MXPA99002387A - Fast decomposing pellets - Google Patents

Abstract

The invention concerns the administration forms of pharmaceuticals shaped as pellets containing a delaying medium, in which the releasing rate of the active substance is not delayed or is substantially identical as compared to other pellets that contain no delaying medium. The releasing rate of these fast decomposing pellets is no less than around 90%within a period of 30 minutes. The present invention also concerns a method to produce such pellets.

Description

RAPIDLY DISINTEGRABLE PELLETES OR PILLOWS DESCRIPTION OF THE INVENTION: The present invention relates to pharmaceutical administration forms in the form of pills or pellets containing at least one disintegration retarding agent for the production of extrusion pellets containing a rounding agent. , wherein the release of the active agent from the pellet (pellet A) is not minor compared to a corresponding reference pellet (Pellet B) which does not contain this rounding agent as an auxiliary pharmaceutical material. The rate of release of this fast disintegrating pellet is at least about 90% within a time period of 30 minutes. It is also object of the invention procedures for the manufacture of that pellet or ball. Pellets are used mostly for modified forms of released medicines. They have, in comparison to the usual medicinal forms with application of active agent release, very clear advantages, such as avoiding the accumulation of doses and local intolerances. Carry to a minimum the intra and interindividual deviations, independence of vacuum times in the stomach, mixtures of different retarding pellets with different active agents (possibly incompatible) and improvement of bioavailability.

REF .: 29694 Frequently the following principles are used for the manufacture of pellets with modified active agent release a) donation modification of the active agent with the help of covers or b) matrix systems. Coatings or covers resistant to gastric juices are stable in the acid medium of the stomach and are dissolved by the formation of salts in the basic or weakly acidic zone, slowly. Since the pellets, however, are generally independent of the rate of emptying of the stomach, the gastric juice-resistant coatings lead to a short-term delay in the release of the active agent. In addition, coatings are used, which are insoluble in the gastrointestinal tract and the dissolved active agent is released by diffusion through the cover. Agui is allowed to adjust the rate of release, for example through diffusion coefficients, the thickness of the film and the concentration of the precipitate, the osmotic pressure and the use of pore formers. In hardly soluble active agents, however, the amount of liguid which diffuses through the cover in the core does not reach to dissolve the active agent, so that only a part of the total dose is released. To avoid these disadvantages, control systems over time have been developed in recent years, in which the cover after a certain delay time is broken or exploded. Milosovich (US 3, 247.066) developed a medicinal form with controlled release of the active agent based on spherical sticks, which are contained in a colloid swellable in water, and covered with an indigestible layer, by means of the diffusion arrives the liguid of the digestion to the nucleus that contains the explosive agent, which swells and breaks. Another variant is the composite of several layers called "Time Controlled Explosion System" (abbreviated TCES) (see EP 0 210 540 B 1) where a layer containing the explosive agent placed directly under the coating triggers the breaking of the cover. Bayer AG (patent DD 297 767) developed a ball or pellet formulation with controlled release over time. With the aid of a double layer, the release control is made of a non-digestible lacquer layer and an internal jacket, which controls the migration of water in the direction of the core, moisture arrives at the core containing the explosive agent, and the cover explodes. . The formulations produced in US 3,247,066, EP 0210 540 Bl and DD 297 767 are not produced in any case by means of extrusion and rounding, so that pellets with a narrow grain size distribution can not be obtained. EP 0 421 921 Bl discloses doubly coated granules, which are obtained by extrusion of a wet granulated kneader, which are formed as spherical pellets with a diameter of 0.3 to 1.5 mm. In any case it is treated with a pellet whose temporary control of the release is made by a film resistant to intestinal juice and not by an explosion mechanism. Although the extrusion processes have the advantage in comparison to the rotary granulation, of which more narrowly limited grain size distributions are attainable, the disadvantage of the extruded ball is basically that in its manufacture, the use can not be waived. of certain additional pharmaceutical substances such as for example microcrystalline cellulose as rounding means, since they provide the extrudate with the plasticizing properties necessary for rounding. Such additional substances also act in many cases as delay agents, that is, they lead to a delayed release of the active agent. This delay, which is forced, is not desirable in many cases. Delay agents, especially microcrystalline cellulose, can establish a matrix system, which prevents the disintegration of the pellet, so that pellets with retarding properties are obtained in reference to the release of the active agent. The additional materials which are used as rounding aids may also act as a means of delaying the disintegration, that is, they prevent the rapid disintegration of the pellet into sticky particles. These effects cause first of all with medicinal substances difficult to dissolve a significant delay in the application of the active agent and a delay in the donation of the medicine. They are active agents that show a solution profile dependent on a strong pH and especially in the basic intestinal juice are hardly soluble, characterized by the formation of a dense matrix system with microcrystalline cellulose. In such cases, the release profile by the composition and the thickness of the coating is not allowed to vary as the release of the drug from the matrix or the rate of disintegration of the pellet decisively influences the release behavior. The invention therefore proposes the task of providing pellets or balls that disintegrate rapidly and with which the active agent in the shortest possible time is released from the core of the pellet, although the pellet contains rounding aids, which also serve as retarding agents and / or disintegration delay agents.

Surprisingly, it has been determined that the nuclei of the pellets disintegrate well when they contain a) a retarding agent or an agent to slow the disintegration; b) a tablet explosion medium (hereinafter also indicated as an intensive blasting agent) and c) at least one auxiliary selected from the group of surfactants and binders, and d) optionally filler or combinations of these auxiliaries. The corresponding active agents are released from the pellet cores quickly and essentially without time delay, compared to a pellet which does not contain a rounding agent. This concerns especially active agents that are difficult to dissolve. In particular, the core pellets, together with the rounding agent, contain an intensive blasting agent and a binder. instead of the surfactant it may also contain a binder, for example polyvinylpyrrolidone (PVP). In a preferred variant PVP is added in the core of the pellet in addition to the surfactant. The pellets according to the invention also have the advantage that they have a limited grain size distribution. At least 90% of the particles have a diameter of approximately 0. 6 -1. 2 mm In addition, the pellets also disintegrate with such active agents in a relatively rapid manner, which show a solubility profile dependent on a high pH. The pellets usually have a diameter between 0. 5-2mm, depending on the size of the disc of holes used for the extrusion. The pellets which rapidly disintegrate (hereinafter also indicated as core pellets A) have a release rate of the active agent, which despite the existence of the rounding agent which acts as a retarding agent of the disintegration, does not retard it. Thus the release of the active agent itself is not retarded. The release is carried out quickly and is especially comparable with a pellet which also according to another procedure can be prepared after the extrusion process, and which does not contain that decay retarding agent (hereinafter also indicated as pellet of core B or pellet of reference). The core pellets according to the present invention do not exhibit any delayed release of the active agent. The rate of release of such core pellets is at least 90% after 30 minutes. The pellets according to the invention (pellets of core A) contain the usual pharmaceutical explosive agent, advantageously in an amount of 5-50% and the surfactants in an amount of 0.l -20%, the binders can be in an amount from 1-10%. The microcrystalline cellulose (for example of the brand Avicel) as auxiliary of the rounding exists especially in an amount of 5-70%. The percentage refers to the weight percent of the core of the pellet, as long as nothing else is indicated . As auxiliaries of the rounding for the manufacture of extrusion pellets, the usual auxiliaries known in the literature are suitable, which allow a rounding of the masses of medicament obtained first as bars. For example, microcrystalline cellulose and its derivatives are suitable, for example Avicel, Avicel 101, Avicel PH 105 Avicel PH 200 (registered trademarks). While these rounding agents cause a delay in the release of the active agent, in comparison to other pellets which do not contain them, but these rounding aids delay the disintegration of the pellet into small particles (agent of delay of disintegration). in the sense of the present invention they enter as delay agents for the manufacture of the core pellet according to the present invention. Suitable agglutination agents are all customary pharmaceutically binders, for example, gelatin, microcrystalline cellulose, L-HPC, starches, hydroxypropylmethyl cellulose derivatives and polyvinylpyrrolidone derivatives (PVP). However, polyvinylpyrrolidone derivatives (PVP) are preferred, since these do not adversely affect the pellet demining, but favor it, so that according to the invention, by the application of PVP. in combination with an intensive blasting agent, the surfactant can be dispensed with. As the tablet explosion agent (disintegrating auxiliary agent) or intensive explosion agent for pharmaceutical purposes, all the usual auxiliaries can be used, which possess the property of swelling in an aqueous medium and are signaled by an increase in volume when received in water. Tablet Explosion Agent is a denomination for such pharmaceutical auxiliaries, which take care of a rapid desmining of the tablets in water or in the gastric juice and of the release of the drugs in a resorbable form. Depending on the active mechanism, these substances are substances that increase the porosity of solid dosage forms and have a high absorption capacity for water (starches, cellulose derivatives, alginates, dextranose, cross-linked polyvinylpyrrolidone and others). as hydrophilic agents, which are used for the wetting of solid administration forms (such as, for example, polyethylene glycol sorbitant fatty acid ester). Sodium carboxymethylcellulose, modified corn starch (for example starch 1500) and carboxymethyl-Na starch are preferred (Explotab or Primojel registered trademarks). Primojel is preferred. Suitable surfactants are pharmaceutically active surface-active materials, such as ionic and non-ionic surfactants, such as benzalkonium chloride, polyoxyethylene-polyoxypropylene copolymers (eg Pluronic F68); polyethylene glycol glyceryl ester, alkyl sulfate, preferably dodecyl sulfate -Na (Texapon) and stearic acid or its alkali metal or alkaline earth metal salts (Mg or Na salts) or stearates such as for example PEG 400 Stearate (Mirj). If appropriate, one or more conventional pharmaceutical filling agents are additionally added. The fraction of filler material can reach up to 80%. As fillers, carbohydrates, such as sugar, preferably glucose, lactose, sucrose, sugar alcohols such as mannitol and sorbitol starch and starch derivatives and dibasic calcium phosphate are used as fillers. In principle, all known fillers are used. According to the invention, formulations comprising 15-25 microcrystalline cellulose, 15-25% explosive agent, 2-10% surfactant and / or 3-7% polyvinylpyrrolidone (weight data) are preferred, as well as optionally binding agents or fillers. Active substances in the sense of the invention, are basically drugs, which come into consideration for the therapeutic treatment of man. Advantageously, those active agents which are hardly soluble are suitable. Substances that are hardly soluble, in the sense of the invention, are those that are indicated in the books of general medicinal agents (for example USP XXII) as not easily soluble active agents. Such active agents have, for example, a solubility of less than 0.1 mg / ml, especially less than 0.05 mg / ml or less than 0.01 mg / ml in an aqueous medium or have a strong pH dependence on their solubility behavior. , for example, are active agents (+/-) -1- (9H-Carbazol-4-yloxy) -3 - [(2- (2-methoxyphenoxy) -ethyl) -amino] -2-propanol; propionic acid from 2- [4- [- [(4-chloro-benzoyl) -amino] -ethyl] -phenoxy] -2-ethyl, (INN-carvedil (INN benzanofibrate) INN glibenclamisa or l-isopropyl-3- [ (4-m-toluidino-3-priidyl) sulfonyl] -urea (INN Torasemide) These active agents are hardly soluble, especially carvediol shows a solubility profile strongly dependent on pH and is hardly soluble in the intestinal juice. according to the invention, however, these active compounds and especially carvedilol are released very well. For the test of the disintegration of the pellets, generally known methods and apparatus which are described in the medical books can be followed or used. in standardized form To measure the disintegration time, the standardized Paddle apparatus can also be used (37 ° C, 90 r.p.m.). As soon as at least 90% of the pellet has disintegrated into small agglomerates, the disintegration time is read. the rate of release of the active agent (data as a percentage refer to a unit of time) are also determined by standardized general procedures (see European Pharmacopoeia or US Phar acopea). The pellets or balls of the present invention surprisingly have a disintegration rate of at least 90% after 30 minutes, in a preferred embodiment already after 20, 10 or 5 or 2 minutes. The release of the active agent is carried out at least 90% after 30 minutes. After 10 minutes the amount of active agent released from the core pellet is at least 50%, preferably at least 70% and more especially 90%. These release rates can be achieved, surprisingly, also for poorly soluble active agents. the release is determined in an aqueous medium, where the pH value of the solution is adjusted to a certain value, wherein the active agent has an optimum solubility. Thus, Texapon® and the carvedilol pellets containing explosive are decomposed or disintegrated until after 2 minutes and show an active agent release of approximately 70% by 5 minutes. By application of pluronic® F 68 the disintegration is accelerated favorably, where already at 5 minutes more than 90% of carvedilol has been released. These pellets according to the invention are not coated, and are suitable as an alternative for a non-retardant monolithic medicinal form. In a particularly advantageous manner, the pellets according to the present invention contain a combination of an explosive tablet agent together with either a surfactant and / or a binder. Especially preferred is the combination of an explosive agent with a surfactant or a combination of an explosive agent with a binder. The addition of a combination of an explosive agent with one of the so-called auxiliaries (surfactant and / or binder) leads to a better rate of release than the single addition of the explosive agent (see Tables 1 and 2). The pellets according to the invention are manufactured, when the active agent is mixed with the pharmaceutical auxiliaries 1, then granulated, extruded and rounded. The rounded / extrusion process according to the invention allows, in contrast to rotary granulation, the manufacture of pellets with a very narrow grain size distribution. When using a hole disk with a hole diameter of 1 mm, approximately 90% of the pellets have a diameter between 0. 6 -1. 2 mm Since no neutral starting core is necessary in the production of the pellets according to the invention, very large quantities of active doses can be prepared. According to the invention, the active agent amounts can be made up to 80% (by weight). Preferably the active agent fraction is for example at least 30%, 50% or 70%. The carvidilol pellets with an active agent fraction of 70% can, within the meaning of the present invention, be completely manufactured without problems and disintegrate within a period of less than 10 minutes, especially less than 5 minutes or even less than 2 minutes. In a particularly preferred embodiment, the core pellets according to the invention can also be coated with a layer, for example to modify the release of the active agent or hide an unpleasant taste. In the sense of the present invention, the fast-disintegrating core pellets may also be provided with a coating, to develop a time-controlled system, where the coating disappears after a certain time delay. The formulations of the core according to the invention are especially suitable as a basis for the development of a medicinal form with a release of modified active substance, where by the disappearance of a film a controlled release of active substance over time is achieved, that the swelling pressure developed in the core of the pellet by the intake of moisture reaches, to tear a non-digestible coating. Such an explosion system offers especially with medicinal agents difficult to solve in water, the advantage compared to diffusion pellets, that the dose of active agent is released from the medicinal form in a comparatively fast and total manner. By the composition and thickness of the film as well as by the recipe of the fast disintegrating core, a variable delay time between 10 minutes and 5 hours can be set. It is known that a thick film layer can delay the start of the release very much on its own, but in such a way that after the disappearance of the cover there is a slow release of the active agent. High amounts of application additionally require a non-economic time to apply the coating. Surprisingly with the pellets according to the present invention by the selection of suitable film materials the thickness of the film can be kept relatively low. The fast disintegrating pellets can also be coated with easily dissolvable films (for example hydroxypropylmethylcellulose) or with films, which dissolve in the gastrointestinal tract in a pH-dependent manner (coatings resistant to gastric juice). the pellets can be coated with different film formers in the form of layers or different recipes of the same film former. The pellets or coated balls, which after different expansion times release the active agent, as well as uncoated pellets that disintegrate rapidly can be mixed, in order to be able to adjust various release profiles (for example pulsed release, release after a kinetic arrangement). or of a grain arrangement, sigmoidal release). The fast disintegrating pellets can be coated by conventional pharmaceutical methods, for example in a swirl layer or in a dragee boiler. Calculating from the moment of the start of the release, the fast disintegrating pellets covered according to the invention present a release of at least 50% after 180 minutes. The applied amount of coating can be varied, so that the weight fraction of the film former is between 1 and 70% based on the weight of the pellets. As materials for the production of coated pellets, the film of which explodes due to the swelling of the core of the pellet advantageously comes into consideration: ethylcelluloses. For example Aquacoat® and methacrylic ester copolymers, for example Eudragit RL / RS®. As materials for easy to dissolve films, cellulose derivatives, (such as hydroxypropylmethylcellulose) or aminoalkylamyl acrylate, copolymers (for example Eudragit E) can be mentioned. Soluble film formers for pH-dependent coatings are suitable, for example, dicarboxylic acid derivatives of cellulose compounds (for example hydroxypropylmethyl cellulose phthalate, hydroxypropyl methylcellulose succinate) and also methacrylic acid copolymers (for example Eudragit L, Eudragit S, brands). Additional film materials can be used: softeners in an amount of 0.50 to 50%; non-stick (0.1 to 70%) as well as especially in films, which have to explode due to the swelling of the core of the pellet, materials which accelerate or retard the diffusion of the release liquid in the core, and in that way can modify the time In addition, pore formers, aromatics, dyes, pigments, as well as fillers can be added as the softeners, all common pharmaceutically acceptable softeners can be used. acetylized fatty acid, acetylethyl citrate, acetyltributyl citrate, butyl phthalate, diethyl phthalate, dimethyl phthalate, glycerol triacetate, propylene glycol, polyethylene glycol, polyoxyethylene-polyoxypropylene copolymers, castor oil and tributyl citrate. of triethyl As non-stick all the usual pharmaceutical release agents can be used e) Talc, aerosil®, kaolin, micronized silicic acid are preferred. Especially preferred is glycerin ester and / or glycerin ether of high fatty acids, for example glycerin monoetherate, laurate, polyethylene glycol-32-glyceryl. As addition materials, which can control the diffusion of water in the core of the pellet, additives which cause hydrophobicity (for example waxes, talc, fatty acids and ester of fatty acids) as well as diffusion-accelerating materials (for example surfactant example, grade acid ester, and fatty acid ether). Especially preferred are mountain glycolic wax, glycerin monostearate, serineic acid, and stearinic acid derivatives or glyceryl polyethylene glycol ester, glyceryl behenate, glyceryl palmito stearate, cetyl palmitate. According to a process known per se, the coated or uncoated pellets according to the present invention can also be pressed with conventional auxiliaries pharmaceutically into tablets or filled into capsules and sachets or embedded in matrices. The formulations are equally suitable for easy or hardly soluble water active agents. The capsules contain the active agent in an amount of up to 350 mg, especially 1-200 mg, preferably 10-100 mg pellet tablets can contain the active agent in an amount of up to 1000 mg, preferably l-500 mg, especially 10-250 mg . The invention will be explained in more detail below with reference to exemplary embodiments. EXAMPLE 1 1250 g of Carvediol, 1682. 5 g of lactose, 1150 g of microcrystalline cellulose, 172. 5 g of sodium dodecyl sulphate, 345 g of Povidon K 25 and 1150 g of Primojel are homogenized in an intensive mixer. The powder mixture is granulated with approximately 3500 ml of distilled water. Then the wet mass is extruded in a double extruder). The extrudate can be formed as pellets in a renderer. After drying in the fluid layer the pellets are sieved (mesh size 0. 6-1.25 mm). EXAMPLE 2 The pellet is manufactured analogously to example 1 with the following recipe: EXAMPLE 3 The pellet is manufactured analogously to example 1 with the following recipe: EXAMPLE 4 The pellet is manufactured analogously to example 1 with the following recipe: EXAMPLE 5 The pellet is manufactured analogously to Example 1 with the following recipe: EXAMPLE 6 The pellet is manufactured analogously to Example 1 with the following recipe: EXAMPLE 7 The pellet is manufactured analogously to Example 1 with the following recipe: EXAMPLE 8 The pellet is manufactured analogously to example 1 with the following recipe: EXAMPLE 9 The pellet is manufactured analogously to Example 1 with the following recipe: EXAMPLE 10 The pellet is manufactured analogously to Example 1 with the following recipe: EXAMPLE 11 Carvedilol, lactose, microcpstalma cellulose, Primojel and Povidon 25 are mixed. Pluronic F 68 is dissolved in distilled water. The powder mixture is granulated with that solution. It is then extruded analogously to Example 1, rounded, dried and sieved. EXAMPLE 12 Mixed Carvedilol, lactose, microcrystalline cellulose, Primojel and Povidon 25. Pluronic F 68 is dissolved in distilled water. The powder mixture is granulated with that solution. It is then extruded analogously to example 1, rounded, dried and sieved. EXAMPLE 13 They are mixed with olives, lactose, microcrystalline cellulose, Primojel and Povidon 25. Pluronic F 68 is dissolved in distilled water. The powder mixture is granulated with that solution. It is then extruded analogously to Example 1, rounded, dried and sieved.

EXAMPLE 14 Mixed Carvedilol, lactose, microcrystalline cellulose, Primojel and Povidon 25. Pluronic F 68 is dissolved in distilled water. The mixture of powders is granulated with this solution, then extruded analogously to Example 1, rounded, dried and sieved. EXAMPLE 15 Mixed Carvedilol, lactose, microcrystalline cellulose, Primojel and Povidon 25. Pluronic F 68 is dissolved in distilled water. The powder mixture is granulated with that solution. It is then extruded analogously to Example 1, rounded, dried and sieved. EXAMPLE 16 They are mixed Carvedilol, lactose, microcrystalline cellulose, Primojel and Povidon 25. Pluronic F 68 is dissolved in distilled water. The powder mixture is granulated with that solution. It is then extruded analogously to Example 1, rounded, dried and sieved. EXAMPLE 17 The pellet is manufactured analogously to example i with the following recipe: Carved lol, lactose, cellulose m crocr stalma, sodium dodecylsulfate, Povidon K24 and Primojel are mixed the polyethyleneglycol-32-glyceryl laurate is dissolved in distilled water. The powder mixture is granulated in that solution. Finally, it is extruded, rounded, dried and sifted analogously to example 1. EXAMPLE 18 The pellet is manufactured analogously to example 1 with the following recipe: EXAMPLE 19 The pellet is manufactured analogously to Example 1 with the following recipe: EXAMPLE 20 The pellet is manufactured analogously to example 1 with the following recipe: EXAMPLE 21 The pellet is manufactured analogously to example 1 with the following recipe: EXAMPLE 22 The pellet is manufactured analogously to Example 1 with the following recipe: EXAMPLE 23 As a comparison, only one explosive agent (without surfactant) was used, which however did not allow the pellets to disintegrate. Analogously to example 1 pellets are prepared with the following recipe: Table 1 Legend of table 1: ++ round + round-oval 0 oval-oval-oblong-oblong nd not determined EXAMPLE 24 With the recipe of the following composition, a disintegration of the pellets is obtained in the course of less than 3 minutes: EXAMPLE 25 With the recipe of the following composition, with a content of carvedilol less than 25%, no disintegration of the pellets can be determined.

EXAMPLE 26 Analogously to Example 24, the following recipe is prepared, in which the sodium dodecyl sulfate part is omitted and the corresponding lactose part is increased. No disintegration of the pellets was observed.

EXAMPLE 27 Rapidly disintegrating pellets according to Example 1 were coated on the fluid layer (Hütting sphere coater) with a film with the following composition: EXAMPLE 28 Rapidly disintegrating pellets according to example I JO were coated on the fluid layer (Hütting sphere coater) with a film with the following composition: EXAMPLE 29 Rapidly disintegrating pellets according to Example 1 were coated on the fluid layer (Hütting sphere spreader) with a film with the following composition: EXAMPLE 30 Rapidly disintegrating pellets according to example i were coated in the fluid layer (Hütting sphere coater) with a film with the following composition: EXAMPLE 31 Rapidly disintegrating pellets according to example 1 were coated on the fluid layer (Hütting sphere coater) with a film with the following composition: EXAMPLE 32 Rapidly disintegrating pellets according to Example 1 were coated on the fluid layer (Hütting sphere coater) with a film with the following composition: EXAMPLE 33 Rapidly disintegrating pellets according to example 1 were coated on the fluid layer (Hütting sphere coater) with a film with the following composition: EXAMPLE 34 Rapidly disintegrating pellets according to example 23 were coated on the fluid layer (Hütting sphere coater) with a film with the following composition: EXAMPLE 35 Rapidly disintegrating pellets according to example 1 were coated on the fluid layer (Hütting sphere coater) with a film with the following composition: Then a film with the following composition is applied: EXAMPLE 36 Rapidly disintegrating pellets according to Example 1 were coated on the fluid layer (Hütting sphere coater) with a film with the following composition: EXAMPLE 37 Rapidly disintegrating pellets according to Example 1 were coated on the fluid layer (Hütting sphere coater) with a film with the following composition: EXAMPLE 38 Rapidly disintegrating pellets according to example 23 were coated on the fluid layer (Hütting sphere coater) with a film with the following composition: EXAMPLE 39 Rapidly disintegrating pellets according to example 1 were coated on the fluid layer (Hütting sphere coater) with a film with the following composition: TABLE 2

Claims (30)

1. CLAIMS 1. - Forms of pharmaceutical administration in the form of pellets, characterized in that they contain one or several active agents and at least one agent of delay or delay of disintegration, which serves as a rounding agent for the manufacture of pellets by extrusion, an agent of explosion of tablets and at least one auxiliary substance selected from the group consisting of surfactants and binders or combinations of these auxiliaries.
2. 2. - Form of pharmaceutical administration according to claim 1, characterized by the rounded content agent is microcrystalline cellulose.
3. 3. - Pharmaceutical administration form according to claim 1 or 2, characterized in that the pellets contain a surfactant.
4. 4. - Form of pharmaceutical presentation according to one of claims 1-3, characterized by, the rate of release of the active agent from pellets is at least 90% at 30 minutes.
5. 5. - pharmaceutical administration form according to one of claims 1-4, comprising microcrystalline cellulose, one or more blowing agents, one or more surfactants and / or one or more binders, as well as optionally one or more agents of filler and, if necessary, one or more film formers.
6. 6. - Form of pharmaceutical administration according to one of claims 1 to 5, characterized by the presence of active ingredients, carvedilol, bezafibrate, glibenclamide or torasemide.
7. 7. - Pharmaceutical administration form according to one of claims 1 to 6, characterized in that the fraction of active agent is up to 80%.
8. 8. - Form of pharmaceutical administration according to one of claims 1 to 7, characterized by, the disintegration time of the pellet is not more than 30 minutes.
9. 9. - Pharmaceutical administration form according to one of claims 1-8, characterized in that the pellets are covered with a film retardant of the release of the active agent.
10. 10. - Form of pharmaceutical administration according to claim 9, characterized by the principle of the release of the active agent takes place after 10 minutes to 5 hours.
11. 11. - Form of pharmaceutical administration according to one of claims 1-10 characterized by porgue, the explosive agent is carboxymethyl cellulose modified corn starch or carboxymethyl sodium starch.
12. 12. - Pharmaceutical administration form according to one of claims 1-11, characterized in that the surfactant is benzalkonium chloride, polyoxyethylene-polyoxypropylene copolymers, polyethylene glycolglyceryl ester, sodium dodecylsulfate or PEG-400 stearate.
13. 13. - administration form according to one of claims 1-12, characterized in that the binder is a polyvinylpyrrolidone derivative.
14. 14. - Form of pharmaceutical administration according to claim 13, characterized in that it does not contain any surfactant.
15. 15. - Pharmaceutical administration form according to one of claims 1-14, characterized in that the filling agent is a carbohydrate, such as sugar, preferably glucose, lactose and sucrose, sugar alcohol, such as mannitol or sorbitol, starch, a derivative of dibasic calcium starch or phosphate.
16. 16. - Pharmaceutical administration form according to one of claims 1-15 containing 5-70% by weight of microcrystalline cellulose, preferably 15-25% by weight.
17. 17. - Pharmaceutical administration form according to one of claims 1-16, containing 5-50% by weight of tablet exploding agent, preferably 15-25%.
18. 18. - Pharmaceutical administration form according to one of claims 1-17 containing 0. 1-20% by weight of surfactant, preferably 2-10%.
19. 19. - Pharmaceutical administration form according to one of claims 1-18 containing 1-10% by weight of binder, preferably 3-7%.
20. 20. Process for the manufacture of pharmaceutical administration forms according to one of claims 1-119, characterized in that the active agents are mixed with the auxiliary agents, then granulated, extruded and rounded into pellets and then If necessary, they are made available as tablets, capsules or sachets and / or, if appropriate, the pellets or tablets are provided with suitable coatings (film formers).
21. 21. Process according to claim 20, characterized in that the pellets contain, as coating material for coated pellets, preferably ethyl cellulose and methacrylic ester copolymers.
22. 22. Process according to claim 20 or 21, characterized in that the pellets contain, as coating material for readily soluble films, preferably cellulose derivatives or aminoalkylmethacrylate copolymers.
23. 23. Process according to one of claims 20-22, characterized in that the pellets as coating materials for pH-dependent soluble coatings contain dicarboxylic acid derivatives of cellulose compounds and methacrylic acid copolymers.
24. 24. - Method according to one of claims 22-23, characterized in that, the coating materials contain as additives of film 0. 1 -50% softener, u.1-70% non-stick, and u. I-5ü% auxiliary material for controlling the diffusion of water in the pellet core.
25. 25. Process according to one of claims 20-24 characterized in that the pellets contain as a softener preferably: acetylated fatty acid glycerides, acetylethyl citrate, acetyl tributyl citrate, butyl phthalate, diethyl phthalate, dimethyl phthalate, glycerol triacetate, propylene glycol, polyethylene glycol, polyoxyethylene-polyoxypropylene copolymers, castor oil and tributyl citrate.
26. 26. Process according to one of claims 20 to 25, characterized in that the pellets contain as a softener preferably triethyl citrate.
27. 27. - Procedure according to the claims 20-26, characterized in that the pellets contain as talcum powder, aerosil, micronized silicic acid or kaolin.
28. 28. Method according to one of claims 20-27, characterized in that the pellets as additional material to be able to control the diffusion of the water in the core of the pellet preferably contain wax glycol of montana, glycerin monostearate, acid and stearinic acid derivatives or polyethylene glyceryl ester, glyceryl behenate, glyceryl palmitate stearate or cetyl palmitate.
29. 29. - Form of pharmaceutical administration in the form of core pellets containing an active agent, and a rounding agent, where the implicitly delaying effect of the rounding agent is avoided, obtaining by extrusion a pharmaceutical mixture containing a rounding agent, a tablet blowing agent and at least one auxiliary substance selected from the group consisting of surfactants and binders or combinations of those auxiliaries.
30. 30. - Application of one or more tablet explosion agents in combination with one or more surfactants and / or a binder for the manufacture of pharmaceutical administration forms according to one of claims 1-19 or 29.