CZ299182B6 - Multiple dosage controlled release pharmaceutical composition in peroral solid form, preferably in tablet or hard gelatin pellet form containing potassium chloride - Google Patents

Abstract

The present invention relates to a multiple dosage controlled release pharmaceutical composition in peroral solid form, preferably in tablet or hard gelatin pellet form containing 500 to 1000 mg of potassium chloride per one dosage unit, wherein the composition being in the form of coated or partially coated pellets contains at least 75 percent by weight of potassium chloride, based on the pellet total weight, 10 to 25 percent by weight of microcrystalline cellulose, based on the composition total weight, 0.1 to 0.5 percent by weight of antiadhesive agent, based on the composition total weight, and 0.1 to 5.0 percent by weight of a hydrophobizing agent, based on the composition total weight. The coating layer applied to said pellets contains 3 to 10 percent by weight of ethyl acrylate/methyl methacrylate copolymer, based on the composition total weight, a hydrophobizing agent, talc and optionally dyestuff and optionally uncoated particles of potassium chloride and other auxiliary agents applied to said coating layer. There is also described a process for preparing the above-described multiple dosage controlled release pharmaceutical composition.

Description

Technical field

The invention relates to multidose pharmaceutical compositions in solid oral form, based on controlled release potassium chloride pellets having a high content of active ingredient, and to a process for their preparation. The pharmaceutical compositions of the present invention contain 500 to 1000 mg (6.70 to 13.4 milliequiv. K ⁺ ) of potassium chloride per unit dose in the form of coated pellets and partially coated pellets.

The term pellet refers to substantially spherical particles.

BACKGROUND OF THE INVENTION

Potassium chloride has long been widely used in therapies for the treatment of hypochalaemia (potassium deficiency) of various origins. In medical practice, potassium chloride is used orally and 20 at characteristic high doses (1 to 6 g per day) [e.g. Pharmindex Compendium (1995),

MediMedia Információs Kft .; Knoll, J .: Gyogyszertan, Konyvkiado Medicine, Budapest, (1983);

Gyógyszer Vademecum (1996), Volume I, pages 706-708, Országos Gyógyszerészeti Intézet,

Budapest, 1996)

According to the most general and oldest methods, potassium is introduced into living organisms by means of an aqueous solution prepared from readily soluble tablets obtained from pre-dissolved potassium salt with the aid of an additional agent and administering said solution as a beverage to patients.

For most of the present compositions, dissolution of tablets is facilitated by the preparation of so-called effervescent tablets. When such compositions are used, the uniform administration of potassium ions depends on the reliability of the manipulator and the patient's cooperation.

The aim of the so-called sustained release compositions (slow release) is to provide sustained and sustained release of potassium ions for the body, i. ensure a sustained release of the active ingredient over a period of 6 to 10 hours.

The simplest method of preparing sustained release compositions is as follows: Tablet / dragee cores containing potassium chloride are prepared and coated with a sustained release coating (eg Hungarian patent HU 194 495 or GB 1 340 921).

Another method is the so-called matrix tablet. Potassium chloride is included with the aid of natural or synthetic coating agents, and the release of the active ingredient occurs by dissolving the salt in the coating system of the layer and diffusing it. After dissolution of the active ingredient, the insoluble spongy coating system may persist and cause undesirable side effects.

The disadvantage of such so-called single-dose compositions is that the tablet can adhere to the wall of the gastrointestinal system and an increased local concentration of released potassium can cause bleeding and ulcer in severe cases (see, eg, Issekutz: Gyógyszerrendelés, Medicine, Budapest, (1975) 461). Sugar coated dragees containing a wax matrix (not enteric) are marketed as slow release compositions of the active ingredient. According to Physicians Desk Reference, Medical Economics Co. Inc., N.Y., 794, (1979), less intestinal injury was observed with wax matrix compositions than with enteric potassium chloride compositions, but bleeding in the upper gastrointestinal system was also observed with this type of composition. U.S. Pat. No. 4,235,870 describes the preparation of matrix tablets comprising aliphatic alcohols and hydrated hydroxyalkyl-cellulose ethers in a ratio of 2: 1 to 4: 1; such matrix tablets release potassium chloride within 5 to 10 hours after oral administration. A disadvantage of said matrix tablets is that the composition does not decompose, but remains unassembled, and this can cause a high concentration of potassium chloride in the gastrointestinal tract.

Hungarian patent HU 191 426 relates to the preparation of potassium chloride sustained release tablets containing a hydrophobic polymer (polyvinyl butyral). There are several pitfalls in this composition. On the one hand, there is a high local concentration of potassium chloride, while, on the other hand, elderly patients having lower peristaltic movement upon release of the active ingredient and residual spongy matrix experience difficulties in the intestines; this is especially the case when a large number of tablets are applied.

Most current forms of pharmaceutical compositions are so-called multi-dose compositions by which many (several hundreds or thousands) of small dosage units are filled into capsules or compressed into fast-dissolving tablets.

The above compositions have the following advantages:

- The release of the active ingredient takes place separately over time and, due to many tiny particles, also in space, avoiding undesirable high local concentrations of potassium chloride which may cause harmful side effects.

The distribution of the residence time of the multidose compositions in the gastrointestinal tract is more advantageous (steady state) than for single dose compositions.

The capsules, if necessary, can be opened and the applied particles can be administered by admixture with food or drink.

Known multi-dose potassium chloride compositions are generally prepared by coating the raw crystal 30 with a layer, thereby achieving prolonged release of the active ingredient and dissolution of the salt (see, for example, Hungarian patent HU 191 102 or WO 86/04 817).

Since the preparation of such compositions requires the use of the starting material in adequate purity, potassium chloride needs to be purified.

This purification is generally carried out by means of recrystallization, which causes a reduction in particle size, i.e., the preparation of crude granular crystals is lengthy and expensive.

The particle size of commercially available, special, coarse potassium chloride crystals is 40, generally 0.3 to 0.5 mm, and their specific surface area is about 10 to 6 m 2 / kg [actual density is

1.984 g / cm 3; see Römpp Vegyészeti lexikon, Másszaki kónyvkiadó, Budapest, (1982)]. That is, in order to achieve a satisfactory high release rate, a large amount (about 10% by weight) of the coating layer (see e.g. European Patent Application 052 075) must be applied to the crystal surface. Potassium chloride crystals prepared in large amounts generally have much lower particle sizes (due to a much higher specific surface area), and therefore the preparation of a sustained release composition requires an unacceptably high amount of coating agent to deposit the layer. Said high amount of coating agent causes technical problems in the coating process and the coated particles are sensitive to adhesion, and therefore special precautions are taken to avoid particle sticking.

According to U.S. Pat. No. 4,259,315, the potassium chloride crystals have an average particle size of about 0.4 mm and are coated by a microencapsulation process using ethylcellulose in cyclohexane as described (U.S. Pat. No. 3,415,758), whereupon 0, 05-5.0% (w / w) of a substance having an HLB value greater than 10 (i.e., a hydrophilic surfactant) is added to ensure an even distribution of the microcapsules filled into hard gelatin capsules

In digestible liquid. Due to the relatively small particle sizes of crystalline potassium chloride, the amount of coating applied must be about 20% (w / w) and a large amount of cyclohexane must be used in the microencapsulation process, which presents a high risk of environmental pollution

According to WO 86/04 817, potassium chloride crystals having a particle size of about 0.3 to 0.5 mm are coated by a fluidization spraying process using a 3: 1 to 30: 1 weight of a mixture of ethylcellulose and hydroxypropylcellulose in a solution formed with a mixture of chloroform and ethanol . The required amount of coating material is 9.5-18% (w / w). The coated crystals are mixed with conventional tableting aids to obtain fast dissolving tablets which carry a large amount of uniformly dispersed particles in the gastrointestinal fluid from which potassium chloride is slowly released. In this way, a high local concentration of potassium chloride can be avoided and separation of the pharmaceutical composition can be achieved. The disadvantage of this process is that a large amount of organic solvent (chloroform / methanol) is used for the coating process and its elimination presents serious problems.

Environmental pollution problems are eliminated by the use of aqueous polymer dispersions. According to European Patent Application No. 52,075, potassium chloride crystals are effectively coated using a 2.5: 1 to 5: 1 mixture consisting of an aqueous dispersion of a 70: 30 mixture of ethyl acrylate and methyl methacrylate (marketed under the trademark Eudragit NE 30 D by Rohm) and aqueous dispersions of ethylcellulose (marketed under the trademark Aquacoat ECD-30 by FMC). However, if the coated crystals have a particle size of 0.3 to 0.8 mm, more than 25% of the coating substance is required to obtain a suitable release, which complicates and makes the preparation of the composition more expensive.

Potassium chloride compositions that meet all the latest requirements are not known in the art. Therapeutic application of potassium chloride is becoming increasingly widespread, and this requires sustained release compositions that can be prepared in an economical manner while eliminating the risk of environmental pollution.

SUMMARY OF THE INVENTION

The present invention relates to providing potassium chloride compositions that meet the following requirements:

- with regard to the high dose, the content of the highly active ingredient and the low content of the adjuvant (coating agent);

a slow-release effect to ensure a long-lasting and uniform blood level of the active ingredient;

A multidose form to reduce the side effects of mucosal damage and the formation of particles having a hydrophilic surface that rapidly dissipates in the gastrointestinal fluid;

- small specific surface, compact particles and smooth surface to reduce the amount of coating applied.

The composition of the present invention must also meet the following additional requirements:

the particles of the composition should not adhere during the manufacturing process and use;

- the particle size of the particles to be coated should be uniform;

- the particles should have low porosity;

- the coating agent should not contain environmentally harmful solvents (eg chlorine-containing solvents).

-3GB 299182 B6

The above objects are achieved by the compositions and methods of the present invention.

The present invention resides in a multidose pharmaceutical composition in solid oral controlled release form; preferably in the form of tablets or hard gelatin capsules; and having a potassium chloride content in the range of 500 to 1000 mg per dosage unit, comprising coated and partially uncoated pellets, wherein the composition comprises at least 75% by weight of the composition. % potassium chloride, based on the total weight of the pellets, 10 to 25 wt. % of microcrystalline cellulose, based on the total weight of the composition, 0.1 to 0.5 wt. % of an anti-sticking agent, based on the total weight of the composition, and 0.1 to 5.0 wt. a hydrophobizing agent, based on the total weight of the composition; a coating layer applied to said pellets containing 3 to 10 wt. ethyl acrylate / methyl methacrylate copolymers, based on the total weight of the composition, of a hydrophobizing agent, talc and optionally a colorant; and optionally uncoated potassium chloride particles and other auxiliary agents applied to said layer.

The term pellet as used in this patent application refers to special granules, characterized in that the particle size is between a few tenths of a millimeter to a few millimeters (generally between 0.5 mm and 2.0 mm), with a small deviation from the size particles, with a substantially spherical shape, low surface roughness and particle density as with the compressed material.

According to a preferred embodiment of the process of the present invention, tablets or hard gelatin capsules are prepared

mixing potassium chloride with 0.1 to 0.5% by weight of an anti-adhesion agent and 10 to 25% by weight of microcrystalline cellulose optionally containing sodium carboxymethylcellulose;

converting the mixture into pellets by reacting successively with 15 to 20% (w / w) aqueous potassium chloride solution, an aqueous hydrophobizing agent diluted to 0.5 to 5% (w / w) and optionally water;

drying said pellets;

- coating said dried pellet with a coating solution comprising aqueous dispersions of ethyl acrylate / methyl methacrylate copolymers and / or ammonium methacrylate copolymers as a film-forming agent, hydrophobicizing agent, 5 to 35% by weight of lower alkanol, talc and optionally a colorant;

applying potassium chloride to the surface of said coated particles;

mixing, if desired, said coated particles with uncoated potassium chloride particles forming the above composition and with suitable auxiliary agents or mixtures thereof;

and compressing said mixture into tablets or filling the same mixture into hard gelatin capsules.

According to a particularly preferred embodiment of the present invention, the compositions are prepared

mixing potassium chloride with 0.1 to 0.3% (w / w) colloidal silica;

- grinding said mixture to particles of which 90% have a particle size of less than 100 μηι;

mixing said milled material with 10 to 25% (w / w) microcrystalline cellulose;

- wetting the mixture thus obtained successively with 5 to 15 wt.% 20 wt. an aqueous potassium chloride solution and 0.3 to 0.7% (w / w) 1.5 to 2.5% (w / w) aqueous dimethyl45 polysiloxane dispersion;

if desired, by spraying water onto said mixture; drying the pellets thus obtained;

separating pellets having a particle size between 0.8 mm and 1.6 mm;

-4GB 299182 B6

- coating said pellet with a coating liquid comprising 4 to 6% (w / w) 35% aqueous ethyl acrylate / methyl methacrylate dispersion, 5 to 35% (w / w) ethanol, 0.5 to 1.0% (w / w) talc, 0.2 up to 1.0% (w / w) dimethylpolysiloxane and 0.01 to 1.0% (w / w) dye;

and applying 0.5 to 2.0% (w / w) potassium chloride to the surface of said coated pellets using an aqueous potassium chloride solution.

According to a preferred embodiment of the present invention, there are provided oral pharmaceutical compositions, preferably in the form of tablets or hard gelatin capsules comprising pellets comprising at least 70% (w / w) potassium chloride, 10% to 25% (w / w) microcrystalline cellulose. 1 to 0.5% by weight of an anti-sticking agent and 0.1 to 5.0% by weight of a hydrophobizing agent; a coating layer applied to said pellets comprising 3 to 10% (w / w) ethyl acrylate / methyl methacrylate copolymer and / or ammonium methacrylate copolymer hydrophobizing agent, talc and optionally a colorant; and optionally potassium chloride particles not covered by the layer, and further a co-agent applied to said layer.

According to the present invention, generally, substances used for this purpose, such as silica, talc, magnesium stearate, preferably silica, can be applied as an anti-adhesion agent.

Dimethylpolysiloxane, magnesium stearate, calcium stearate, hydrogenated fatty oils may be preferably used as the hydrophobizing agent, particularly preferred is the use of dimethylpolysiloxane.

Microcrystalline cellulose may be replaced by microcrystalline cellulose containing sodium carboxymethylcellulose.

The major component of the composition (more than 80% (w / w)) is composed of potassium chloride pellets having a particle size of 0.5 to 2.0 mm and coated with a layer that provides controlled release of the active ingredient. Said pellets are substantially spherical particles. In pellets, 90% of the potassium chloride particles are less than 100 µm in size; 90% (w / w) of the microcrystalline cellulose particle size is less than 50 µm; the size of the colloidal silica particles is less than 1 µm and dimethylpolysiloxane (preferably an aqueous emulsion) is used as the liquid. The pellet coating layer comprises a thin film forming agent, an ethyl acrylate / methyl methacrylate copolymer and / or an ammonium methacrylate copolymer, and as a further talc and hydrophobizing agent, preferably dimethylpolysiloxane.

In addition to coated pellets that provide controlled release of the active ingredient, the compositions of the present invention may also include pellets not coated and other excipients generally used in the preparation of oral pharmaceutical compositions (eg, magnesium stearate, microcrystalline cellulose, etc.) that facilitate filling into hard gelatin capsules and pellet tableting.

According to the prior art, the content of the active ingredient of the pellets prepared from organic substances, which are much more easily plasticizable than the inorganic salts, does not exceed 50% [see, e.g., Capes, C.E .: Particle Size Eniargement, Elsevier Scientific Publ. Co., Amsterdam, (1980);

Ghebre-Sellasie, I .: Pharmaceutical Pelletization Technology, Marcel Dekker Inc., N.Y. Basel, (1989)]. In view of the above teachings of the prior art, it is surprising that the compositions can be prepared from non-plastic potassium chloride pellets having an active ingredient content greater than 70% (w / w). Therefore, the finding of the present invention could not be known in advance.

It has been found that the smaller the particles used as starting material in the pellet manufacturing process, the more compact pellets having a smoother surface and a more uniform particle size distribution are obtained. For this reason, the starting potassium chloride should be ground. Since potassium chloride is strongly sensitive to agglomeration, it is possible to facilitate grinding and to prevent further adherence of the milled material by preferably adding an anti-sticking agent. For this purpose it may

Preferably, colloidal silica (e.g., Aerosil 200; manufactured in Degussa, Germany) is used. The amount of colloidal silica is generally 0.1 to 0.5% (w / w), preferably 0.1 to 0.2% (w / w).

The ground potassium chloride is then mixed in a suitable microcrystalline cellulose apparatus also with a small particle size. For example, Avicel PH 105 (manufactured by FMC Corp.) can be used for this purpose. Microcrystalline cellulose may be used as such or as a mixture formed with sodium carboxymethylcellulose (Avicel CF-611 or Avicel RC-581). The mixing may be carried out in a conventional apparatus (e.g. a high speed kneading machine or in a centrifugal fluidization granulator). The mixture is then wetted with a concentrated solution of potassium chloride at a concentration of 15 to 25% (w / w), preferably 20% (w / w), and then further wetted with the hydrophobizing agent. An emulsion of dimethylpolysiloxane, in particular an emulsion of dimethylpolysiloxane diluted to 0.5 to 5% by weight (Pharsil E 1049; Wacker), can advantageously be used as the hydrophobizing agent.

Chemistry).

Further steps of the pellet manufacturing process can be performed in various ways. According to the process, the wetted material is extruded in a suitable apparatus, processed into a spherical shape in another apparatus and finally dried in a third apparatus. According to a further process, particle formation and drying are carried out in the starting apparatus. Alternatively, the process in the first apparatus can be started and transferred to the second apparatus before drying.

It is known that during the pellet manufacturing process, when pellets begin to form and the particle size increase continues, a suitable moisture content must be achieved.

It has surprisingly been found that using a concentrated potassium chloride solution, a plasticizable state (pellet formation) can be achieved with less liquid than water, and using a concentrated potassium chloride solution results in more compact pellets having less porosity, a rougher surface and a higher density. The mechanism of this complicated phenomenon is not clearly known. To the best of our knowledge, the following procedure is likely to take place. Since potassium chloride is readily soluble in water, water dissolves part of the potassium chloride during the pellet manufacturing process. This dissolution process cannot be one-sided and over time is accompanied by an uncontrolled change in the consistency of the wetted particle agglomeration. When wetting the granules with a saturated or almost saturated potassium chloride solution, the liquid to solid ratio is of fundamental importance from the point of view of pellet formation and is not affected by such a dissolution process. However, it is not intended to limit the scope of protection to any theoretical statement.

The use of water is accompanied by other adverse events. When drying the solution, an uncontrollable amount of concentration reaches the surface from which the crystals of random size are returned and returned. Part of such crystals may be abraded and lead to a pulverulent substance which adversely affects the sustained release effect. The amount of crystals which adversely affects the smoothness of the particle surface and consequently the coating process is considerably less when a potassium chloride solution is used, due to the smaller amount of liquid and the higher amount of local concentration.

Another advantage of using a concentrated or near concentrated potassium chloride solution as a liquid to prepare is that it remains in the pores of the pellets and partially fills them when drying the potassium chloride crystals.

Indeed, it is essential whether during pellet formation, during growth and spheronification phase, the pores of the growing pellets could be filled with fluid (to facilitate formation). During this procedure (compaction increase, spheronification) a part of the fluid reaches the surface, but another part remains in the pores of the unprocessed (wet) particles until it begins to dry. This solvent is removed during drying, but after the solvent pores remain in the pellets.

-6GB 299182 B6

Using less liquid and potassium chloride solution instead of water yields more compact pellets having a higher potassium chloride content.

The concentration of the potassium chloride solution used in the process of the present invention is close to a saturated concentration at room temperature (34.0 g of potassium chloride is soluble in 100 g of water at 20 ° C, corresponding to a concentration of 25.37% (w / w). zsebkónyv, Muszaki Kónyvkiadó, Budapest, (1971)] However, due to technical problems, the actual concentration used is lower than the above value (eg soldering head disturbance).

It is preferred to use a potassium chloride solution having about 15 to 20% (w / w) concentration.

The present invention is based on the further discovery that the silicone emulsion plays an important role in uniformly distributing the particle size of the pellets and in increasing the amount of product fraction having the desired particle size.

It has been found that in the most critical phase of the pelleting procedure, in which the particle size increase proceeds very rapidly, ie in an explosive manner, the silicone emulsion (hydrophobising) injection procedure may be slowed down, the process may be more manageable, deviation from particle size dispersion may be reduced. and the amount of desired product fraction can be significantly increased.

In addition to the above, the use of a silicone emulsion also has secondary non-negligible advantages. The surface of the particles becomes more hydrophobic, the particles are not as susceptible to adhering to the walls, the surface of the particles becomes smoother and is later subject to adhesion of the deposited layer.

Drying and fractionation of pellet size is accomplished by methods known in the art.

In a further step of the process of the present invention, the pellets are coated. This coating step 30 relates to the desired kinetics, i. slow release of the active ingredient. According to one method of coating, the release rate of the active ingredient of the readily soluble salt is provided by sustained release with the aid of a lipophilic (hydrophobic) deposited layer. Natural, semisynthetic or synthetic fats, solidified vegetable oils, waxes or wax derivatives may be used for this purpose.

This process can, for example, be carried out by heating the mixture of inorganic salt and solid fat to a temperature higher than the melting point of the fat, uniformly distributing the salt in the melt, and then cooling and granulating the system (e.g. DE 1 948 019). According to another method, the fat is dissolved in a solvent (e.g. chloroform, carbon tetrachloride) and sprayed onto the particles (e.g.

HU 191 202).

According to another known coating method, a thin layer is formed on the surface of the particles, thereby achieving a gradual release of the active ingredient. The release rate is determined by the rate of diffusion of the active ingredient through the thin film.

The deposited layer may be formed by dissolving the polymer in an organic solvent or mixture of organic solvents and spraying the solution onto the surface of the particles. The dissolved particles chained into the polymer form a loose structure and, after drying the thin layer, adhere to each other to form a monotonous, compact, well-coated layer.

In order to ensure the protection of the environment, the replacement of solvent coating methods with dispersion coating procedures is beginning to be promoted. For this reason, manufacturers have developed their well known and widely used polymer thin film system also in the form of aqueous dispersions. It is a clear trend to use dispersed coatings and continuous quality improvement

-7EN 299182 B6 dispersed coatings. Polymer particles in the form of small latex spheres are present in the dispersions and these spheres are attached to each other during the coating process. This can be easily realized, for example, such that the coating is less compact and, according to theoretical considerations, also true that a greater amount than from the corresponding type of solvent is used to achieve the same sustained release effect from the dispersed coated fluids. In addition, there is a greater risk of the so-called orange-shell structure of the deposited coating (for more details see Cole, G., Hogan, J., Aulton, M., Pharmaceutical Coating Technology).

The present invention is based on the further discovery that both of the above systems can be combined using a coating fluid of a suitable composition.

According to another aspect of the present invention, a lower alkanol is added to a commercially available dispersion of ethyl acrylate / methacrylate copolymer and / or ammonium methacrylate copolymer containing conventional pharmaceutical auxiliary agents (e.g. talc, dimethylpolysiloxane, optionally dyes, etc.) in an amount of 5-35% ( wt.). Isopropanol or mixtures of ethanol and isopropanol, preferably ethanol, may be used as lower alkanol, branched or unbranched alkanol chains having 1 to 3 carbon atoms. It has been found that the addition of lower alkanols advantageously affects the behavior of the deposited dispersion. This finding is all the more surprising since, according to the manufacturer's instructions, the addition of organic solvents to dispersed coatings is generally prohibited. When using the special water / alcohol mixture of the present invention, the polymer does not precipitate, during the process mainly water evaporates while forming the coating, the quality of the dry coating and its amount are similar to those obtained by known procedures using pure organic solvents.

The major thin film is the component used in the process of the present invention and is known for such purposes is an ethyl acrylate / methyl methacrylate copolymer and / or an ammonium methacrylate copolymer. Some may prefer to use Eudragit®, sold by Rohm Pharma. The following three products sold by the company are particularly proven to be used: dry powder or granules; a solution consisting of isopropanol or a mixture of isopropanol and acetone; or aqueous dispersions.

It is an object of the present invention to achieve with the aqueous dispersing agents intended to coat the same or similar release of the active ingredient as when using the organic solvent system. The above object is achieved by adding 5 to 35 wt. lower alkanols (preferably ethanol and / or isopropanol) to the aqueous polymer dispersion.

By virtue of the ethanol or isopropanol used in relatively minor amounts, the polymer appears to form an intermediate state between the dispersion and the organic solvent. The occurrence of the polymer is still similar to that of the dispersion (white, cloudy), but its behavior is close to the organic solvent system. Namely, the lower alkanol (ethanol or isopropanol) partially dissolves the polymer particles found on the surface of the latex micelle, thereby facilitating its agglomeration by coming into contact on the surface of the particles to be coated.

In addition to the above, ethanol and isopropanol have two other roles: on the one hand, it facilitates the use of suspensions of hardly wettable powders in the coating (talc, silica gel) known to cause major technical difficulties in preparing coating systems for suspensions / dispersions; improve the deposition of the dispersion particles (the smaller the droplets are formed, the more uniform the coating is) because the surface tension of the aqueous system is reduced.

The pellets prepared according to the present invention have very advantageous properties. The pellets are compact, have low porosity, their surface is uniform and smooth, the particles are relatively hydrophobic, the particle size distribution interval is uniform, the specific surface is considerably more advantageous than the crystals, and the coating exhibits the above advantages. In addition, when approximately the same amount of coating (or thin polymer layer) is applied, substantially less potassium chloride is released from the product of the present invention than from known

-8GB 299182 B6 products. The results of these comparative experiments are shown in Table 1. Rohm Pharma data is used as reference data in Fig. 3 of the INFO 2.4 leaflet.

Table 1

Release of potassium chloride - active ingredient

Polymer (%) weight) Release of active ingredient (%) Product according to the invention Reference product 2 hours 4 o'clock 2 hours 4 o'clock 5 36 81 94 100 ALIGN! 5.5 32 75 6 24 65 85 99 7 75 96 8 67 93

From the above table, it can be seen that the amount of active ingredient released from the composition of the invention is only about 25 to 40% of the amount released by the reference product.

The composition of the present invention with a coated dispersion solvent layer has other advantages that are particularly significant and surprising in terms of the stability of the composition. After application of the layer, the thin layer formed on the surface of the particles obtains the final properties very quickly, in a range of several days, and therefore no further treatment (e.g. heat treatment) is required. This also means that the coated layer does not age. According to our tests, the quality of the coating remains unchanged for at least 3 years.

It is very important to protect the particles against adhesion both during the manufacturing process and in the stomach. According to the present invention this can be achieved by applying potassium chloride to the coated particles, preferably by spraying a saturated solution of potassium chloride onto the particles. Thus, on the one hand, the particles are coated with an anti-adhesion polymer layer (otherwise the particles are susceptible to adherence despite added talc and silica), while on the other hand the surface of the coated particles becomes hydrophilic, thereby rendering the particles wettable in an aqueous medium. stomach) and don't stick to each other. The amount of potassium chloride applied to the surface is 0.5 to 5.0% (w / w) of the total active ingredient content and therefore does not significantly affect the release rate.

According to the prior art surfactants are used for this purpose but may have adverse and undesirable properties (they affect the release and absorption of the active ingredient, cause digestive problems, stomach foaming, etc.). According to this feature of the present invention, the substance applied to the particle surface is the same as the active ingredient and its amount is negligible compared to the total active ingredient content; therefore, there are no adverse effects.

It follows from the above that the present invention is fundamentally different from the prior art.

According to Hungarian patent HU 194 495 to influence the release rate, a water-soluble agent is incorporated into the coating of the particle (i.e. the tablet core), whereas according to U.S. Pat. No. 4,295,315 a surfactant is used to prevent adhesion.

-9EN 299182 B6

Since, according to the present invention, adhesion is prevented by using the active ingredient as described herein, the active ingredient content of the pellets is increased.

The present invention does not only relate to the preparation of a potassium chloride composition characterized by a release profile of the type provided, but the present invention also provides a means to influence the release profile from any point in the production process of the composition.

According to a particularly preferred embodiment of the present invention, the coated potassium chloride pellets are admixed with the uncoated potassium chloride particles (i.e. before tabletting or encapsulation) before further processing. This is accomplished by a very simple and elegant process for preparing pharmaceutical compositions of varying release rates, including compositions of the type provided (e.g., zero or first order kinetics).

Further details of the present invention can be found in the following examples, which are given without limiting the scope of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

The composition is filled into capsules containing coated and uncoated pellets. The preparation and coating of the pellets is performed in a laboratory centrifugal fluidized granulation apparatus.

Process of preparation of starting material

14.97 kg of potassium chloride (pharmaceutical grade) are pre-crushed in a pilot plant, high-speed granulating apparatus (Lodige FM50.Iz type) for 5 minutes. After adding 0.03 kg of Aerosil 200, the mixture is stirred for 10 minutes and then comminuted in a grinding machine (Alpine type).

160Z) until 90% (w / w) of the product has a particle size of less than 100 μηι. This product will hereinafter be referred to as a potassium chloride masterbatch.

Production of pellets

255 g of the above mixed potassium chloride are mixed with 45 g of Avicel PH 105 in a laboratory 35 centrifugal fluidization pelletizer. The mixture is granulated successively with 150 g of a 20% (w / w) potassium chloride solution, 50 g of a silicone emulsion diluted with distilled water to 2% (w / w) (type E2; dry matter content 35%; manufactured by Wacker Chemie) and about 35 g distilled water and transferred into pellets. The wet pellets are dried in the same apparatus and the product is sieved through a 0.8 and 1.6 mm screen. 150 to 200 g of pellets having a particle size of 0.8 to 1.6 mm (hereinafter the pellet core) are obtained in this way. This pellet processing step is repeated at least three times. Only pellet cores (particle size between 0.8 and 1.6 mm) are used in the pellet coating step. Coating of pellets

A coating layer of 180 g of dispersion is applied to 400 g of pellet cores in a laboratory centrifugal fluidization granulation apparatus according to a method known in the art. The dispersion is prepared as follows:

0.03 g of dye (Ariavit indigo carmine) is dissolved in 38.21 g of distilled water. To this solution was added 18.00 g of 96% ethanol, followed by the sequential addition of 3.20 g of talc, 42.37 g of distilled water, 6.17 g of a 35% silicone emulsion and 72.00 g of a 30% dispersion of Eudragit NE 30 D. .

After applying 38.2 g of the polymer dispersion, a 20% by weight solution of potassium chloride is deposited on the surface of the coated particles.

-10GB 299182 B6

Release of coated pellets

Test method: 750 mg coated pellets in 900 ml distilled water at 37 ° C; the release measuring apparatus corresponding to the USP has a rotary drum; determination of chloride by titration with silver nitrate; potentiometric determination of end of titration.

hour: 11%; 2 hours: 27%; 4 hours: 52%; 6 hours: 72%;

hour: 85%.

Mixing of pellets

The coated pellets and the pellet cores were mixed at a ratio of 82: 18, after which a 750 mg portion of the mixture was filled into capsules.

Release results

Test Method: See above method except that each capsule is tested separately.

hour: 30%; 2 hours: 43%; 4 hours: 64%;

hours: 79%; 8 hours: 89%; 10 hours: 95%.

Example 2

The compositions are filled into capsules containing coated and uncoated pellets. The preparation and coating of the pellets is carried out in a pilot plant for centrifugal fluidization granulation.

Process of preparation of starting material

The potassium chloride premix is prepared as described in Example 1 above.

Production of pellets

7703.9 g of mixed potassium chloride is mixed with 1359.5 g of Avicel PH 105, the mixture is granulated in a pilot plant for centrifugal fluidization granulation sequentially with 4,531.8 g of a 20% by weight solution of potassium chloride, 1,510.5 g of silicone emulsion (type E2, dry matter content 35%, manufactured by Wacker Chemie) diluted to 2% by weight with distilled water, and 266 to 925 g distilled water. The pellets are then formed. The wet pellets are dried in the same apparatus and the product is sieved through a 0.8 and 1.6 mm sieve to give 6-7 kg of particles having a size between 0.8 and 1.6 mm (the pellet cores). This procedure is repeated at least twice. In the pellet coating step, only pellet cores (particle size between 0.8 and 1.6 mm) are used.

Coating of pellets

A layer of 4887 g of coating dispersion in a pilot-operated centrifugal fluidization pelletizer (type Glatt GPCH 5) was applied per 10 kg of pellet cores according to a method known in the art. The coating is prepared as follows:

Dissolve 1 g of dye (Ariavit indigo carmine) in 500 g of distilled water. The solution is mixed with 488.69 g of 96% ethanol, then 86.99 g of talc, 1000 g of distilled water, 167.55 g of a 35% silicone oil emulsion, 1 954.75 g of a 30% dispersion of Eudragit NE 30 D are gradually added. and the mixture is filled with distilled water up to 4887 g.

After applying 955 g of polymer dispersion, a 20% by weight solution of potassium chloride is deposited on the surface of the coated particles.

-11 CZ 299182 B6

Release of coated pellets Test method: see above hour: 1%; 2 hours: 4%; 4 hours: 31%;

hours: 50%; 8 hours: 68%.

Mixing of pellets

To achieve the desired release rate, the coated pellets and the pellet cores are mixed at a ratio of 80:20, and then a 750 mg dose of the mixture is filled into capsules.

Release of the pellet mixture Test method: see Example 1 above.

hour: 20%; 2 hours: 25%; 4 hours: 43%;

hours: 58%; 8 hours: 71%; 10 hours: 81%.

Example 3

The compositions are filled into capsules containing coated and uncoated pellets. The preparation and coating of the pellets is carried out in an industrial centrifugal fluidization granulation apparatus.

Process of preparation of starting material

174.65 kg of pharmaceutical grade potassium chloride are pre-crushed in an operating, high-speed granulating machine (type Diosna A400) for 5 minutes. After adding 0.35 kg

Aerosil 200 was stirred for 10 minutes. Then the mixture is comminuted in a milling machine (Alpine type) until 90% by weight of the product has a particle size of less than 100 µm. (This product will hereinafter be referred to as a potassium chloride premix.)

Production of pellets

85 kg of mixed potassium chloride is mixed with 15 kg of Avicel PH 105, the mixture is granulated in an operating centrifugal fluidization pelletizer (those of Glatt GPCG 200) sequentially with 50 kg of a 20% (w / w) potassium chloride solution, 16.6 kg silicone emulsion type Pharsil E 1049 diluted to% (w / w) and about 10 kg of distilled water. The pellets are then formed. The wet pellets are dried in the same apparatus and the product is sieved through a 0.8 and 1.6 mm sieve to give 60 to 70 kg of pellets having a particle size between 0.8 and 1.6 mm (the pellet cores). This procedure is repeated at least three times. The pellet core fraction (particle size between 0.8 and 1.6 mm) is used in the pellet coating step.

Coating of pellets

A layer of 105 kg of the coating dispersion in a working-size centrifugal fluidization pelletizer (type Glatt GPCG 200) is applied to 175 kg of pellet cores according to a method known in the art. The dispersion is prepared as follows:

20.8 g of dye (Ariavit indigo carmine) are dissolved in 36 kg of distilled water. 10.27 kg of 96% ethanol are admixed with this solution, followed by 1.84 kg of talc, 3.18 kg of 39% silicone emulsion, 2 kg of distilled water and 41.38 kg of Eudragit NE 30D dispersion. The mixture is filled with distilled water up to 105 kg.

After applying 16.7 kg of polymer dispersion, a 20% (w / w) potassium chloride solution is deposited on the surface of the coated particles.

- 12GB 299182 B6

Release of the coated pellets Test method: see above hour: 2%; 2 hours: 24%; 4 hours: 65%;

hours: 84%.

Mixing of pellets

To achieve the desired release rate, the coated pellets and the pellet cores are mixed at a ratio of 87: 13, and then a 750 mg dose of the mixture is filled into capsules.

Release of the pellet mixture

Test method: see example 1 above.

hour: 18%; 2 hours: 35%; 4 hours: 67%;

hours: 86%; 8 hours: 94%.

Example 4

The composition is filled into capsules. The pellets are prepared in a laboratory extruder and spheronizer, dried in a laboratory apparatus for fluidization granulation and drying, and coated in a laboratory vessel.

Process of preparation of starting material

The potassium chloride premix is prepared according to Example 1.

Production of pellets

11.12 kg of mixed potassium chloride are mixed with 1.20 kg of Avicel PH 105 and 0.60 kg of Avicel CL 611 in a pharmaceutical high speed pelletizer (Lodige type FMZ50.Iz). The mixture is moistened and kneaded with 2.40 kg of a 20% (w / w) potassium chloride solution and a silicone emulsion (type E2, manufacturer: Wacker Chemie) diluted with 0.54 kg of distilled water to 3.5% (w / w) in several portions. . The wet mixture is added to a pilot plant extruder (Schüter type PP85) using a screw feeder and extruded. 2 kg of extruded fibers are placed in a pilot plant spheronizer (diameter 300 mm; type RM300; grooved disk) and adjusted to spherical shape at about 800 rpm. 4000 g of the spherical particles obtained are dried in a laboratory apparatus for fluidization granulation and drying. Fractions of 1.2 to 1.6 mm are separated from the dried product by manual sieving and used in the coating process.

Coating of pellets

In a known manner, a layer of 1670 g of coating dispersion in a laboratory vessel is applied to 1800 g of pellet cores. The coating dispersion is prepared as follows:

0.333 g of dye (Ariavit indigocarmine) is dissolved in 520.5 g of distilled water, followed by the sequential addition of 7.26 g of SE 2 type silicone emulsion and 20.04 g of Cirtoglex 2. In a separate container, 1.67 g of Aerosil 972 are mixed with 103.54 g of micronized talc and 150.0 g of 96% ethanol are added. This mixture and 98.657 g of distilled water were added to the first solution. 601.20 g of Eudragit RS30D, 66.80 g of Eudragit RL30D dispersion and 100 g of distilled water are added to the homo45 gene solution thus obtained.

A dose of 750 mg of coated pellets is filled into capsules.

Release results of encapsulated, coated pellets Test method: see Example 1 above.

-13GB 299182 B6 hour: 22%; 2 hours: 43%; 4 hours: 71%; 6 hours: 92%.

Example 5

The compositions are filled into capsules containing pellets. The pellets are prepared in a high speed laboratory kneader and coated in a laboratory centrifugal fluidization granulation apparatus.

The process of preparing the starting material

The potassium chloride premix is prepared according to the method of Example 1.

Production of pellets

913.25 g of mixed potassium chloride is mixed with 150 g of Avicel PH 105. The mixture is granulated in a high speed laboratory, pharmaceutical mixer (Zanchetta Roto-Junior type) 183.75 g of a 20% (w / w) potassium chloride solution, 75 g of silicone emulsion diluted to 4.34% (w / w) and about 40 g of distilled water. The pellets are then formed. The wet pellets are dried in the same apparatus and the product is sieved through a 0.8 and 1.6 mm screen to give 600 g of pellet cores having a size between 0.8 and 1.6 mm. This fraction is used in coating (particle size between 0.8 and

1.6 mm).

Coating of pellets

A layer of 400 g of pellet cores was coated as described in Example 1.

A dose of 750 mg of coated pellets is filled into capsules.

Example 6

Tablet composition comprising coated pellets. The pellets are prepared in a laboratory extruder and spheronizer, dried in a laboratory apparatus for fluidization granulation and drying, and coated in a laboratory vessel.

Process of preparation of starting material

The potassium chloride premix is prepared according to the method of Example 1.

Production of pellets

12.75 kg of mixed potassium chloride are mixed with 1.50 kg of Avicel PH 105 and 0.75 kg of Avicel CL 611, moistened and kneaded in a high speed pelletizer (Lódige FM50.Iz type) with 2.75 kg of 20% (wt. .) potassium chloride solution and silicone emulsion diluted 0.63 kg to 3.5% (w / w) in several portions. The wet mixture is added to the pilot plant extruder (type Schuter PP85) using a screw feeder and extruded. 2 kg of extruded fibers are placed in a pilot plant (Schuter RM300 type; 300 mm diameter; grooved disc) and spheronized at 800 rpm. 4000 g of spherical particles are dried in a laboratory apparatus for fluidization granulation and drying. From the dried product are separated by manual sieving 1.2 to 1.5

1.6 mm fractions and used for coating.

Coating of pellets

In a known manner, a layer of 1,670 g of coating dispersion is applied to 1,850 g of pellet cores in a laboratory apparatus for fluidization granulation, drying and coating. The coating dispersion is prepared as follows:

-14GB 299182 B6

0.333 g of dye (Ariavit indigo carmine) is dissolved in 520.5 g of distilled water. To this solution is added 14.52 g of SE type 2 silicone emulsion. In a separate vessel, 1.67 g of Aerosil 972 is mixed with 103.54 g of micronized talc, and 150.0 g of 96% ethanol are added to form a mixture and added. with 111.437 g of distilled water to the first solution. To the homogeneous solution thus obtained was added 668.00 g of a dispersion of Eudragit NE30D and 100 g of distilled water.

Tableting pellets

The coated pellets and Avicel PH 102 are mixed in a ratio of 70:30 and compressed to give tablets weighing 1.3 g and 15 mm in diameter.

Claims (22)

PATENT CLAIMS A multidose pharmaceutical composition in solid oral controlled release form, preferably in the form of tablets or hard gelatin capsules, and having a potassium chloride content in the range of 500 to 1000 mg per unit dose, comprising coated and partially uncoated 20 pellets, characterized in that it contains at least 75 wt. % of potassium chloride, based on the total weight of the pellets, 10 to 25 wt. % microcrystalline cellulose, based on the total weight of the composition, 0.1 to 0.5 wt. % of an anti-sticking agent, based on the total weight of the composition, and 0.1 to 5.0 wt. a hydrophobizing agent, based on the total weight of the composition; a coating layer applied to said pellets containing 3 to 10 wt. 25 ethyl acrylate / methyl methacrylate copolymers based on the total weight of the composition, a hydrophobizing agent, talc and optionally a colorant; and optionally uncoated potassium chloride particles and other auxiliary agents applied to said layer. Composition according to claim 1, characterized in that it comprises a colloidal oxide Silica as an anti-adhesion agent. Composition according to claim 1, characterized in that it contains dimethylpolysiloxane as a hydrophobizing agent. 35 Composition according to any one of claims 1 to 3, characterized in that the coated particles comprise on the top a polyacrylate coating layer of 0.5 to 5% by weight. of potassium chloride, based on the total weight of the composition. Composition according to any one of claims 1 to 4, characterized in that the micro40 crystalline cellulose comprises sodium carboxymethylcellulose. Composition according to any one of claims 1 to 5, characterized in that the pellets comprise 85 to 90 wt. % of potassium chloride, based on the total weight of the pellets, 8 to 14.8 wt. microcrystalline cellulose, based on the total weight of the pellets, 0.1 to 0.5% 45 wt. % colloidal silica, based on the total weight of the pellets, and 0.1 to 5.0 wt. % dimethylpolysiloxane based on the total weight of the pellets. Composition according to any one of claims 1 to 6, characterized in that the coating layer contains 2 to 10 wt. ethyl acrylate / methyl methacrylate copolymers based on % Total weight of the composition, 0.2 to 2.0 wt. % talc and 0.1 to 5.0 wt. % dimethylpolysiloxane, based on the total weight of the composition. Composition according to any one of claims 1 to 7, characterized in that it contains 2.3 to 13 wt. of the coating layer, based on the total weight of the particles. -15GB 299182 B6 Composition according to any one of claims 1 to 8, characterized in that it comprises particles having a diameter of 0.5 to 2.0 mm. 5 10. A process for preparing a multidose pharmaceutical composition according to claim 1 comprising preparing controlled release tablets or hard gelatin capsules from pellets containing at least 85% by weight of the composition. of potassium chloride, based on the total weight of the pellets. ío 11. The method of claim 10 comprising mixing potassium chloride with 0.1 to 0.5 wt. % of an anti-sticking agent, based on the total weight of potassium chloride, and 10 to 15 wt. microcrystalline cellulose, optionally containing sodium carboxymethylcellulose, based on the total weight of potassium chloride; converting the mixture into pellets by treating it sequentially with 15 to 20 wt. % aqueous solution of potassium chloride, an aqueous hydrophobizing agent diluted to 0.5 to 5 wt. and optionally water; drying said pellets; - coating said dried pellets with a coating solution comprising an aqueous dispersion of an ethyl acrylate / methyl methacrylate copolymer as a film-forming agent, hydrophobic 20 agents, 5 to 35 wt. a lower alkanol, talc and optionally a colorant; applying potassium chloride to the surface of said coated particles; - if desired, mixing said coated particles with uncoated potassium chloride particles having the above composition and suitable auxiliary agents or mixtures thereof; and compressing said mixture into tablets or filling into hard gelatin capsules. 12. The method of claim 11 comprising using colloidal silica as an anti-sticking agent. 13. The method of claim 12 comprising using dimethyl30 polysiloxane as a hydrophobizing agent. A process according to any one of claims 11 to 13, comprising grinding a mixture of potassium chloride and an anti-sticking agent to a stage where 90 wt. the milled product has a particle size of less than 100 µm. The method of claim 11, comprising the use of ethanol, isopropanol or a mixture thereof in the preparation of a coating solution. 16. The method of claim 11, comprising applying aqueous 40 of the potassium chloride solution onto the surface of the coated pellets, preferably by spraying. 17. The method of claim 11 comprising using microcrystalline cellulose or lactose as an auxiliary agent when the coated and uncoated pellets are mixed. 18. The method of claim 11 comprising mixing potassium chloride with 0.1 to 0.3 wt. colloidal silica grinding said mixture to particles of which 90% have a particle size of less than 100 µm; mixing said milled material with 10 to 25 wt. microcrystalline celluloses; -16GB 299182 B6 - wetting the mixture thus obtained successively with 5 to 15 wt. 20 wt. % aqueous potassium chloride solution and 0.3 to 0.7 wt. 1.5 to 2.5 wt. aqueous dispersions of dimethylpolysiloxane; spraying water onto said mixture, if desired; 5 - drying the pellets thus obtained; separating pellets having a particle size between 0.8 mm and 1.6 mm; - coating said pellets with a coating liquid containing 4 to 6 wt. % Aqueous dispersion of ethyl acrylate / methyl methacrylate, 5 to 35 wt. % ethanol, 0.5 to 1.0 wt. 0.2 to 1.0 wt. % dimethylpolysiloxane and 0.01 to 1.0 wt. dyes; and - applying 0.5 to 2.0 wt. potassium chloride on the surface of said coated pellets using an aqueous potassium chloride solution. The method of claim 18, comprising wetting the mixture in a centrifugal fluidization pelletizer. 20. The method of claim 18, comprising performing the process in a fluidization apparatus equipped with a rotating plate. A method according to claim 11 or 18, characterized in that it comprises performing 20 pellet forming in an extruder adjusting their spherical shape. A method according to claim 11 or 18, characterized in that it comprises carrying out the production of pellets in a high-speed kneading machine.