SK287281B6 - Controlled release multi-dosage pharmaceutical composition in solid peroral form and method for the preparation thereof - Google Patents

Abstract

Controlled release multi-dosage pharmaceutical compositions in solid peroral form having a potassium chloride content of 500 to 1000 mg per dosage unit, comprising coated and partially uncoated pellets. Described is also a method for the preparation of the multi-dosage pharmaceutical composition.

Description

Technical field

The invention relates to pharmaceutical compositions based on controlled release potassium chloride pellets with a high content of active ingredient and methods for their preparation. The pharmaceutical compositions of the present invention contain 500-1000 mg (6.7-13.4 milliquiv. 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 over a long period has been widely used in therapies to treat hypochalemia (potassium deficiency) of various origins. In medical practice, potassium chloride is used orally and at characteristic high doses (1-6 g per day) [e.g. Pharmindex Compendium (1995), MediMedia Információs Kft .; Knoll, J .: Gyogyszertan, Konynykiado Medicine, Budapest, (1983); Gyógyszer Vademecum (1996) Vol. I, pages 706-708, Országos Gyógyszerészeti Intézet, Budapest, (1996).]

According to the most common 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 by means of an additive agent and by 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 intention of the so-called. The sustained release composition (slow release) is to provide sustained and sustained release of potassium ions to the body, i. j. ensure a sustained release of the active ingredient over a period of 6-10 hours.

The simplest method of preparing sustained release compositions is as follows: Tablet cores / dragees containing potassium chloride are prepared and coated with a sustained release coating (e.g., Hungarian Patent No. 194,495 or United Kingdom Patent No. 1,340,921).

Another way is so-called. matrix tablet. Potassium chloride is included by means 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 sponge-like coating system may persist and cause undesirable side effects.

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

Hungarian Patent No. 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, in elderly patients having lower peristaltic movement, the residual sponge matrix leaves the intestines with difficulty upon release of the active ingredient; this is especially the case when a large number of tablets are applied.

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

Said compositions have the following advantages:

- The release of the active ingredient takes place separately over time and, due to the 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 multi-dose 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 usually prepared by coating the crude crystals with a layer to provide a sustained release of the active ingredient and dissolution of the salt (see, e.g., Hungarian Patent No. 191,102 or WO 86/04817).

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 usually carried out by means of recrystallization, which causes a reduction in the particle size, thus the preparation of crude granular crystals is lengthy and expensive.

The particle size of commercially available, special, thick potassium chloride crystals is typically 0.3-0.5 mm and their specific surface area is about 10-6 m ² / kg [actual density is 1.984 g / cm ³ ; see Rômpp Vegyészeti lexicon, Miiszaki konynykiado, Budapest, (1982)]. That is, a large amount (about 10-30% by weight) of the coating layer must be applied to the surface of the crystals to achieve a satisfactory high release rate (see, e.g., European Patent Application No. 052,075). Potassium chloride crystals prepared in large amounts usually have much lower particle sizes (due to a much higher specific surface area), and therefore, the preparation of a sustained release composition requires unacceptably high levels of coating agent for coating. Said high amount of coating agent causes technical problems in the coating process and the coated particles are sensitive to adhesion, and for this reason special precautions are taken to avoid particle adhesion.

According to U.S. Pat. No. 4,259,315, 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), with the addition of 0.05- 5.0 wt. For example, a substance having an HLB value greater than 10 (i.e., a hydrophilic surfactant) is added to ensure uniform distribution of the microcapsules filled into hard gelatin capsules in the digestible liquid. Due to the relatively small particle sizes of crystalline potassium chloride, the amount of coating applied must be about 20% by weight. and in the microencapsulation process a large amount of cyclohexane must be used, which presents a high risk of environmental pollution.

According to WO 86/04817, potassium chloride crystals having a particle size of about 0.3-0.5 mm are coated by a fluidized-bed spray method using a 3: 1 - 30: 1 weight of a mixture of ethylcellulose and hydroxypropylcellulose in a solution consisting of a mixture of chloroform and ethanol. The required amount of coating material is 9.5-18% by weight. The coated crystals are mixed with conventional tableting aids to obtain rapidly dissolving tablets that carry a large amount of uniformly dispersed particles in the gastrointestinal fluid from which chloride is slowly released potassium. 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 - 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 Rôhm) and aqueous dispersions of ethylcellulose (marketed under the trademark Aqua-coat ECD-30 by FMC). However, if the coated crystals have a particle size of 0.3-0.8 mm then 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. The 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.

The essence of you finding

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

- having regard to the high dose, the high content of active ingredient and the low level of auxiliary agent (coating agent);

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

a multi-dose form to reduce the side effects of mucosal damage and the formation of particles having a hydrophilic surface that rapidly disperse in the gastrointestinal fluid;

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

The compositions 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).

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

The essence of the present invention consists in a multi-dose controlled-release pharmaceutical composition in the form of tablets or hard gelatin capsules containing 500-1000 mg of potassium chloride prepared by so-called " potassium chloride " "Pellet manufacturing process" and coating.

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 and several millimeters (usually between 0.5 mm and 2.0 mm), further characterized by: a small deviation from the particle size, a substantially spherical shape, a low surface unevenness and a particle density like a compressed material.

According to the present invention there is provided a multidose pharmaceutical composition in solid oral controlled release form, preferably in the form of tablets or hard gelatin capsules, having a potassium chloride content ranging from 500 to 1000 mg per unit dose, comprising coated and partially uncoated pellets, wherein it contains at least 70 wt. % potassium chloride, based on the total weight of the composition, 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 coated pellets containing 3 to 10 wt. an ethyl acrylate / methyl methacrylate copolymer and / or an ammonium methacrylate copolymer, 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.

According to a further aspect of the present invention there is provided a process for preparing multidose pharmaceutical compositions in solid oral controlled release form comprising pellets comprising at least 70% by weight of the composition. potassium chloride, preferably in the form of tablets or hard gelatin capsules, having a potassium chloride content in the range 500 to 1000 mg per unit dose, comprising preparing tablets or hard gelatin capsules with a controlled release of the active ingredient from pellets having a potassium chloride content of at least 70% weight.

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

mixing potassium chloride with 0.1-0.5 wt. % of an anti-sticking agent and 10-25 wt. microcrystalline cellulose optionally containing sodium carboxymethylcellulose;

- converting the mixture into pellets by treating it successively with 15 - 20 wt. % aqueous potassium chloride solution, an aqueous hydrophobizing agent diluted to 0.5-5 wt. and optionally with water;

drying said pellets;

- coating said dried pellets with a coating solution comprising an aqueous dispersion of an ethyl acrylate / methyl methacrylate copolymer and / or an ammonium methacrylate copolymer as a film-forming agent, hydrophobizing agent, 5-35 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 said composition and with suitable auxiliary agents or a mixture 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 0.1-0.3 wt. colloidal silica;

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

mixing said ground material with 10-25 wt. microcrystalline cellulose;

- wetting the mixture thus obtained successively with 5 - 15 wt. 20 wt. % aqueous potassium chloride solution and 0.3-0.7 wt. 1.5 - 2.5 wt. an aqueous dispersion of dimethyl polysiloxane;

- if desired, by spraying water onto said mixture;

drying the pellets thus obtained;

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

- coating said pellets with a coating liquid containing 4-6 wt. 35% aqueous ethyl acrylate / methyl methacrylate dispersion, 5-35 wt. % ethanol, 0.5 - 1.0 wt. talc, 0.2 - 1.0 wt. % of dimethylpolysiloxane and 0.01-1.0 wt. dye;

and 0.5 to 2.0 wt. potassium chloride on the surface of said coated pellets using an aqueous potassium chloride solution.

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

According to the present invention, substances used for this purpose, e.g. silica, talc, magnesium stearate, preferably silica.

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% by weight) is composed of potassium chloride pellets having a particle size of 0.5-2.0 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 have a particle size of less than 100 μηι; 90 wt. the particle size of the microcrystalline cellulose is less than 50 µm; the colloidal silica particle size 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 further auxiliary agents, talc and a hydrophobizing agent, preferably dimethylpolysiloxane.

In addition to coated pellets that provide controlled release of the active ingredient, the composition of the present invention may also include uncoated pellets and other excipients commonly used in the preparation of oral pharmaceutical compositions (e.g., magnesium stearate, microcrystalline cellulose, etc.) to facilitate filling into hard coatings. 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 easier to plasticize than the inorganic salts, does not exceed 50% [see e.g. Capes, CE .: Particle Size Enlargement, 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% by weight. Thus, the finding of the present invention could not be predicted.

It has been found that the smaller the particles are used as the 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 highly susceptible to agglomeration, anti-sticking agents may be advantageously added to facilitate grinding and to prevent further adhesion of the milled material. Colloidal silicon dioxide (e.g. Aerosil 200; manufactured in Degussa, Germany) may be advantageously used for this purpose. The amount of colloidal silica is usually 0.1-0.5% by weight, preferably 0.1-0.2% by weight.

The ground potassium chloride is then mixed in a suitable apparatus with microcrystalline cellulose, also with a small particle size. For this purpose, e.g. Avicel PH 105 (manufactured by FMC Corp.). Microcrystalline cellulose can be used alone or as a mixture formed with sodium carboxymethylcellulose (Avicel CL-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 granulation apparatus). The mixture is then wetted with a concentrated solution of potassium chloride at a concentration of 15-25% by weight, preferably 20% by weight, and then further wetted with the hydrophobizing agent. An emulsion of dimethylpolysiloxane, in particular an emulsion of dimethylpolysiloxane diluted to 0.5 - 5 wt. (Pharsil E1049; Wacker Chemie).

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

It is known that during the pellet manufacturing process, when pellets start 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 the use of a concentrated potassium chloride solution results in more compact pellets having less porosity, a rougher surface and higher density. The mechanism of this complicated phenomenon is not entirely known. To the best of our knowledge, the following procedure is likely to proceed. 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 is accompanied by an uncontrolled change in the consistency of the wetted particle agglomeration over time. When wetting the granules with a saturated or almost saturated potassium chloride solution, the liquid to solids ratio is essential for 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 phenomena. When drying the solution, an uncontrollable amount of concentration reaches the surface from which the crystals of random size and amount are 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 using potassium chloride solution, due to the smaller amount of fluid and higher amount of local concentration.

A further advantage of using a concentrated or nearly concentrated potassium chloride solution as a liquid for formulation is that it remains in the pores of the pellets and partially fills them when drying the potassium chloride crystals.

It is expressly essential that during pellet formation, as it grows and the spheronification phase, the pores of the growing pellets could be filled with fluid (to allow formation). During this process (compaction increase, spheronification) some of the fluid reaches the surface, but another part remains in the pores of the raw (wet) particles until they begin to dry. This solvent is removed during drying, but after the solvent pores remain in the pellets.

By using less liquid and potassium chloride solution instead of water, more compact pellets having a higher potassium chloride content are obtained.

The concentration of the potassium chloride solution used in the process of the present invention is close to the saturation 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% by weight.) ["Analitikai zsebkônyv ", Muszaki Kônyvkiadó, Budapest, (1971)] However, due to technical problems, the actual concentration used is lower than this value (eg coupling head obstruction).

It is preferred to use a potassium chloride solution having a concentration of about 15-20% by weight.

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 pellet formation process, the particle size increase proceeds very rapidly, i. j. in an explosive manner, the process can be slowed by injecting a silicone emulsion (hydrophobising), the process can be more manageable, the deviation from the particle size dispersion can be reduced, and the amount of desired product fraction can be significantly increased.

In addition, the use of a silicone emulsion also has secondary non-negligible advantages. The surface of the particles becomes more hydrophobic, the particles are less susceptible to sticking to the walls, the surface of the particles becomes smoother and later undergoes adhesion of the deposited layer.

Drying and fractionation of the 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 refers to the desired kinetics, i. j. 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 ensured by sustained release with a lipophilic (hydrophobic) deposited layer. For this purpose, natural, semi-synthetic or synthetic fats, hardened vegetable oils, waxes or wax derivatives may be used.

This process can be e.g. by heating the mixture of inorganic salt and solid fat to a temperature above the melting point of the fat, uniformly distributing the salt in the melt, and then cooling and granulating the system (e.g., German Patent No. 1,948,019). In another method, the fat is dissolved in a solvent (e.g., chloroform, carbon tetrachloride) and sprayed onto the particles (e.g., Hungarian Patent No. 191,202).

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

The coating 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. Dissolved chain forming polymer particles form a loose structure and, after drying the thin layer, attach to one another to form a uniform, compact, well covering layer.

In order to ensure the protection of the environment, the replacement of so-called "Solvent coating methods" "Dispersion coating procedures". For this reason, manufacturers have developed their well known and frequently used polymer thin film forming system also in the form of aqueous dispersions. It is a clear trend to use dispersion coatings and the quality of the dispersed coatings is constantly improving. Polymeric particles are present in the dispersions in the form of small latex beads, and these beads are attached to each other during the coating process. It can easily happen that such a coating layer is less compact and, according to theoretical considerations, it is also true that a greater amount than from the corresponding type of solvent is used to achieve the same sustained release effect from the dispersion coating fluids. In addition, there is a greater risk of developing a so-called. Orange-shell structures of the applied coating (for more details see Cole, G., Hogan, J., Aulton, M., "Pharmaceutical Coating Technology").

The present invention is based on the further discovery that the use of a coating fluid of a suitable composition can combine the advantages of both systems.

In accordance with another aspect of the present invention, a lower alkanol in an amount of 5-35% by weight is added to a commercially available aqueous dispersion of an ethyl acrylate / methacrylate copolymer and / or an ammonium methacrylate copolymer containing conventional pharmaceutical auxiliary agents (e.g. talc, dimethylpolysiloxane, optionally dyes, etc.). Branched or unbranched alkanol chains having 1-3 carbon atoms, preferably ethanol, isopropanol or mixtures of ethanol and isopropanol, may be used as the lower alkanol. It has been found that the addition of a lower alkanol advantageously affects the behavior of the deposited dispersion. This finding is all the more surprising since, according to the manufacturer's instructions for use, the addition of organic solvents to dispersed coatings is usually 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 hitherto by known processes using pure "organic solvents".

The major thin layer is the component used according to the method of the present invention and 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 commercial products of the company have proven to be particularly suitable for use: dry powder or granules; a solution consisting of isopropanol or a mixture of isopropanol and acetone; or an aqueous dispersion.

It is an object of the present invention to achieve the same or similar release of the active ingredient with an aqueous dispersion agent to be coated as with an organic solvent system. This object is achieved by adding 5-35 wt. a lower alkanol (preferably ethanol and / or isopropanol) into an 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 appearance of the polymer is still similar to that of the dispersion (white, cloudy), but its behavior is close to the organic solvent system. That is, the lower alkanol (ethanol or isopropanol) partially dissolves the polymer particles present on the surface of the latex micellia, thereby facilitating their agglomeration by coming into contact on the surface of the particles to be coated.

In addition, ethanol and isopropanol have two other tasks: on the one hand, it facilitates the use of suspensions of difficult-to-wettable powders in the coating (talc, silica gel) known to cause major technical problems in the preparation of coating systems for suspensions / dispersions; On the other hand, they improve the deposition of 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 substantially more advantageous than the crystals, and the coating has the advantages mentioned. In addition, when approximately the same amount of coating (or thin film of polymer) is applied, substantially less potassium chloride is released from the product of the present invention than from known products. The results of these comparative experiments are shown in Table 1. The data of FIG. 3 of the “INFO 2.4” leaflet from Rohm Pharma.

Table 1

Release of potassium chloride as an active ingredient

Polymer (% by weight) Release of active ingredient (%) Product according to the invention Reference product 2 hours 4 hours 2 hours 4 hours 5 36 81 94 100 5.5 32 75 6 24 65 85 99 7 75 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 25-40% 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 film formed on the surface of the particles obtains the final properties very quickly, within a few 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 potassium chloride solution onto the particles. Thus, on the one hand, the particles are coated with an adhesion-inhibiting 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 (e.g. in the stomach) and do not stick to each other. The amount of potassium chloride applied to the surface is 0.5-5.0% by weight. 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 they 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 surface of the particles 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.

Accordingly, the present invention is fundamentally different from the prior art.

According to Hungarian Patent No. 194,495, a water-soluble agent is incorporated into the particle (i.e., tablet core) to affect the release rate, while a surfactant is used to prevent adhesion according to U.S. Patent No. 4,295,315.

Since according to the present invention adhesion is prevented by the use of the active ingredient in the manner described above, 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 for influencing the release profile from any point in the method of making the composition.

According to a particularly preferred embodiment of the present invention, the coated potassium chloride pellets are mixed in said ratio with the uncoated potassium chloride particles (i.e. before tabletting or encapsulation) before further processing. This provides a very simple and elegant method of preparing pharmaceutical compositions of varying release rates, including compositions of the type provided (i.e., 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 in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Capsule filled composition comprising coated and uncoated pellets. The preparation and coating of the pellets is carried out in a laboratory centrifugal fluidized-bed granulation apparatus.

Process of preparation of starting material

14.97 kg of potassium chloride (pharmaceutical grade) are pre-crushed in a semi-high speed, high-speed granulation machine (Lodige FM50.Iz type) for 5 minutes. After addition of 0.03 kg of Aerosil 200, the mixture is stirred for 10 minutes and then milled in a grinding machine (Alpine 160Z type) until 90% by weight. the product has a particle size of less than 100 µm. This product will hereinafter be referred to as "potassium chloride master batch".

Production of pellets

255 g of said premix potassium chloride are mixed with 45 g of Avicel PH 105 in a laboratory centrifugal fluidization pelletizer. The mixture is granulated successively with 150 g of 20 wt. of a potassium chloride solution, 50 g of a silicone emulsion diluted with distilled water to 2 wt. (type E2; dry substance 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. In this way, 150-200 g of pellets having a particle size of 0.8-1.6 mm (hereinafter referred to as "pellet core") are obtained. This pellet processing step is repeated at least three times. Only the 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 applied 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 are 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 polymer dispersion, 20 wt. a solution of potassium chloride on the surface of the coated particles.

Release of coated pellets

Test method: 750 mg of coated pellets in 900 ml of 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 titration.

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

hours: 72%; 8 hours: 85%.

Mixing of pellets

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

Release results

Test Method: See the Test 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

Capsule filled composition comprising coated and uncoated pellets. The preparation and coating of the pellets is carried out in a pilot plant apparatus for centrifugal fluidization granulation.

Process of preparation of starting material

The potassium chloride masterbatch is prepared as described in Example 1.

Production of pellets

7703.9 g of the potassium chloride masterbatch are mixed with 1359.5 g of Avicel PH 105, the mixture is granulated in a pilot plant for centrifugal fluidization granulation successively with 453 1.8 g of 20 wt. solution of potassium chloride, 1510.5 g of silicone emulsion (type E2, dry substance content 35%, manufactured by Wacker Chemistry) diluted with distilled water to 2% by weight. and 266-925 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 sieve to give 6-7 kg of particles having a size between 0.8 and 1.6 mm (hereinafter referred to as "pellet cores"). This procedure is repeated at least twice. Only the pellet cores (particle size between 0.8 and 1.6 mm) are used in the pellet coating step.

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 dispersion is prepared as follows:

Dissolve 1 g of dye (Ariavit indigocarmine) in 500 g of distilled water. The solution is mixed with 488.69 g 96% ethanol, then 86.99 g talc, 1000 g distilled water, 167.55 g 35% silicone oil emulsion, 1954.75 g 30% Eudragit NE 30 D dispersion and the mixture make up to 4887 g with distilled water.

After applying 955 g of polymer dispersion, 20 wt. a solution of potassium chloride on the surface of the coated particles.

Release of coated pellets

Test method: see earlier 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 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.

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

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

Example 3

Capsule filled composition comprising 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 addition of 0.35 kg of Aerosil 200, the mixture was stirred for 10 minutes. The mixture is then milled in a grinding machine (Alpine type) until 90% by weight. the product has a particle size of less than 100 µm. (This product will be hereinafter referred to as "potassium chloride master batch").

Production of pellets Kg of potassium chloride premix is mixed with 15 kg of Avicel PH 105, the mixture is granulated in an operating centrifugal fluidization pelletizer (type Glatt GPCG 200) successively with 50 kg of 20 wt. of potassium chloride solution, 16.6 kg of a Pharsil E 1049 type silicone emulsion diluted to 2 wt. 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 60-70 kg of pellets having a particle size between 0.8 and 1.6 mm (hereinafter referred to as "pellet cores"). . This procedure is repeated at least three times. In the pellet coating step, only the pellet core fraction (particle size between 0.8 and 1.6 mm) is used.

Coating of pellets

A layer of 105 kg of coating dispersion in a centrifugal fluidized-bed pelletizer (Glatt GPCG 200 type) according to a method known in the art is applied to 175 kg of pellet cores. The applied 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 added to this solution, followed by the addition of 1.84 kg of talc, 3.18 kg of a 39% silicone emulsion, 2 kg of distilled water and 41.38 kg of a 30% dispersion of Eudragit NE 30D. Fill up to 105 kg with distilled water.

After application of 16.7 kg of polymer dispersion, 20 wt. a solution of potassium chloride on the surface of the coated particles.

Release of coated pellets

Test method: see Example 1 hour: 2%; 2 hours: 24%; 4 hours: 65%;

hours: 84%.

Mixing of pellets

To achieve the desired release rate, the coated pellets and 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.

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

hours: 86%; 8 hours: 94%.

Example 4

Capsule-filled composition. 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 masterbatch is prepared according to Example 1.

Production of pellets

11.12 kg of premix 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 20 wt. potassium chloride solution and silicone emulsion (type E2, manufacturer: Wacker Chemie) diluted with 0.54 kg of distilled water to 3.5 wt. in several doses. The wet blend is added to a pilot-operated roll extruder (Schuter type PP85) using a screw feeder and extruded. 2 kg of extruded fibers are placed in a semi-operational spheronizer (diameter 300 mm; type RM300; grooved disc) 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. 1.2-1.6 mm fractions are separated from the dried product by manual sieving and used for coating.

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 silicone emulsion type SA 2 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 homogeneous solution thus obtained.

750 mg portions of the coated pellets are filled into capsules.

Release results of the encapsulated coated pellets

Test method: see Example 1.

hour: 22%; 2 hours: 43%; 4 hours: 71%;

hours: 92%.

Example 5

Capsule filled composition comprising pellets. The pellets are prepared in a high speed laboratory mixer and coated in a centrifugal fluidization granulation laboratory apparatus.

Process of preparation of starting material

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

Production of pellets

913.25 g of the potassium chloride masterbatch are mixed with 150 g of Avicel PH 105. The mixture is granulated in a laboratory, high speed pharmaceutical mixer (Zanchetta Roto-Junior type) 183.75 g of 20 wt. potassium chloride solution, 76.75 g of a silicone emulsion diluted to 4.34 wt. 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 sieve 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

400 g of the pellet cores were coated as described in Example 1. 750 mg portions of the coated pellets were filled into capsules.

Example 6

A 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 masterbatch is prepared according to the method of Example 1.

Production of pellets

12.75 kg of the potassium chloride masterbatch 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 (Lödige FM50.Iz type) with 2.75 kg of 20 wt. % potassium chloride solution and a silicone emulsion diluted 0.63 kg to 3.5 wt. in several doses.

II

The wet blend is added via a screw feeder to a pilot-operated extruder (type Schiiter PP85) and extruded. 2 kg of extruded fibers are placed in a pilot plant spheronizer (Schiiter RM300 type; 300 mm diameter; grooved disc) and spheronized at 800 rpm. 4000 g of spherical particles are dried in a laboratory fluidization granulation and drying apparatus. 1.2-1.6 mm fractions are separated from the dried product by manual sieving and used for coating.

Coating of pellets

In a known manner, 1670 g of coating dispersion is applied to 1850 g of pellet cores in a laboratory apparatus for fluidization granulation, drying and coating. The coating dispersion is prepared as follows:

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

Tab pellet summer

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 a diameter of 15 mm.

PATENT CLAIMS

Claims (21)

A multidose pharmaceutical composition in solid oral controlled release form, preferably in the form of tablets or hard gelatine capsules, and having a potassium chloride content in the range of 500 to 1000 mg per unit dose, comprising coated and partially uncoated pellets, characterized in that: % containing at least 70 wt. % potassium chloride, based on the total weight of the composition, 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 coated pellets containing 3 to 10 wt. an ethyl acrylate / methyl methacrylate copolymer and / or an ammonium methacrylate copolymer, 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. Composition according to claim 1, characterized in that it contains colloidal silica as an anti-sticking agent. Composition according to claim 1, characterized in that it contains dimethylpolysiloxane as a hydrophobizing agent. Composition according to any one of claims 1 to 3, characterized in that the coated particles comprise at the top of the polyacrylate coating layer 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 microcrystalline cellulose comprises sodium carboxymethylcellulose. Composition according to any one of claims 1 to 5, characterized in that the coated and uncoated particles comprise 75 to 85.5% by weight. % potassium chloride, 13.5 to 24.8 wt. % of microcrystalline cellulose, 0.1 to 0.5 wt. % colloidal silica and 0.1 to 5.0 wt. dimethyl polysiloxane. 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 copolymer, 0.2 to 2.0 wt. % talc and 0.1 to 5.0 wt. dimethyl polysiloxane. Composition according to any one of claims 1 to 7, characterized in that it contains 2.3 to 13% by weight of the composition. the coating layer based on the total weight of the particles. 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. 10. A process for the preparation of a multi-dose pharmaceutical composition according to claim 1, comprising mixing potassium chloride with 0.1 to 0.5 wt. % of an anti-sticking agent and 10 to 25 wt. microcrystalline cellulose optionally containing sodium carboxymethylcellulose; converting the mixture into pellets by treating it successively with 15 to 20 wt. % aqueous potassium chloride solution, 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 and / or an ammonium methacrylate copolymer as a film-forming agent, a hydrophobizing agent, 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 said composition and with suitable auxiliary agents or a mixture thereof; and compressing said mixture into tablets or filling into hard gelatin capsules. Method according to claim 10, characterized in that colloidal silicon dioxide is added as an anti-sticking agent. 12. The process of claim 10 wherein the hydrophobizing agent is dimethylpolysiloxane. The method according to any one of claims 10 to 12, characterized in that the mixture of potassium chloride and anti-sticking agent is ground to a degree where 90% by weight of the composition is obtained. the milled product has a particle size of less than 100 µm. 14. A process according to claim 10, wherein ethanol, isopropanol or a mixture thereof is added in the preparation of the coating solution. Method according to claim 10, characterized in that the aqueous potassium chloride solution is applied to the surface of the coated pellets, preferably by spraying. Method according to claim 10, characterized in that microcrystalline cellulose or lactose is added as auxiliary agent when the coated and partially uncoated pellets are mixed. 17. The method of claim 10, comprising mixing potassium chloride with 0.1 to 0.3 wt. colloidal silica grinding said mixture into particles of which 90% have a particle size of less than 100 µm; admixing said milled material with 10 to 25 wt. microcrystalline cellulose; wetting the mixture so 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. an aqueous dispersion of dimethyl polysiloxane; if desired, spraying water onto said mixture; drying the pellets thus obtained; separating the pellets having a particle size between 0.8 mm and 1.6 mm; coating said pellets with a deposited liquid containing 4 to 6 wt. % By weight of an aqueous ethyl acrylate / methyl methacrylate dispersion; % ethanol, 0.5 to 1.0 wt. % talc, 0.2 to 1.0 wt. % of dimethylpolysiloxane and 0.01 to 1.0 wt. dye; and 0.5 to 2.0 wt. potassium chloride on the surface of said coated pellets using an aqueous potassium chloride solution. Process according to claim 17, characterized in that the mixture is wetted in a centrifugal fluidization pelletizer. 19. The method of claim 17, wherein the process is carried out in a fluidization apparatus equipped with a rotating plate. Method according to claim 10 or 17, characterized in that the pellets are formed in an extruder adjusting their spherical shape. Method according to claims 10 or 17, characterized in that the production of pellets is carried out in a high-speed kneading machine.