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WO1988010150A1 - Procede de fabrication de granules constitues d'un noyau entoure d'une gaine, dispositif pour la mise en oeuvre de ce procede et granules fabriques selon ce procede - Google Patents

Procede de fabrication de granules constitues d'un noyau entoure d'une gaine, dispositif pour la mise en oeuvre de ce procede et granules fabriques selon ce procede Download PDF

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Publication number
WO1988010150A1
WO1988010150A1 PCT/CH1988/000106 CH8800106W WO8810150A1 WO 1988010150 A1 WO1988010150 A1 WO 1988010150A1 CH 8800106 W CH8800106 W CH 8800106W WO 8810150 A1 WO8810150 A1 WO 8810150A1
Authority
WO
WIPO (PCT)
Prior art keywords
particles
liquid
core
core material
substance
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CH1988/000106
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German (de)
English (en)
Inventor
Hans Leuenberger
Alain Kahn
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GLATT MASCHINEN- und APPARATEBAU AG
Original Assignee
GLATT MASCHINEN- und APPARATEBAU AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by GLATT MASCHINEN- und APPARATEBAU AG filed Critical GLATT MASCHINEN- und APPARATEBAU AG
Publication of WO1988010150A1 publication Critical patent/WO1988010150A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/04—Making microcapsules or microballoons by physical processes, e.g. drying, spraying
    • B01J13/043—Drying and spraying

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • FIG. 1 shows a schematic vertical section through a device for producing capsule-like particles with a core and a jacket
  • FIG. 4 shows a section through a particle with a multi-part core.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the spray elements 19, 23 and feed devices 21, 27 can be provided with cooling and / or heating elements.
  • 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.
  • a bypass line 59 i.e. a "bypass" with a valve
  • 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.
  • 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.
  • adsorbent such as the agent known under the trade name Silica gel or lithium chloride or zeolite
  • the vapor / liquid separators could possibly contain an absorbent as a sorbent instead of an adsorbent or in addition to this.
  • 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.
  • 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.
  • 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.
  • 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.
  • temperature sensors 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.
  • 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.
  • pressure sensors can be provided in order to determine the pressure in the swirl chamber 11 and the pressure drop that arises over it.
  • 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.
  • 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.
  • a gas which is toxic to microorganisms for example formaldehyde
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • the inner walls of the two chamber parts 5 and 7 delimiting the swirl chamber 11 can be cooled with the cooling devices 13.
  • 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.
  • 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.
  • 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.
  • the spraying in of core material and of cladding material may also take place entirely or partially simultaneously instead of at separate time intervals.
  • coating of the cladding material is also stopped.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • a separate warming-up process can of course be dispensed with.
  • 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
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the liquid core 93 of the particles 91 consists of this active and / or auxiliary substance which is liquid per se.
  • 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.
  • 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.
  • FIG. 3 shows a particle 101 produced in this way with a core 103 and a shell 105.
  • both the core 103 and the shell 105 are solid at room temperature in accordance with its production process.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • liposomes 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • thermolabile substances which, above normal room temperature, irreversibly change at least one chemical and / or physical property .
  • thermolabile substances are biotechnologically obtained active substances, such as interferons and interleukins.
  • the device and the methods can still be modified in various ways.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dispersion Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Manufacturing Of Micro-Capsules (AREA)

Abstract

La fabrication de granules servant de médicament est obtenue par la projection dans une chambre (11) d'une matière au moins partiellement liquide pour former le noyau des granules et d'une matière aussi au moins partiellement liquide pour former la gaine de ces granules, puis par mise en tourbillon dans la chambre au moyen d'un gaz froid, notamment d'air. La matière destinée à former les noyaux, d'abord au moins sous la forme de particules partiellement liquides, est solidifiée par tourbillonnement et refroidissement puis enveloppée par la matière de la gaine. Les granules obtenus peuvent avoir soit suelement la gaine à l'état sec, le noyau restant au moins partiellement liquide à la température ambiante, soit avour aussi le noyau sec grâce à une congélation supplémentaire, de façon qu'à la température ambiante les granules soient en état d'agrégation. Le procédé permet, au moins pour l'essentiel, d'encapsuler économiquement et de ménager la matière liquide du noyau et ainsi de produire un médicament sous forme de granules, pourvu de caractéristiques avantageuses et d'aptitudes à la résorption pour une substance pharmaceutique active ou auxiliaire.
PCT/CH1988/000106 1987-06-15 1988-06-09 Procede de fabrication de granules constitues d'un noyau entoure d'une gaine, dispositif pour la mise en oeuvre de ce procede et granules fabriques selon ce procede Ceased WO1988010150A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH225987 1987-06-15
CH2259/87-6 1987-06-15

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WO1988010150A1 true WO1988010150A1 (fr) 1988-12-29

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989012207A1 (fr) * 1988-06-03 1989-12-14 Glatt Maschinen- Und Apparatebau Ag Procede et agencement de sechage d'un materiau particulaire
EP0413865A1 (fr) * 1989-08-22 1991-02-27 Taisho Pharmaceutical Co. Ltd Procédé de préparation de particules enrobées
US6224939B1 (en) 1998-05-22 2001-05-01 Fuisz International Ltd. Method and apparatus for forming an encapsulated product matrix
EP1700633A1 (fr) * 2005-03-07 2006-09-13 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Procédé pour l'encapsulation d'un liquide
US8322046B2 (en) * 2003-12-22 2012-12-04 Zhaolin Wang Powder formation by atmospheric spray-freeze drying
DE102005020561B4 (de) * 2005-05-03 2017-09-14 Glatt Gmbh Verfahren zur Herstellung von Mikropartikeln sowie daraus erhältliches Trockenprodukt

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1444410B (de) * International Business Machines Corp , Armonk, NY (V St A ) Verfahren zum Einkapseln von Flus sigkeiten
EP0116311A1 (fr) * 1983-01-17 1984-08-22 Morishita Jintan Co., Ltd. Capsules molles doubles et leur production
EP0152285A2 (fr) * 1984-02-09 1985-08-21 Southwest Research Institute Procédé et appareil pour la production et pour la collection de microcapsules

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1444410B (de) * International Business Machines Corp , Armonk, NY (V St A ) Verfahren zum Einkapseln von Flus sigkeiten
EP0116311A1 (fr) * 1983-01-17 1984-08-22 Morishita Jintan Co., Ltd. Capsules molles doubles et leur production
EP0152285A2 (fr) * 1984-02-09 1985-08-21 Southwest Research Institute Procédé et appareil pour la production et pour la collection de microcapsules

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989012207A1 (fr) * 1988-06-03 1989-12-14 Glatt Maschinen- Und Apparatebau Ag Procede et agencement de sechage d'un materiau particulaire
EP0413865A1 (fr) * 1989-08-22 1991-02-27 Taisho Pharmaceutical Co. Ltd Procédé de préparation de particules enrobées
US5017383A (en) * 1989-08-22 1991-05-21 Taisho Pharmaceutical Co., Ltd. Method of producing fine coated pharmaceutical preparation
US6224939B1 (en) 1998-05-22 2001-05-01 Fuisz International Ltd. Method and apparatus for forming an encapsulated product matrix
US8322046B2 (en) * 2003-12-22 2012-12-04 Zhaolin Wang Powder formation by atmospheric spray-freeze drying
EP1700633A1 (fr) * 2005-03-07 2006-09-13 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Procédé pour l'encapsulation d'un liquide
WO2006096051A1 (fr) * 2005-03-07 2006-09-14 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Procede pour encapsuler un liquide
US8628851B2 (en) 2005-03-07 2014-01-14 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Method for encapsulating a liquid
DE102005020561B4 (de) * 2005-05-03 2017-09-14 Glatt Gmbh Verfahren zur Herstellung von Mikropartikeln sowie daraus erhältliches Trockenprodukt

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