WO1988010150A1 - Process and device for manufacturing particles with a core and a coating, and particles so obtained - Google Patents

Abstract

To manufacture particles used as drugs, an at least partly fluid core material and an at least partly fluid coating material are sprayed into a cyclone chamber (11) and swirled with refrigerated gas, in particular air. The initially at least partly fluid particles formed from the sprayed core material are hardened by cooling during swirling and enveloped in coating material. Then either the coating alone is dried so that the core of the finished particles is at least partly fluid at ambient temperature, or in addition the core is also dried by freeze-drying so that the core of the finished particles is a solid aggregate at ambient temperature. The process makes it possible to encapsulate at least essentially fluid core materials economically and without damage and to confer on the drug particles so formed desirable release and resorption properties of at least one pharmaceutical active ingredient and/or auxiliary.

Description

 Process for the production of particles with a core and a shell, device for carrying out the process and particles produced by the process

description

Technical field of the invention

The invention relates to a process for the production of particles according to the preamble of claim 1, namely a process for the production of particles, in particular medicament particles, with a core and a solid shell surrounding it, particles being formed from core material to form the cores, are swirled with gas in a swirling space and cooled and enveloped with the jacket material used to form the jacket.

The invention further relates to a device according to the preamble of claim 11 for carrying out the method and thus with a container and means for cooling and introducing gas into the vortex space, which limits a vortex space.

The device further relates to particles produced by the process.

State of the art

Particles whose cores were formed from a core material which is in the solid state at normal room temperature are, for example, according to a process known from US Pat. No. 4,656,056, in which particles consisting of the solid core material are swirled to form a fluidized bed with an air flow in the interior of a container, wetted by condensation of water vapor on their surfaces, with a sprayed to form the jacket serving jacket material and then dried in an air stream. Drying can be carried out in a conventional manner, ie at a particle temperature at which the water to be extracted from the particles is present in the liquid state. Instead, however, the particles can be cooled after being sprayed with the jacket material according to a method for freezing the water present in them from another publication, namely US Pat. No. 4,608,764, and then dried by a freeze-drying method. However, the process for coating particles in a fluidized bed known from US-A-4 656 056 has the disadvantage that it cannot be used for the encapsulation of core materials which are more or less at normal, about 20 to 25 ° C. room temperature are liquid.

In known encapsulation processes which can be used both for encapsulating solid and liquid core materials, two shell parts are first produced from gelatin strips for each capsule, then core material is poured into one of the shell parts and the two shell parts are put together, for example by welding and / or Applying a coating tightly connected. However, this method has the disadvantages that each capsule has to be manufactured individually through several work steps and inevitably has to have relatively large minimum dimensions. Such capsules usually have an elongated shape and at least about 4 mm in diameter and at least about 10 mm in length, while for many applications, capsules are much smaller, So-called microcapsules are desired, the maximum dimensions of which are, for example, about 0.05 mm to 0.1 mm. Another disadvantage of the capsules with shells consisting of gelatin is that such shells are not water-resistant and therefore do not contain more water to encapsulate them Core materials are suitable.

Methods are known for the production of microcapsules which work by means of so-called coacervation. In these methods, the core material and the jacket material are brought together and treated as liquids or, more precisely, liquid phases in such a way that the jacket material encloses the core material and is then solidified . Methods of this type are known, for example, from FR-A-1 144 768. In these processes, a gelatin melted by heating to a temperature of about 60 to 70 ° C. is sprayed together with the core material into a cooling liquid in such a way that the gelatin forms capsule walls enclosing core material droplets after cooling. Such processes, in which the material used to form the capsule walls must be melted by heating, are, however, not suitable for encapsulating thermolabile substances whose chemical and / or physical properties are undesirably irreversible at temperatures above normal room temperature ¬ change sibel.

Presentation of the invention

The invention is therefore based on the object of creating a method for producing particles having a core and a solid shell, which avoids disadvantages of the known methods and in particular makes it possible to also at least partially comprise core materials consisting of a liquid, with swirling To wrap gas. This object is achieved on the basis of the method described above, known from US Pat. No. 4,656,056, by a method of the type mentioned in the introduction, which according to the invention is characterized by the characterizing part of claim 1 and thus characterized in that the Particles consisting of core material, at least part of the core material is sprayed as a liquid into the vortex space and this liquid is brought into the solid state by cooling.

The device of the type mentioned in the introduction for carrying out the method, which likewise forms an object of the invention, is characterized according to the invention by the characterizing part of claim 11 and therefore by at least one spraying element for spraying at least partially liquid core material into the swirl chamber.

The particles which are also an object of the invention and are produced by the process are, according to the invention, characterized by the characterizing part of claim 12 and therefore characterized in that their core and / or their shell contains at least one active pharmaceutical substance and / or auxiliary substance.

The method according to the invention in particular enables the production of capsule-like medicament particles which have a core and a jacket which consists at least partly of a different material and in which the core and / or the jacket have at least one active pharmaceutical substance and / or auxiliary substance ent¬ holds, the division of the particle material into a core and a shell, for example, has the purpose of enabling the delivery and subsequent absorption of the active and / or auxiliary substance in a living human or animal body in a predetermined manner. For the rest, here is the term "auxiliary substance" notes that in the case of a substance serving to influence the delivery and / or absorption of a pharmaceutically active substance, it is somewhat a question of judgment as to whether this substance is to be regarded as an auxiliary substance or also as an active substance.

The capsule-like particles produced can, for example, preferably be at least some spherical, but could also have ellipsoidal or other shapes deviating from the spherical shape. In addition, particles serving as medicaments can form so-called microcapsules, the largest dimension of which is at most about 2 mm, normally at most 1 mm, typically at most 0.2 mm, frequently at most 0.1 mm and, for example, at least 0.05 mm. Microcapsules of this type can then be filled into larger, conventionally produced hard gelatin capsules for oral or rectal administration or without additional encapsulation after temporary storage in plug-in ampoules or other containers by injections or in other ways in veins, muscle tissue or other body areas of a living human or animal. However, larger particles can also be produced, the dimensions of which are, for example, at least 3 mm.

The core and the shell of the finished particles can each consist of a single, chemically pure substance or also contain two or more different substances, the different substances in the latter case being homogeneously or inhomogeneously distributed in the core or shell. However, the core and the cladding should at least partially consist of different substances.

The shell of the finished capsule-like particles produced should be at normal room temperature, i.e. at about

Temperatures between 20 and 25 ° C. The coat can also normally also be fixed at the temperatures typically around 36 to 40 ° C. which are present in the interior of a body of a living human or animal and in this case should preferably be for an intended area of human or animal Liquid present in the body is permeable and / or soluble in this liquid. The jacket can, for example, be designed such that it is in a water-containing liquid at pH values present in the stomach and / or intestine and / or in a specific enzymatic environment and / or in the blood and / or in the synovial fluid and / or in the spinal fluid dissolves. However, the coat may also be designed such that it is present in the body of a living human and / or animal

Temperatures. melts or at least softens and therefore has a melting or softening temperature which is at most about 38 ° C. and preferably at most 36 ° C.

The core of the finished, capsule-like particles can be liquid or solid at normal room temperature, 20 to 25 ° C, or be in a soft transition state between solid and liquid, or contain both at least one liquid and at least one solid substance and in the latter For example, have a dispersion with a liquid dispersant and solid particles dispersed therein.

Brief description of the drawing

The invention will now be described on the basis of an exemplary embodiment of a device for producing particles shown in the drawing and on the basis of various examples of production methods and of various ones produced particles, also shown in the drawing. In the drawing shows

1 shows a schematic vertical section through a device for producing capsule-like particles with a core and a jacket,

2 shows a section through a particle with a ^* liquid core, on a larger scale,

3 shows a section through a part chemical with a core solidified by drying and

4 shows a section through a particle with a multi-part core.

Preferred embodiments of the invention

The visible in Figure 1, for the production of

Particle with a core and a jacket serving device has a container 1 held by a frame (not shown), which has a bottom part 3 from bottom to top, a lower chamber part 5 which widens conically upwards, and a conical part also upwards expanding upper chamber part 7 and a cover part 9. The upper chamber part 7 is higher than the lower chamber part and, for example, has a somewhat smaller conicity than the latter. The area of the container interior delimited by the two chamber parts 5 and 7 forms the swirling space 11 which serves for swirling particles when the device is in operation. The ratio between the height of the swirling space 11 and the diameter of its lower end should be compared to the corresponding ratio conventional fluidized bed dryers must be relatively large and is preferably at least 5, for example at least 8 or even at least or approximately 10. Furthermore, the ratio between the diameter of the upper end of the vertebral space and that of the lower end should also be relatively large and is preferably at least 2, for example at least 3 or even at least or approximately 4. The various parts of the container are provided at ^'their mutually in pairs facing edges with flanges, by connecting means such as screws and / or quick-clamping members, detachably interconnected and sealed with sealing means against each other. The walls of the bottom part 3, the lower chamber part 5 and the upper chamber part 7 and preferably also that of the cover part 9 are heat-insulating and have, for example, a metallic inner wall, namely made of stainless steel, and heat insulation arranged on the outside thereof. The container 1 and in particular the walls of its parts 3, 5, 7, 9 and the sealing means mentioned are designed such that the temperatures in the interior of the container vary at least in the range from -60 ° C. to + 120 ° C. and preferably even up to at least 125 ° C and that the pressure in the interior of the container may be at least 200 kPa and thus may be at least about 100 kPa greater than the ambient air pressure. Furthermore, the wall of the lower chamber part 5 and at least the lower wall area of the upper chamber part 1, ie at least the regions of the container wall which delimit the largest part of the fluidized bed formed by the swirled particles during operation, each with a cooling / heating device 13 provided. Each of the latter has at least one channel with a good heat-conducting connection to the inner wall of the chamber part 5 or 7, for example formed by a helical pipe coil for a liquid and / or gaseous cooling / heating fluid and connections for supplying and discharging it Fluids on. These connections are connected to each other and / or to a fluid cooler / heater, not shown. Furthermore, the container can possibly also be equipped with an explosion pressure relief device _. be equipped.

The bottom part 3 is provided with a connection serving as a gas inlet 15 for the container 1. Between the interior of the bottom part 3 and the vortex chamber 11 there is a gas-permeable, level, horizontal sieve 17 which is as releasable as possible, but is as impermeable as possible to the particles present in the vortex chamber 11 during operation. The sieve 17 is designed, for example, to generate a gas flow during operation in the swirl chamber 11, which swirls the particles in such a way that they are largely prevented from touching the container wall. Furthermore, the wall of the chamber part 5 and / or 7 can be provided with gas outlet openings distributed over at least part of its inner surface in order to blow gas, in particular air, into the vortex space during operation and thereby additionally cause particles to come into contact with the container wall to counteract and to blow away particles that should have stuck to the wall. These gas outlet openings can be connected to the means for supplying gas to the gas inlet 15 or a separate gas source, not shown, such as a compressed air source, via channels in the wall and at least one line (not shown) connected to them, for supplying gas to the gas inlet 15 , the latter also having means for optionally cooling and heating and / or drying the gas. A first, lower, for example penetrating the central region of the sieve spraying device 19 has at least one nozzle located just above the sieve 17 and directed upwards and with a first one located outside the container 1 Feed device 21 connected. A second, upper spray element 23 has at least one nozzle arranged in the interior of the upper chamber part 7 and is held vertically adjustable by means of a schematically indicated adjusting device 25

Container 1 arranged, second feed device 27 connected. The nozzle of the second spray element 23 is directed vertically downwards. However, the second spray member could instead or additionally have at least one vertically upwardly directed nozzle and / or at least one downwardly or upwardly inclined nozzle and / or at least one nozzle which can be pivoted about a horizontal axis. The spray elements 19, 23 can be designed for spraying materials with air or another gas or for gas-free spraying. The feed devices 21, 27 have reservoirs for the materials to be sprayed as well as valves and / or conveying devices. Furthermore, the spray elements 19, 23 and feed devices 21, 27 can be provided with cooling and / or heating elements.

A filter 29 with two filter sections 29a, 29b, which can be shaken independently of one another, is arranged in the interior of the cover part 9. A filter control and filter cleaning device 31 has valves connected to the outputs of the two filter sections 29a, 29b, in order to connect or block the two filter sections with the gas outlet 33 of the container 1 either in terms of flow. The device 29 also has at least one vibrator to selectively vibrate one of the two filter sections.

The container 11 is also provided with a particle outlet 35 which is located in the middle or upper region of the vortex chamber 11, for example approximately at the height of the upper end of the fluidized bed formed during operation by the vortexed particles, the latter of course has no sharp boundary at the top. The particle outlet 35, which, for example, has a connection piece with a flange, can be detachably connected to a particle separator 39 having a cyclone, for example by means of a blocking / suction device 37 having a valve and a pump, or tightly sealed with a closure element, for example a cover, if it is not used for a long time be closed.

The gas outlet 33 of the container 1 is via a line 45, a valve 47, a pump 49, a filter 51, a vapor / liquid separator 53, a gas cooling device 55 and a valve 57 with the gas inlet 15 of the container 1 connected. There is a branch between the valve 47 and the pump 49, from which a bypass line 59, i.e. a "bypass" with a valve

61 leads to a branch of the connection connecting the cooling device 55 to the valve 57, the bridging line 59 possibly also having a heat-insulated gas reservoir (not shown). The gas outlet 33 of the container 1 is also connected to the container gas inlet 15 via a line 65, with a valve 67, a pump 69, a filter 71, a vapor / liquid separator 73, a gas heating device 75 and a valve 77 . The inlet of the pump 69 is connected to the outlet of the gas heating device 75 via a bridging line 79 containing a valve 80.

If the device is used to produce particles from water-containing core and / or cladding materials, the two vapor / liquid separators 53 and 73 can be, for example, a solid sorbent, in particular an adsorbent, such as the agent known under the trade name Silica gel or lithium chloride or zeolite as well as cooling and heating devices to cool the sorbent when it is used for drying and to warm up for regeneration. The vapor / liquid separators could possibly contain an absorbent as a sorbent instead of an adsorbent or in addition to this. If the core and / or cladding materials used to produce the particles contain organic solvents and / or dispersing agents instead of or in addition to water, the vapor / liquid separators 53, 73 can include devices for separating and for recovering the or each organic Solvent and / or dispersant may be formed.

The gas cooling device 55 can, for example, have a channel for passing a cooling fluid through and, in addition to cooling the gas flowing through it, can also be used for further drying of the latter by using water vapor and / or vapor from another solution and / or or dispersant is eliminated by condensation or solidification. The gas heating device 75 can, for example, have a channel for the passage of a heating fluid. Furthermore, the fluid cooler / heater connected to the cooling / heating devices 13 and / or the gas cooling device 55 and / or the gas heating device 75 can be adjusted manually and / or by means of an automatic control and adjustment device Change the relevant cooling or heating temperature. Furthermore, heat exchange and / or heat pumping means can be present in order to use heat energy given off in one device for cooling in another device for heating.

As will be explained in more detail, the container 1 and the lines 45, 59, 65 enable the formation of various closed circuits. These are also provided with gas supply / gas discharge means in order to supply them with gas, in particular air, and to discharge them again from them. These means can be, for example, via a valve 81 with the inlet of the pump 49 and a suction line connected to the inlet of the pump 69 via a valve 83 and opening into the environment and a vent line connected to the gas outlet 33 of the container 1 via a valve 85 and opening into the surrounding area.

The device also has temperature sensors (not shown), for example thermocouples or temperature-dependent resistors, around the gas temperatures at the outlet of the gas cooling device 55 and at the outlet of the gas heating device 75, and the gas and / or particle temperature in the vortex chamber 11 and possibly to measure the temperature of the materials to be sprayed in the spray members 19, 23 and / or in the feed devices 21, 27. Furthermore, for example at the outlet of the gas cooling device 51 and possibly at the outlet of the gas heating device 75 and / or in the swirl chamber, there may be at least one sensor for measuring the absolute or relative humidity. If, instead of water, other solvents and / or dispersants which are liquid at room temperature are used during operation of the device, sensors for measuring that in the air or in any other, if necessary, can of course be used instead of sensors for measuring the air humidity Swirling of particles used gas present vapor content of these solvents and / or dispersants can be provided. Furthermore, pressure sensors can be provided in order to determine the pressure in the swirl chamber 11 and the pressure drop that arises over it. In addition, measuring and display means connected to the sensors and electronic and electrical as well as possibly pneumatic and / or hydraulic control and regulating means are provided in order to enable manual and / or automatic control and / or regulation of the various devices that are operated during operation of the device. to enable finding processes. Various methods for the production of capsule-like particles with a core and a jacket that is solid at room temperature will now be described with the device and / or configurations of the device shown in FIG.

The interior of the container 1 and in particular the vortex space are made sterile before first use for the production of drug particles and after each time after long interruptions in operation and / or as required.

For this purpose, for example, superheated steam with a temperature of, for example, approximately 120 ° to 125 ° C. and a corresponding pressure in the range of 200 kPa and thus exceeding the normal ambient air pressure by at least approximately 100 kPA can be introduced into the container. Instead, sterilization could also be provided with a gas which is toxic to microorganisms, for example formaldehyde, or with an ultraviolet light irradiation device which enables the interior of the container 1 to be irradiated. The remaining parts of the device, from which microorganisms could get into the particles produced, are also made sterile as far as necessary.

In the production of particles, their core is formed from a core material which, before being introduced into the whirling space and when being introduced into the whirling space, consists at least in part of a liquid which can be fed to a spraying device as a continuum and sprayed by it. The liquid should consist of at least one substance which, when it has the normal room temperature, which is about 20 to 25 ° C., or a somewhat lower temperature, is liquid and enables spraying. The melting temperature of the liquid or the substance forming it should therefore be at most 25 ° C., preferably at most 20 ° C. and for example at most 10 ° C. If the liquid or substance has a melting temperature range, at least its lower limit and preferably also its upper limit should have the maximum values mentioned and should therefore be at most 25 ° C., preferably at most 20 ° C. and for example at most 10 ° C.

In an important group of manufacturing processes, the active pharmaceutical ingredient and / or auxiliary substance to be introduced into the cores of the particles is in a liquid, i.e. dissolved and / or dispersed in a solvent and / or dispersion medium which is liquid at a normal room temperature of about 20 ° C. to 25 ° C. The solution and / or dispersion formed in this way can be aqueous or partially aqueous or non-aqueous. Usable, non-aqueous, organic solvents are, for example, glycerol, polyethylene glycols, lactic acid, ethyl lactate, oils such as peanut, olive, castor or neutral oil, and alcohols, especially ethanol, isopropanol and butanol.

With regard to the polyethylene glycols, it should be noted that these can have molecular weights in the range from 200 to approximately 20,000 and, depending on the molecular weight, melting temperatures between approximately -25 ° C. and + 60 ° C. If a polyethylene glycol is intended as a solvent which is liquid at room temperature, it should have a relatively low, for example approximately a maximum of 400 molecular weight.

The pharmaceutical active substance and / or auxiliary substance to be introduced into the core can be readily soluble or relatively poorly soluble, such as nifedipine, for example, or not soluble at all in the liquid of the core material mentioned. In the latter case, the active substance and / or auxiliary substance then forms a dispersion together with the liquid, the active substance and / or auxiliary substance in Form- of solid particles, such as colloidal, or in the liquid state as a disperse phase can be present. Mannitol, for example, can be provided as an auxiliary substance. In addition, the active and / or auxiliary substance can consist of a single chemically pure substance or a mixture of substances.

The shell material used to form the shell of the particles can have at least one polymer. Suitable polymers include ethyl cellulose, methyl cellulose, polylactic acid, hydroxypropyl methyl cellulose, polyacrylic acid, acrylates, shellac and cellulose acetate phthalate. These polymeric substances can be dissolved and / or finely dispersed in a liquid with or without plasticizer additives, the as

Solvent and / or dispersant liquid can contain water and / or a liquid, organic substance, and the solutions or dispersions for coating fine particles are preferably highly diluted.

The production of particles is now explained for the case that air is used for the swirling and that the core material and possibly also the cladding material consist of an aqueous solution and / or dispersion. For the production of particles, the core material can be filled into the reservoir of the first feed device 21 and the mat material into the reservoir of the second feed device 27. Furthermore, the valves 47, 57 are opened and the valves 61, 67, 77 are closed and, with the pump 49, air is pumped via the filter 51, the vapor / liquid separator 53 and the gas cooling device 55 to the gas inlet 15 of the container 1, which is then pumped through the sieve 17 and the swirl chamber 11 upwards to the filter 29 and through one of its sections to the gas outlet 33 of the container 1 and back again Pump 49 flows. The air is therefore circulated, and in the starting phase, if necessary, fresh air can be sucked into the circuit via the temporarily opened valve 81. The air supplied to the vapor / liquid separator 53 contains water vapor and possibly also water droplets and is at least partially dried by the separator 53. The gas cooling device 55 cools the air flowing through it to a temperature which is below the freezing temperature of the liquid which forms the core material and brings about additional drying by freezing out water which is still in the air in the form of water vapor and / or water droplets.

If there is now a cold air stream flowing through the swirl chamber 11 of the container 1 from the bottom up, the first feed device 21 feeds core material to the first, lower spray member 19, which is upward from the spray member 19, ie more or less parallel to the air stream mentioned is sprayed into the vertebral space 11. When spraying, at least essentially liquid particles, ie droplets, form from the core material. These are swirled by the cooled air in the swirl chamber 11, cooled and completely solidified in a solidification process by freezing. In this case, the core material can possibly be pre-cooled in the feed device 21 and / or in the spraying element 19 before the spraying to a temperature which is only slightly above its freezing temperature. Furthermore, if necessary, the inner walls of the two chamber parts 5 and 7 delimiting the swirl chamber 11 can be cooled with the cooling devices 13. For the production of fine particles, such as spherical microcapsules with a diameter of, for example, at most or less than 0.1 mm, the air speed in the lower end of the vortex space, in which the core material is sprayed, should be relatively high and for example at least 1 m / s or even at least 2 / s. The droplets formed during the spraying of the core material are therefore quickly transported upwards away from the first spraying element 19 and thereby reach larger diameter swirling space regions. Although a large number of droplets per unit time is generated by the first spray element 19, adjacent droplets can quickly move away from one another and solidify without agglomeration. Because of the relatively large ratios mentioned above between the height of the swirl chamber 11 and its diameter at the lower end and between the diameters of the upper and lower ends of the swirl chamber 11, the flow velocity of the air at the upper end of the swirl chamber is significantly less than at the bottom

End of the vortex chamber, so that despite the high flow velocity of the air when entering the vortex chamber, only relatively few particles are transported up to the filter 29 and the majority of the vortexed particles, i.e. the actual fluidized bed, indicated schematically in FIG. 1 by particles shown in exaggerated size, for example in the lower two thirds of the interior of the two chamber parts 5 and 7.

To accelerate the freezing process, if necessary, a solid and / or liquid coolant can also be introduced into the vortex chamber 11, which additionally cools the air present in the vortex chamber and the droplets or particles of the core material and thereby evaporates. The coolant can consist, for example, of dry ice powder or liquid nitrogen or liquid air and can be introduced into the swirl space before the core material is sprayed in and / or at the same time. The coolant can be used with the second one Feed device 27 can be introduced into the swirl chamber 11 via the second spray element 23 or with an additional, third feed device, not shown, via an additional inlet, not shown.

When a batch with the desired quantity of particles consisting of core material has been introduced into container 1, the spraying of core material is terminated. Thereafter, immediately or after the time period required for the solidification of the core material particles, shell material is fed to the second, upper spraying element 23 with the second feed device 27 and downwards, i.e. sprayed against the general direction of flow of the air flowing through the swirl chamber onto the swirled particles consisting of solidified core material. If necessary, the jacket material can be cooled or heated in the feed device 27 and / or in the spray element 23 before spraying. Otherwise, the height of the second spray member 23 can be adjusted to a favorable value using the adjusting device 25, so that the second spray member 23 is located, for example, approximately at the upper limit region of the actual fluidized bed. In addition, the spraying in of core material and of cladding material may also take place entirely or partially simultaneously instead of at separate time intervals. When the amount of cladding material required to achieve the desired cladding thickness has been applied to the core material particles, coating of the cladding material is also stopped.

In the subsequent drying process, the core material particles coated with the jacket material are swirled in the vortex chamber 11 with air that is as dry as possible, without the core or jacket material being sprayed into it. The drying process can, for example, be carried out in such a way that at least essentially only the man The particles are dried and the core at least largely retains the liquid originally present in the core material. For this purpose, air can continue to be supplied to the gas inlet 15 in the same way as before during the freezing process and when spraying on the jacket material by means of the pump 49 via the steam / liquid separator 53 drying this and the gas cooling device 55. The latter is said to cool this air to such an extent that the core remains frozen, ie remains in the solid state and the sheath is preferably dried by freeze-drying, although it may also be possible to dry the sheath in a conventional manner, that is to say when it dries entapor¬ de solvent and / or dispersant to evaporate starting from the liquid state. The drying process is carried out until the shell of the particles is at least somewhat dry and solid and is also impermeable to the solvent and / or dispersion medium present in the core material and solidified by freezing, even if it is in the liquid and / or Gaseous ^J- shaped state.

When the particle shells have been dried in this way with cold air, the valves 47, 57 can be closed by opening the valves 67, 77 and dried with the pump 69 in the vapor / liquid separator 73 and roughly with the gas heating device 75 pass through the container 1 at room temperature or a little above this heated air and whirl the particles in a heating process with air circulating through the container 1 and the line 65 until the particles reach approximately room temperature ¬ are warmed. As a result, during the subsequent removal of the particles from the container 1, it can be avoided that the particles wet upon contact with moist ambient air by condensation and / or freezing out of water vapor present therein and / or with a Ice layer to be covered. However, if a certain wetting of the particles is permitted when they are removed, or if the drying process or at least its final phase has been carried out with air at least at room temperature, a separate warming-up process can of course be dispensed with.

If the particles are warmed up in a warming-up process with air circulated through the container 1 and the line 65 or if the entire drying process is carried out with air circulated via the line 65, the valve 61 can be opened in the meantime so that the bypass line 59 together with the pump 49, the filter 51, the vapor / liquid separator 53 and the gas cooling device 55 are closed

Cycle forms. The air present in this can then be circulated with the pump 49 and conditioned for the processing of the next batch of particles, i.e. be dried and cooled. In an analogous manner, during the time intervals in which no air heated in the gas heating device 75 is supplied to the gas inlet 15, air can be circulated with the pump 69 via the filter 71, the vapor / liquid separator 73, the gas heating device 75 and the Circulate and condition bypass line 79. The circulation of air not required for swirling via the bypass lines 59 and 79, in addition to the continuous conditioning of the circulating air, also helps to counteract the penetration of microorganisms and other contaminants into the lines, since the pumps 49, 69 are not switched off have to be

If the particles present in the container 1 are to be removed therefrom, they can be sucked out of the container 1 by means of the blocking / suction device 37 via the particle outlet 35 and removed from the container with the particle separator 39 along with them, air flowing through the particle outlet 35 is separated.

After that, a new batch of core material can be placed in the vortex _. sprayed into it and processed in the manner described. As mentioned, the swirl chamber is designed in such a way that even when swirling very small particles by means of air entering the swirl chamber at a high flow velocity, as few particles as possible get to the filter 29. However, if a certain amount of particles has nevertheless accumulated in the filter section currently used for filtering the air, for example filter section 29a, during operation, the filter control and filter cleaning device 31 can be used to exit the filter section 29a blocked and the output of the filter section 29b released and connected to the gas outlet 33. Furthermore, the previously used filter section 29a can be shaken with the shaker of the device 31, so that the particles present in the filter section 29a fall back into the vortex space. After a certain time, the filter section 29a can then be used again for filtering and the filter section 29b can be freed of particles by shaking. Since the vapor / liquid separators 53, 73 separate water vapor and / or droplets and / or other solvents and / or dispersing agents during operation, and since ice can accumulate in the gas cooling device 55 when water vapor and / or water droplets freeze out, these are Separators 53, 73 and the cooling device 55 can be borrowed continuously or at least regenerated from time to time.

In the case of separators 53, 73 having an adsorbent, the adsorbent can be attached, for example, to disks which are rotated slowly or stepwise during operation and in front of which one section is used for vapor / liquid separation and another is generated. The cooling device 55 can, for example during interruptions in particle production, for example at night, are de-iced by heating or have two coolers which can be used alternately for cooling or de-icing. In addition, the various processes can be controlled and regulated either manually or partially or completely automatically.

FIG. 2 shows an at least approximately spherical particle 91, produced according to the previously described manufacturing process, with a core 93 and a jacket 95 enclosing it on all sides. The core 93 consists of core material originally sprayed into the vortex chamber, accordingly has at least one solution and / or dispersion with a liquid solvent and / or dispersing agent and is therefore complete at normal room temperature or, with the exception of any dispersed solid particles present, is liquid. The jacket 95, on the other hand, is solid and impermeable to both the liquid core material and the vapor thereof. Furthermore, the sheath 95 should be of such a nature that it dissolves in a human or animal body after being introduced into it, for example when it is administered orally in its gastrointestinal tract.

Instead of a core material consisting of a solution and / or dispersion and having at least one dissolved and / or dispersed pharmaceutical active substance and / or auxiliary substance, a core material consisting of an active and / or auxiliary substance which is already liquid per se could also be used in an analogous manner Particles are sprayed and coated. In this case, the liquid core 93 of the particles 91 consists of this active and / or auxiliary substance which is liquid per se.

The process described for the production of

Particles can also be varied in such a way that one a core material consisting of a solution and / or dispersion which contains, for example, at least some active ingredient and possibly additionally an auxiliary, such as mannitol, as in the previously described method, sprayed into the vertebral space 11 and the resulting core material droplets solidified by freezing and sprayed with a jacket material which, for example, has the acrylic resin obtainable under the trade name Eudragit S. The drying process is now carried out in a departure from the previously described method in such a way that not only are the jackets dried, but the originally liquid solvent and / or dispersion medium is also removed from the core material. This is preferably done with air cooled to such a depth that at least the core material and preferably also the cladding material are dried by freeze-drying and thus at least the solvent and / or dispersing agent of the core material and preferably also that of the cladding material is removed from the particles by sublimation. The shells of the particles must on the one hand be sufficient to enable such drying of the core material for its solvent and / or dispersion medium, at least when it is in the gaseous state, for example for water vapor and possibly for water in a liquid state be permeable, but on the other hand with the finished ones

Particles have sufficient mechanical stability.

These requirements can be met, for example, by coats made of the Eudragit S mentioned above

Two thicknesses of 0.025 mm and 5 to 15 g / mh permeability for water vapor are met, the water vapor permeability being defined and measured in accordance with the DIN 53122 standard. In the case of very small particles and / or if the mechanical stability of the shells is not very demanding, the latter can also be made thinner. After done Drying of the core and jacket, analogously to the method described above, the particles can first be warmed to room temperature in the swirl chamber and then removed from the container.

FIG. 3 shows a particle 101 produced in this way with a core 103 and a shell 105. In this particle, both the core 103 and the shell 105 are solid at room temperature in accordance with its production process. Since the core, for example, the solvent present in the original core material, for example consisting of water, has been removed by sublimation, the pharmaceutical active ingredient and / or auxiliary substance remaining in the core has a loose, porous structure and is also very readily soluble in the solvent ¬ Lich and therefore has so-called instant release properties. The jacket 195 can be designed in such a way that, after being introduced into the gastrointestinal tract or another part of the body of a human or animal, it is permeable to a liquid, in particular water-containing, present in the relevant part of the body and to the core material dissolved therein so that it Liquid can penetrate into the shell 105 of the particle 101, dissolve the core 105 quickly and completely and can transport the active substance and / or auxiliary substance contained in the core through the shell 105 out of the core region of the particle 101 in the dissolved state. The jacket 105 then forms a diffusion barrier which determines the release rate of the active substance and / or auxiliary substance present in the core. Freeze-drying, ie, sublimation of the solvent and / or dispersion medium, allows the cores to be dried, particularly with poorly soluble active substances, to achieve a reproducible, optionally slow or relatively fast release of active substances with good bioavailability. If a particularly rapid release of active substance is desired, can you design the coat so that it dissolves in the body. If the active and / or auxiliary substance was contained in the original core material in the form of dispersed solid particles, after drying the finished, capsule-like particles then form a powder which is released after the particles have been administered, for example by dissolving their mantles can be.

The process in which an originally liquid core material is solidified by freeze-drying could possibly also be modified in such a way that conventional drying is carried out instead of freeze-drying.

The processes described above are particularly good for producing small particles, i.e. Suitable for microcapsules. However, it is now also possible to produce relatively large particles without further ado, for example by using core material particles as described in the preceding

Were formed by freezing droplets in the vortex, agglomerated before coating. The swirling is carried out in such a way that occasionally particles collide. If the original core material contained water, water can be sprayed into the swirl chamber with the second spraying element 23 and / or an additional spraying element to promote agglomeration, if necessary a little beforehand has been heated and can then form ice bridges between the particles and thus serves as a binder. The agglomerated particles consisting of solidified core material can then be coated with a jacket analogously to the previously described methods.

In a further process variant, which is also suitable, inter alia, for producing larger particles to form the cores, first at room temperature already in the solid state or in a transition state between solid and liquid core material particles in the container, which are to serve as internal parts for the cores to be formed. Such more or less solid particles can be introduced into the container, for example, by one of the spraying elements or by an additional particle inlet or by temporarily separating the bottom part 3 from the lower chamber part 5 or the chamber part from the chamber parts 7 and swirling it in this with cooled air. Thereafter, by means of the first spraying device, as in the previously described processes, liquid core material which consists of a solution and / or dispersion containing active substance can be sprayed into the vortex space at room temperature. The solid core material particles already present in the vortex space then form, to a certain extent, solidification nuclei on which sprayed-on core material accumulates in the liquid state, which is brought into the solid state of aggregation when they are deposited and / or subsequently cooled.

The particles formed in the process can then be sprayed with jacket material and dried in the manner described above, preferably the layer formed by the original core material and, for example, the jacket also being dried by freeze-drying. The maximum external dimension of such particles, i.e. in the case of spherical particles, their outside diameter can be, for example, at least approximately 0.1 mm and can be made, for example, 0.3 mm to 3 mm or even larger.

FIG. 4 shows a particle 111 produced in this way with a core 113 and a jacket 115 enclosing it. In accordance with the production method described, the core 113 has an approximately spherical inner part 113a and an inner part 113a brought layer 113b. The inner part can consist, for example, of a physiologically completely inert auxiliary substance and can only serve as a carrier for at least one active pharmaceutical substance contained in layer 113b or can also itself contain at least one active substance. The inner part 113a of the core can consist, for example, of a substance which melts only after it has been introduced into a human or animal body. Since the temperatures in the inner regions of a living body are typically approximately 37 + 1 ° C. and immediately below the skin approximately 32 + 2 ° C., certain core inner parts for melting inside the body can be produced at least in part from a substance , whose melting temperature is at most 38 ° C and preferably at most 36 ° C. If the latter substance has a melting temperature range, its lower limit and preferably also its upper limit should be at most 38 ° C. and for example at most 36 ° C. In the case of medicaments which are intended for subcutaneous applications, the melting temperature or at least the upper limit and, for example, the lower limit of the substance serving as the carrier should be at most 32 ° C. or even only at most 30 ° C. So that a substance that is at least somewhat liquid at 36 to 38 ° C. or even at 30 to 32 ° C. is at least somewhat solid at normal room temperature, its melting temperature should of course be more than 25 ° C. or, if the substance has a melting temperature range, its upper limit and preferably also its lower limit are more than 25 ° C. Substances that are liquid at 36 to 38 ° C or even 30 to 32 ° C are often already in a soft transition state between solid and liquid at the normal room temperature of about 20 to 25 ° C and are often also more or less sticky at room temperature . Whirling with cooled air will be whole or at least Particles consisting largely of such soft and possibly sticky substances at room temperature are then rapidly cooled and solidified, as a result of which undesired agglomeration can be prevented. The auxiliary substance present in the core inner part 113a could, instead of or in addition to the described melting properties, have the property that it can be dissolved by a liquid which is present in a designated area of a human or animal body.

The inner part 113a of the core 113 can have, for example, one of the following substances or a mixture of at least two of the following substances: lactose, calcium hydrogen phosphate, corn starch or another starch, sucrose, glucose, calcium hydrogen phosphate, barium sulfate, titanium dioxide, silicon dioxide (Aerosil), Magnesium oxide, polyethylene glycol, a gelatin-glycerol mixture, trigliceride fatty acid, wax, 01 and additionally a binder and / or a viscosity-increasing substance such as polyvinylpyrrolidone, a cellulose derivative, for example methyl cellulose, and bentonite. Certain of these substances, such as lactose or calcium hydrogen phosphate, may contain or be free of water of crystallization.

Particles can also be produced by processes in which the core and the cladding material are combined with one another and sprayed together into the swirl chamber. The combined core and jacket material intended for spraying in this case consists of a solution and / or dispersion and is liquid at normal room temperature apart from any dispersed solid particles which may be present. The core and shell material should be such that liquid particles are at least partially produced when it is broken up, which have a core area made of core material on the inside and a jacket area made of jacket material on the outside. The material to be sprayed in can be a core and a solution and / or dispersion with a water-containing and / or hydrophilic solvent and / or dispersing agent and with at least one dispersed pharmaceutical active and / or auxiliary substance and as a jacket material at least one micelle-forming surfactant and / or at least contain a liposome-forming substance. For example, dioxane, 2-methyl-2-propanol, dimethyl sulfoxide or dimethylformamide can be used as the hydrophilic solvent and / or dispersion medium. Both ionic and non-ionic surfactants are suitable as surfactants. Suitable surfactants are, for example, the sorbitan fatty acid ester available under the trade name Span 80, the polyoxyethylene sorbitan fatty acid ester commercially available under the name Tween 80, the poly (oxyethylenej-poly (oxypropylene) polymer and sodium lauryl sulfate available under the name Pluronic F68. Instead of a single surfactant, you can also use a surfactant mixture with the appropriate, suitable HLB value, where "HLB" is the abbreviation for "hydrophilic-lipophilic balance." If liposomes are formed, it can be small or large, unilamellar liposomes, which are usually referred to as SUV or LUV, or are multilamellar liposomes (abbreviation: MLV). The core material can be formed, for example, by an aqueous phosphate buffer active substance / auxiliary substance solution, which is at least one as the sheath material swellable phospholipid such as lecithin, phosphatidylinositol, sphingomyelin, or Monoglyceride, alpha-hydroxy fatty acid and possibly cholesterol is added. For example, a mixture of lecithin, cholesterol and dicethyl phosphate or a mixture of lecithin, cholesterol and stearylamine in a molar ratio of 4: 2: 1 can be used to form liposomes. When a such core and shell material is sprayed into the vertebral space, the micelles or liposomes form droplets including core material droplets. The particles can then be solidified by freeze-drying the core and cladding material and possibly sprayed with additional, other cladding material, so that in the latter case a multilayered cladding is produced.

Instead of micellar solutions and / or dispersions, certain microemulsions or liquid-crystalline materials can also be processed in a similar manner with polymers that can be solidified into shells.

Furthermore, solutions and / or dispersions can be used as the combined core and shell materials which contain at least one complexing agent, such as polyvinylpyrrolidone or the ethylene diamine tetraacetic acid known under the English abbreviation EDTA, or at least one as the shell material Contain substance which can form an inclusion compound together with a pharmaceutical active and / or auxiliary substance, such as urea, a cyclodextrin, a starch or deoxycholic acid. The jacket can be formed, for example, by montmorillonite (clathrate, aluminum silicate), sodium bentonite or Veegum and include as the core material an ethereal oil which is sensitive to oxidation. A jacket made of deoxycholic acid or alpha-cyclodextrin can include, for example, vitamin D_ or D.

Such combined core and cladding materials can then in turn be sprayed together into the vortex space and the particles formed thereby can be solidified by freezing the core material and then freeze-drying. Since the methods described make it possible to produce capsule-like particles without heating beyond the normal room temperature, these methods are also particularly suitable for processing thermolabile substances which, above normal room temperature, irreversibly change at least one chemical and / or physical property . Examples of such thermolabile substances are biotechnologically obtained active substances, such as interferons and interleukins.

The device and the methods can still be modified in various ways. For example, when swirling particles, at least a portion of the air flowing out of the swirl chamber at the top can be replaced by fresh air drawn in from the surroundings. Another gas, such as nitrogen or carbon dioxide, can also be used for swirling instead of air. If the core and / or cladding material contains organic solvents and / or dispersing agents, these can be recovered with the steam / liquid separators and / or additional devices. Furthermore, in certain cases, provision can be made for the particle production to be carried out continuously or quasi-continuously, and at the same time to spray in the core material and shell material and to remove finished particles, ie capsules, from the container. On the other hand, it would be possible to dispense with the use of the particle outlet in the case of certain products and to permanently close it with a closure element detachably attached to it, or to omit it at all, and to remove the finished particles by temporarily separating the bottom part 3 from the lower chamber part 5 or the lower from the upper chamber part remove from the container, in this case it would then be expedient not only to remove not only the particles, but also after the production of a batch of capsule-shaped particles from the container 1 to heat the wall of the container 1 to approximately room temperature so that it does not ice up when ambient air flows in. For this purpose, as has been described for heating the particles, air at least at room temperature could be circulated via line 65 and / or the container wall could be heated with the cooling / heating devices 33. Furthermore, the core material could be sprayed into the vortex space instead of downwards.

A method can also be provided in which solid cores are introduced into the vortex chamber, which are made from a biologically inert core material that has a relatively high density, such as ceramic, glass, metal, metal oxide, barium sulfate, calcium sulfate, calcium carbonate or a min there are at least two of these substances. The cores can, for example, be spherical and have sizes or diameters which, depending on their density, are at least 1 mm or at least 3 mm or even at least or approximately 5 mm, so that the particles have a relatively large mass. When swirling, the particles can be sprayed by means of one of the spraying organs 19, 23 with a jacket material which at least partly consists of a liquid and, for example, an at least one pharmaceutical

Solution and / or dispersion containing active substance and / or auxiliary substance is formed. Analogously to the previously described methods, the sprayed-on jacket material can be brought into the solid aggregate state by cooling the swirled, unsprayed or sprayed cores before and / or during and / or after the jacket material is sprayed on and then dried by freeze-drying become. The particles are swirled after drying and / or possibly already during this in such a way that the particles are frequently against one another and / or against the wall of the container nudge. If the cores are sufficiently large and hard, such collisions of the T-particles can cause the shells to be broken up and / or ground and thus broken up into smaller particles, ie pulverized, so that at least part of the shell material sprayed and solidified on the cores falling off the cores. The particles consisting of divided shells can then be separated from the cores by sieving, for example, and used as a medicament and encapsulated, for example. The cores, which normally still contain a remainder of the solidified and dried core material, can be used for processing a new batch. Such a method enables the processing of solutions and / or dispersions into a particulate, for example powdery material, which have a strong tendency to agglomerate and which, if they were not sprayed onto cores, but were sprayed into a vortex space containing no cores would agglomerate large lumps which could then no longer be swirled or only swirled and dried poorly. The solutions and / or dispersions can be aqueous or non-aqueous. A tetracycline-mannitol solution may be mentioned as an example of a material which can be processed by spraying on cores and subsequently separating them from them to form a particulate material.

Claims

Claims 1. A process for the production of particles (91, 101, 111), in particular drug particles, with a core (93, 103, 113) and a solid shell (95, 105, 115) enclosing them, whereby to form the cores (93, 103, 113) formed from core material particles, swirled with gas in a swirl chamber (11) and cooled and coated with jacket material used to form the jackets (95, 105, 115), characterized in that to form the At least a part of the core material consisting of core material is sprayed as a liquid into the vortex chamber (11) and this liquid is brought into the solid state by cooling. 2. The method according to claim 1, characterized in that the melting temperature or the lower limit, and preferably also the upper limit of the melting temperature range of the liquid forming at least part of the core material is at most 25 ° C and preferably at most 20 ° C. 3. The method according to claim 2, characterized in that the liquid at least in part by a Solvent and / or dispersant is formed in which at least one active pharmaceutical substance and / or auxiliary substance is dissolved and / or dispersed, the solvent and / or dispersant comprising, for example, water and / or at least one liquid, organic substance. 4. The method according to any one of claims 1 to 3, characterized in that the shell (95) is formed such that the cores (93) after the completion of the particles (91) at least a part of the Liquid originally contained in the core material. 5. The method according to any one of claims 1 to 3, characterized in that the particles formed from core material when swirling in the vortex space, at least part of the substance originally contained as a liquid in the core material and solidified by cooling, and for example the whole originally substance removed as a liquid is withdrawn. 6. The method according to any one of claims 1 to 3, characterized in that the coating process of the particles consisting of core material is carried out with jacket material in such a way that the latter at least for a part of the substance contained in the original core material as a liquid and solidified on cooling, if this has been brought into the gaseous state of matter and, for example, also if it has been brought into the liquid state, is permeable, and that this substance is at least partially removed from the core material by sublimation through the jacket material. 7. The method according to any one of claims 1 to 6, characterized in that the jacket material is sprayed into the swirl chamber (11) in a state separated from the core material, a batch of, for example, first being sprayed in by core material and by swirling and cooling solid particles formed from core material and is sprayed into the vortex chamber (11) and onto the particles consisting of solid core material only after the end of the spraying of core material. 8. The method according to any one of claims 1, 2, 3, 5, 6 or 7, characterized in that solid inner parts (113a) forming part of the core material are introduced into the vortex chamber (11) and swirled therein and that these inner parts (113a) are coated with the part of the core material sprayed as liquid into the vortex chamber (11), this liquid preferably forming a solution and / or dispersion, preferably after it has solidified by cooling before and / or during and / or after the coating process with jacket material, for example by sublimation, at least part of the solvent and / or dispersion medium is removed. 9. The method according to any one of claims 1 to 6, characterized in that the core and sheath material are sprayed together as a solution and / or dispersion having a liquid solvent and / or dispersant into the vortex chamber (11), that the solution and / or dispersion is such that, when sprayed, it forms at least partially liquid particles having a core area and a jacket area, the jacket area of which consists of the outer area of an inclusion compound and / or of a polymer and / or at least a micelle-forming surfactant, a liposome and / or a solidifiable phase of an emulsion is formed such that the particles are cooled below the melting temperature of the solvent and / or dispersion medium and that they dry at least part of the solution and / or dispersant is withdrawn by sublimation. 10. The method according to any one of claims 1 to 9, characterized in that in the vortex chamber (11) solidified by cooling, consisting of core material particles with agitation to larger particles agglomerate. and then coated with jacket material, preferably for agglomeration, a liquid binder is sprayed into the swirl chamber (11), which preferably consists at least partly of a solvent and / or dispersion medium, such as water, which is also present in the core material, and after Cooling below its melting temperature forms solid bridges, in the case of a water-containing binder ice bridges. 11. Device for performing the method according to one of claims 1 to 10, with a vortex chamber (11) delimiting container (1) and means (45, 49, 55) for cooling and introducing gas into the vortex chamber (11) by at least one spray element (19) for spraying at least partially liquid core material into the swirl chamber (11). 12. Particles produced by the method according to one of claims 1 to 10, characterized in that their core (93, 103, 113) and / or their shell (95, 105, 115) contains at least one active pharmaceutical ingredient and / or auxiliary substance . 13. Particle according to claim 12, characterized in that the core (93, 113) containing at least one pharmaceutical active substance and / or auxiliary substance consists at least in part of a substance, its melting temperature or its lower melting temperature range limit and preferably also whose upper melting temperature range limit is at most 38 ° C and expediently at most 36 ° C, the core (93) consisting, for example, at least in part of a liquid liquid at 25 ° C, or the core (113), for example, an inner part (113a ) and a layer carried by the latter, preferably having at least one active pharmaceutical substance and / or auxiliary substance (113b), the melting temperature or the lower limit and preferably also the upper limit of the melting temperature range of the inner part (113a) is at most 38 ° C. or even at most 36 ° C. and the melting temperature or the upper limit and, for example, also the lower limit of the melting temperature range of the inner part (113a) is more than 25 ° C. 14. Particle according to claim 12 or 13, characterized in that the core (103, 113) contains at least one solid pharmaceutical active substance and / or auxiliary substance which has been dried by sublimation by removal of a solvent and / or dispersant , wherein the jacket (105, 115) is preferably water-permeable and / or can be dissolved in an aqueous liquid. 15. Process for the production of particles, in particular drug particles, wherein cores are swirled with gas in a fluidized space (11), sprayed with jacket material which serves to form jackets and consists at least partly of a liquid, the liquid by cooling brought into the solid aggregate state and the coats are dried, characterized in that at least a portion of the coat material sprayed and solidified onto the cores is broken up into particles during and / or after drying and separated from the cores.