing machines providing the preparation of the product fraction (that is the ratio of pellets used for further processing) in a high yield, that is in a yield of at least 75%, preferably more that 80%, and in a suitable quality.

Summary of the invention

The invention is based on the surprising recognition that if in the course of the pelletization process 10 to 60% by weight of sodium chloride and/or potassium chloride are added to the powder mixture to be pelletized in addition to at most 80% by weight of 5-chloro-4- [ {3- ( {2- (3,4-dιmethoxyphenyl) ethyl }methylamιno) - propyl} ammo] -3 (2H) -pyridazinone (E) -2-butene- dioate (1:1) and 10 to 60% by weight of microcrystalline cellulose, pellets very advantageous in shape (approximately spherical) and having a particle size suitable for pharmaceutical purposes can be produced with a product fraction exceeding 80%. Besides, from the thus-obtained pellets a nearly total release of the active ingredient can be achieved at a speed independent of the pH of the medium.

Details of the invention

According to an aspect of the present invention there are provided nearly spherical pellets comprising the pharmaceutical ingredient 5- chloro-4- [{3- ({2- (3, 4-dιmethoxyphenyl) ethyl } - methylamino) propyl }amino] -3 (2H) -pyridazinone (E) -2-butenedioate (1:1), whereby said pellets contain, in addition to the active ingredient, 10 to 60% by weight of sodium chloride and/or potassium chloride, 10 to 60% by weight of microcrystalline cellulose and optionally other pharmaceutically acceptable auxiliary agents and/or pelletization promoting additives.

According to another aspect of the present invention there is provided a process for the preparation of nearly spherical pellets containing the pharmaceutical ingredient 5- chloro-4- [ {3- ({2- (3,4-dimethoxyphenyl) ethyl } - methylamino) propyl } -amino] -3 (2H) -pyridazinone (E) -2-butene-dioate (1:1), which comprises admixing at most 80% of the active ingredient with 10 to 60% by weight of microcrystalline cellulose, 10 to 60% by weight of sodium chloride and/or potassium chloride and optionally other, pharmaceutically acceptable auxiliary agents and/or additives promoting pelletization, converting the thus-obtained mixture into pellets by high-shear mixing, rotofluidization or extrusion-spheronization method, preferably by rotofluidization by spraying water or preferably an aqueous dimethyl polysiloxane emulsion and/or an aqueous solution of xanthane gum, drying the pellets, separating the desired product fraction and optionally coating the pellets with a layer to modify the drug release.

In order to achieve a further improvement in the efficiency of the pelletization dimethyl polysiloxane is emulged in the pelletizing liquid. In this way the particle size of the thus- obtained pellets can be controlled much better, the size or the pellets is more uniform and the product fraction may exceed even 90%. Similar results can be achieved when xanthane gum is dissolved in the pelletezing liquid, or when the pelletizing liquid contains both dimethyl poly- siloxane and xanthane gum. The exact mechanism of the effect of sodium chloride and/or potassium chloride, dimethyl polysiloxane and xanthane gum is not known at the moment, but it can be supposed that the formation of a more uniform particle size may be the result of a decrease in the solubility of the active ingredient upon the effect of the ionic filler materials, an increase in the plasticity of the powder mixture to be pelletized and some advantageous changes of the cohesion between the particles .

The pharmaceutical compositions containing pelletized active ingredient are usually prepared in dosage unit forms. During the pelletization process the concentration of the active ingredient is determined by the single dose of the active agent finished in a dose unit so that the weight of the pellets containing a single dose of the active ingredient should vary between 50 to 1500 mg, preferably between 100 to 700 mg. In the knowledge of the weight of the pellets containing a single dose of the active ingredient the sodium chloride and/or potassium chloride and microcrystalline cellulose content of the pellet can be determined. The premix used for the preparation of the pellets according to the invention possessing advantageous properties should contain a total amount of at least 10% by weight of the excipients. If the active ingredient content of the pellets is lower than 80% by weight as a consequence of the lower dose, the sodium chloride and/or potassium chloride and microcrystalline cellulose content may be increased. The two types of excipients can be used in nearly identical amounts.

As to the quality of the microcrystalline cellulose used for the preparation of pellets according to the invention, there are no restrictions. Various types of microcrystalline cellulose of different particle size and of different density may freely be applied. Even the application of microcrystalline cellulose with a low moisture content is not required, since during pelletization the substance mixture is moistened with water or contacted with an aqueous solution or dispersion. In addition to the so-called pure or monocomponent micro- crystalline cellulose varieties mixtures of various types of microcrystalline cellulose formed with colloidal silicon dioxide can also be used, which contain about 98% by weight of microcrystalline cellulose and about 2% by weight of colloidal silicon dioxide.

From the viewpoint of pelletization both sodium chloride and potassium chloride can be used to advantage, but due to their different physiological effects it is preferable to chose their concentrations on the basis of the extracellular physiological concentration. This constitutes a weight ratio of sodium chloride to potassium chloride of about 20:1. Thus, choosing e.g. 10% by weight as sodium chloride/potassium chloride concentration, preferably 9.5% by weight of sodium chloride and 0,5% by weight of potassium chloride can be applied.

Furthermore, by applying excipients in the compositions of the pellets according to the invention, the quality of the pellets and the quantity of the amount of pellets falling into the preferable particle size region can be improved. For this purpose xanthane gum or dimethyl polysiloxane may be used. These auxiliary agents are dissolved or disperged either individually or together in water used for the pelletization, and added to the premix to be pelletized in the beginning of the pelletization procedure.

Xanthane gum used in the compositions according to the invention is a natural polysaccharide produced by the microorganism Xantomonas campestris . The skeleton of xanthane gum, such as that of cellulose, consists of 1,4- glucopyranose units, while the side-chains contain mannose, acetate and glucuronic acid. The average molecular weight is a few million Dalton.

In the pharmaceutical industry xanthane gum is mostly used to increase the stability of suspensions used for coating of medicines or films (e.g. Hungarian patent specification No. 202120) or as a viscosity-increasing agent (The United States Pharmacopoeia ed. 26., 2003, United States Pharmacopoeial Convention, Inc, Rockwille, USA) or as a matrix building material for extended release tablets . When used for pelletization, xanthane gum increases the stability of the pellets. This advantageous effect of this substance has not so far been mentioned in the literature and could not be aforeseen. Xanthane gum can be used in the pelletization liquid in an amount of not exceeding 2% by weight related to the final weight of the pellet.

Dimethyl polysiloxane used in the compositions according to the invention is a liquid substance, a completely methylated polymeric siloxane having a viscosity value between 100 and 1000 centistokes. The aqueous dimethyl polysiloxane dispersions are commercially available products, which are used for surface treatments, as skin softening additives for pharmaceutical and cosmetic compositions, as antifriction agents for tabletting or as antiadhesives for film-coating (Hungarian patent specification No. 190,693). The United States Pharmacopoeia (USP 26) classifies dimethyl polysiloxane into the group of antifoam additives. A surprising - and so far fully unknown - property of dimethyl polysiloxane is that in the course of pelletization, when emulged in an amount of not exceeding 5% by weight into water or an aqueous colloidal solution of xanthane gum used for the pelletization, it improves the spherical shape of the pellets and augments the ratio of the product fraction.

The pellets according to the invention can be prepared by build-up (high-shear or roto- fluidization) or by extrusion-spheronization methods known from the literature. In the course of the pelletization process the powdered active ingredient is mixed with sodium chloride and/or potassium chloride and microcrystalline cellulose The mixture is homogenized and the thus-obtained powdered premix is moistened with water or with an aqueous solution of the binder (s) and/or other, pharmaceutically acceptable excipients. The mixture is converted into pellets of the desired particle size by using an appropriate equipment (extruder- spheronizator-drier , high-shear granulator- drier, roto luidization apparatus). Then the product fraction having the desired particle size is isolated by size, e.g. by sieving. The pellet fraction having an unsuitable particle size is recycled to the pelletization process after grinding. The advantageous effect of sodium chloride, potassium chloride and dimethyl polysiloxane used as excipients for the pelletization manifests itself in the fact that even in case of a pharmaceutical quality product their price is low, so their application results in a reduction of the manufacturing costs .

Besides, due to the relatively high water- solubility of the applied sodium chloride and potassium chloride - which is independent of the pH of the dissolution medium - these substances promote the complete and pH- mdependent release of poorly soluble active ingredients .

In case of pellets prepared according to methods known from the prior art containing 10% by weight of 5-chloro-4- [ {3- ( {2- (3, 4-dιmethoxy- phenyl) ethyl }methylamιno) propyl }amιno] -3 (2H) - pyridazinone (E) -2-butenedioate (1:1) and micro- crystalline cellulose, the dissolution of the active ingredient from the pellets in the physiological pH interval does not meet the requirements specified in the European Pharmacopoeia (Edition 4, Directorate for the Quality of Medicines of the Council of Europe, Strasbourg, 2003) . According to the said requirements the amount of the active ingredient released within 45 minutes should be as high as at least 70% related to the total amount of the active ingredient. The data characteristic of the release of the active ingredient from the pellets composed as specified in the prior art are shown in Table 1.

Table 1

For the purpose of comparison pellets having the same particle size (1.0 - 1.6 mm) were prepared according to Example 1 comprising 10% by weight of 5-chloro-4-[{3-({2- (3, 4-dιmethoxyphenyl) - ethyl } -methylamino) propyl}amino] -3 (2H) -pyridazinone (E) -2-butenedioate (1:1), 20% by weight of microcrystalline cellulose, 64.3% by weight of sodium chloride, 3.4% by weight of potassium chloride, 0.67% by weight of colloidal silicon dioxide, 0.17% by weight of xanthane gum and 1.46% by weight of dimethyl polysiloxane. The data of the release of the active ingredient are provided in Table 2. It can be established that from the pellets according to the invention the dissolution of the active ingredient is quick, it is practically complete - independently of the pH of the releasing medium - within 15 minutes .

Table 2 pH 6,8 pH 7 Time pH 1.2 (phosphate distilled (min) ( 0.1 M HC1) buffer) water 15 96.6 98.4 100.7 30 97.9 100.9 100.9 45 97.8 100.9 101.3 60 97.8 101.1 101.7 120 97.1 99.2 101.4

The pellets according to the invention are particularly suitable for further coating operations. In the course of coating film- forming substances soluble in water (e.g. hydroxypropyl-methyl cellulose, polyvinyl alcohol) , insoluble in water (e.g. ethyl cellulose, ethyl acrylate - methyl methacrylate copolymer, polyvinyl acetate) or showing a solubility depending on the pH of the aqueous medium (e.g. cellulose acetate phtalate, hydroxypropyl-methyl cellulose acetate succinate, ethyl acrylate methacrylic acid copolymer) can be used. Coating can be carried out with an aqueous or organic solution or an aqueous dispersion of the film-forming substances. Depending on the characteristics of the film coating immediate release (a coating soluble in water) , extended release (a coating insoluble in water) or delayed release (a coating with a solubility depending on the pH of the dissolution medium) can be prepared. The quality and quantity of the coating substance are to be determined on the basis of the dissolution profile, that is the desired dependence of the release on time.

The pellets according to the invention and the preparation thereof are illustrated by the following Example without limiting the scope of protection to said Example.

Example

Preparation of pellets containing 5-chloro-4- [{3-({2-(3,4-dimethoxyphenyl) ethyl } -methyl- ammo) propyl }amιno] -3 (2H) -pyridazinone (E) -2- butene-dioate (1:1)

185 g of 5-chloro-4-[{3-({2-(3,4-dιmethoxy- phenyl) ethyl }methylamιno) propyl }amιno] -3 (2H) - pyridazinone (E) -2-butene-dιoate (1:1), 370 g of microcrystalline cellulose, 8 g of colloidal silicon dioxide, 770.0 g of sodium chloride and 40.2 g of potassium chloride were mixed in an acid-proof vessel . The mixture was transferred to a fluidization rotogranulator of Glatt GPCG1 type, a mixture of a solution of 2 g of xanthane gum in 500 ml of ion-exchanged water and 50 g of 35% dimethyl polysiloxane and further 1000 ml of ion-exchanged water were sprayed onto it. Spraying speed of the pelletizing liquid was set at 50 ml/mm, pressure of the spraying air was 2.5 bar. The speed of the rotor was set at 450 rev/min in the first 15 minutes of the pelletization and later kept at 600 rev/min. Speed by volume of the fluidization air was kept at 60 m³/hour in the first 15 minutes of the pelletization and later at 90 m³/hour. The temperature of the fluidization air was set at 25 °C in the firs part of the pelletization and at 40 °C for the drying procedure.

The dried pellets were passed through sieves having hole widths of 1.6 mm and 0.8 mm, respectively and divided into 3 fractions . The product fraction, that is the amount of the granules in the range between 0.8 mm and 1.6 mm, amounts to 96% by weight.

For the preparation of sustained release composition a fluidization apparatus of Glatt GPCGl type was equipped with a bottom spraying Wurster insert, and 500 g of the product fraction were fed into the container. As coating liquid 200.0 g of an aqueous polymeric dispersion containing 30% of polyvinyl acetate (trademark name: Kollicoat SR) were applied. To the said dispersion 8.4 g of propylene glycol dissolved in 240 g of water were added. Coating was carried out under the following conditions:

- temperature of the fluidization air: 60 °C

- rate of feed: 8 ml/min

- pressure of spraying: 2 bar

Claims

What we claim is:

1. Pellets in nearly spherical shape comprising pharmaceutically active 5-chloro-4- [ {3- ( {2- (3, 4- dimethoxyphenyl) ethyl }methylamino) propyl Jamino] - 3 (2H) -pyridazinone (E) -2-butenedioate (1:1) of the formula (I) ,

(I)

whereby said pellets contain, in addition to the active ingredient, 10 to 60% by weight of sodium chloride and/or potassium chloride, 10 to 60% by weight of microcrystalline cellulose and optionally other pharmaceutically acceptable excipients and/or pelletization promoting additives .

2. Pellets according to claim 1, wherein the pellet has a particle size in the range between

0.2 mm and 2 mm, preferably between 0.5 mm and 1.6 mm.

3. Pellets according to claim 2 comprising 0.4 to 60% by weight of 5-chloro-4- [ {3- ( {2- (3, 4- dimethoxyphenyl) ethyl Jmethylamino) propyl }amino] - 3 (2H) -pyridazinone (E) -2-butenedioate (1:1) as active ingredient, 20 to 60% by weight of sodium chloride and/or potassium chloride, 20 to 60% by weight of microcrystalline cellulose, 0.5 to 3.0% by weight of dimethyl polysiloxane and/or 0.1 to 1.0% by weight of xanthane gum and, if desired, 0.1 to 0.6% by weight of colloidal silicon dioxide.

4. Pellets according to claim 3, wherein the total amount of the potassium chloride and sodium chloride is 20 to 60% by weight.

5. Pellets according to claim 4, wherein the weight ratio of the sodium chloride:potassium chloride is about 20:1.

6. Pellets according to claim 5 optionally supplied with a coating to modify the drug release and having a particle size between 0.8 mm and 1.6 mm, comprising as active ingredient 35 to 45% by weight of 5-chloro-4- [ {3- ( {2- (3, 4- dimethoxyphenyl) ethyl }methylamιno) propyl } - ammo] -3 (2H) -pyridazinone (E) -2-butenedioate (1:1) in admixture with 25 to 35% by weight of microcrystalline cellulose, 2.0 to 3% by weight of potassium chloride, 50 to 60% by weight of sodium chloride, 1.4 to 1.8% by weight of dimethyl polysiloxane, 0.1 to 0.2% by weight of xanthane gum and 0.4 to 0.6% by weight of colloidal silicon dioxide.

7. A process for the preparation of pellets according to any of claims 1 to 9, which comprises admixing at most 80% of 5-chloro-4- [ {3- ({2- (3,4-dιmethoxyphenyl) ethyl }methylamιno) - propyl } -ammo] -3 (2H) -pyridazinone (E) -2-butene- dioate (1:1) with 10 to 60% by weight of micro- crystalline cellulose, 10 to 60% by weight of sodium chloride and/or potassium chloride and optionally other, pharmaceutically acceptable excipients and/or pelletization promoting additives, converting the thus-obtained mixture into pellets by high-shear blending, rotofluidization or extrusion-spheronization method, preferably by rotofluidization by spraying water or preferably an aqueous dimethyl polysiloxane emulsion and/or an aqueous solution of xanthane gum, drying the pellets, separating the desired product fraction and optionally coating the pellets with a layer to modify the drug release.