Patent Grant
11045778
This application is a national stage entry of international application no. PCT/IB2017/054782, filed on Aug. 4, 2017, which claims priority to Italian application no. 102016000083055, filed Aug. 5, 2016; Italian application no. 102016000083078, filed on Aug. 5, 2016; and Italian application no. 102016000083121, filed on Aug. 5, 2016.
The invention relates to a maturation device for curing uncured dosage forms, a machine and a process for producing dosage forms that use said device.
This disclosure relates to the production of seamless dosage forms by processes wherein droplets of a first fluid containing structuring substances such as monomers, polymers or polyelectrolytes, are placed in a bath of a second fluid containing suitable reagent in order to determine polymerization and/or crosslinking of the structuring agent contained in the first fluid.
It is known that dosage forms obtained by said processes are able to encapsulate and deliver a high number of substances such as active substances, cells, microorganisms, flavours, foods, proteins, metals, seeds, oils and essences. An example of said process is the so-called ionotropic gelation/gelification or ionic reticulation technique. Such technique provides a gelation process that occurs when a polymeric fluid, that is a fluid (for example a polymeric solution) comprising a polyelectrolyte (for example alginate or chitosan) is put in contact with a cation fluid, that is a fluid containing divalent or trivalent cations (for example a cationic solution comprising Ca2+ e/o Ba2+ e/o Sr2+ e/o Fe2+ e/o Zn2+ e/o Al3+) able to cause the polyelectrolyte gelation.
Within the description of the present invention, the polymeric fluid and/or the cationic fluid (or, in processes other than ionotropic gelation, the equivalent fluids with structuring substance and polymerizing/crosslinking reagent) are intended to comprise at least one liquid phase, and could be in a simple form, preferably a solution, or in a complex form, such as a suspension, emulsion or colloid, according to the desired final dosage form features.
In the most common instances of application, the gelling polyelectrolyte (for example alginate) of the polymeric fluid comprises carboxylic groups which, upon contact with gelling fluid, chelate the cationic fluid cations leading to the formation of complex and rigid lattices, that determine the formation of a defined structure. Such lattices are able to encapsulate any substance present in the polymeric fluid and/or the cationic fluid, which for this purpose could be supplemented with further appropriate excipients (such as for example surfactants, salts, lipids, polymers, sugars).
Generally, the process is performed by dispensing one or more droplets of polymeric fluid to a bath of cationic fluid, although the two phases can also be inverted. The substance to be encapsulated/delivered could be contained in the dispensed droplets or in the bath, according to the formulation needs.
The formation of the external polymeric lattice is fast and the droplet that falls in the bath retains its shape upon contact with the same bath; however, the internal structure takes at least some minutes to cure, resulting in a complete consolidation. The result is a corresponding number of dosage forms consisting of macro, micro- or nano-capsules, depending on the droplet size.
The spherical shape of the resulting dosage forms is specifically dependent on the feeding and dripping rates of the dispensed fluid droplets towards the other fluid's bath: processes with very slow feeding dripping speed rates correspond to a good spherical shape, while by increasing the feeing and/or the drop rates, the dispensed droplets progressively tend to taper, at the expense of the spherical shape of the final obtained product.
It is also known that said dosage forms are produced with appropriate machines that carry out processes comprising a feeding and a dispensing step, wherein droplets of one of the two fluids are dispensed towards a bath of the other fluid, and a formation step in which said droplets are put in contact with the bath of the other fluid for the lattices formation.
U.S. Pat. No. 4,224,258 A and EP 1 686 094 A1 describe an apparatus for producing nuclear fuel spherical particles, comprising a dripping unit for dispensing droplets of a first fluid towards a bath of second fluid, a chamber for the pre-treatment of the dispensed droplet by gas dispensing devices for the superficial consolidation of the dispensed droplets, and a second fluid hardening bath for the consolidation and formation of nuclear fuel spherical particles.
After the formation, a “curing phase” is required in order to allow the forming polymeric structure to consolidate even in the inner part of the dosage form.
A particular issue associated with the curing phase is the accurate control of the maturation time of the individual dosage forms. The curing time does not particularly affect the strength of the dosage form, but influences the release or storage performance of the encapsulated substance by the dosage form within the environment for which it was produced.
There are known techniques for managing this curing phase using systems with conveyor belts (EP 0 391 803 A1), or auger systems (WO2012/0177727).
It is also known that said steps may also be distinctly performed on different machines that perform the feeding, dispensing, forming, and maturation phases respectively, for obtaining the final dosage form.
Conversely, the different production phases can be combined into a single machine. In both cases, the machines generally comprise a device for dispensing droplets of a first fluid, such as a polymeric solution or a solution containing another structuring substance, in a bath of a second fluid containing the polymerizing/crosslinking reagent, such as a cationic solution, or vice versa, and a device that allows for the removal of the dosage forms newly-formed in other areas, therefore allowing them to cure within the second fluid bath.
However, such known machines, while being functional, exhibit some drawbacks such as having a large footprint due to the necessary horizontal positioning of certain components, particularly of the maturation devices, and a reduced productivity due to the feeding and dispensing phase. It is known that said step is a limiting factor for the production rate because the droplets cannot be dispensed too quickly since, beside the occurrence of a tapering effect, if more droplets were to fall in the same bath area, the bath would lose the cations (or the polymer in the case of a reverse production) too quickly. By doing so, the following droplet that would fall into the same bath area would not have the ability to gelify or otherwise to gelify optimally. To overcome this drawback, it has been proposed to agitate the bath by stirring. However, the stirring speed must be carefully controlled for at least two reasons:
1) an excessive stirring rate of the bath results in the formation of excessive shear forces upon impact of the droplet with the bath. This results in the loss of the substantially spherical shape of the single droplet, and thus of the final dosage form;
2) an excessive stirring rate of the bath causes the contact of the individual droplets before they can reach a degree of polymerization that allows them not to aggregate with one another.
A reduced productivity is also due to the curing phase because said step requires a specific time (usually between 10 and 30 minutes) during which the curing/consolidating dosage form remains immersed in the correlative solution.
The discharge of newly-formed dosage forms by the currently available techniques using conveyor belts or auger cannot be carried out at the maximum potential speed of the dispensing and forming phase.
Conveyor belts and the coil system occupy a linear space, and consequently a high-speed rate of such systems is related to a correspondingly greater length in order to maintain an adequate maturation time. This also creates further problems in the implementation of a continuous production process with limitations on production capacity.
In a completely different technical field, WO 2012/006344 A2 describes a dual flow direction valve for use in well drilling, wherein an adapter is needed between the top-drive and the pumping system of the liquid and drilling sludge, which are extracted by two concentric pipes. The valve has an outer valve body and an internal valve body that define two concentric pipes between an input and an output, and a rotating opening/closing ball of the pipes.
Therefore, a technical problem arises related to the production of a curing device for a production machine of seamless dosage forms by the ionotropic gelation technique, or by a similar technique wherein droplets of a first fluid are immersed in a bath of a second fluid, which solves or at least alleviate one or more of the aforementioned problems of the prior art.
Within said problem, it is particularly desirable that the device allows the machine to operate at high hourly productivity levels, allowing a substantially continuous production process and/or an accurate curing time for each single dosage form.
It is also desirable for the machine to be able to operate maintaining a spherical shape of the individual dosage forms.
It is also preferable that during the curing phase the device allows for the addition of further components to the dosage forms and/or a rapid separation thereof from the liquid in which they are immersed through a continuous process and/or that said process is adaptable to dosage forms with different densities (for example floating or sinking).
It is further desirable for the device and the machine to have a reduced footprint, and to permit a simple and inexpensive production and installation.
These results are obtained according to the present invention by a maturation device for uncured dosage forms according to the herein described subject matter.
The invention also relates to a machine and a process for the production of seamless dosage forms according to the herein described subject matter.
Preferred embodiments are described in the dependent claims, hereby incorporated by reference in their entirety.
More details can be obtained from the following description of non-limiting examples of embodiments of the object of the present invention with reference to the attached drawings, in which it is shown:
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For description purposes of the present invention, the following definitions will also be taken into consideration in addition to those exposed in the introductory part.
FIRST FLUID (A): fluid containing a structuring substance, preferably a polymeric fluid, or fluid containing a polymerizing/crosslinking reagent of said substance, preferably a cationic fluid,
SECOND FLUID (B): fluid containing a polymerizing/crosslinking reagent, preferably a cationic fluid, or fluid containing a structuring substance, preferably a polymeric fluid,
The second fluid is a fluid containing a polymerizing/crosslinking reagent of the structuring substance of the first fluid if the latter is a fluid containing a structuring substance, and vice versa.
The first and/or second fluid may contain substances to be encapsulated/delivered and/or additional substances such as excipients, as previously described.
PRE-DOSAGE FORM: dosage form in the production phase, having a poorly consolidated structure (e.g. polymeric), only present on its outer surface; within the scope of the present invention, this condition occurs from the moment when the dispensed droplet comes into contact with an aerosol containing the second fluid, until the droplet is submerged in a second fluid bath.
UNCURED DOSAGE FORM: dosage form in the production phase, having a substantially consolidated structure (e.g. polymeric) on the outer surface, and undergoing consolidation towards the inside of the dosage form; within the present invention, this condition occurs from the moment when a pre-dosage form comes into contact with a second fluid bath.
CURED DOSAGE FORM: dosage form that has reached the desired superficial and internal consolidation following an appropriate maturation; within the present invention, the term identifies a finished dosage form.
FEEDING AND DISPENSING PHASE: part of the seamless dosage forms production process comprising the actions of feeding and delivering a droplet of first fluid towards a second fluid bath.
PRE-DOSAGE FORM FORMATION PHASE: production process step of the seamless dosage forms that determines a superficial pre-consolidation of the dispensed droplet of the first fluid. It involves contacting a first fluid dispensed droplet with an aerosol containing the second fluid.
UNCURED DOSAGE FORMS FORMATION PHASE: step that determines a consolidation of the external portion and partly of the inner portion of the pre-dosage form. It comprises the immersion of a pre-dosage form in a bath of second fluid.
CURING/MATURATION PHASE: step that determines a desired consolidation of the structure of uncured dosage forms in a maturation device.
GELATION or GELIFICATION: chemical reaction that occurs when a pair of gelling polysaccharides binds to a cation.
AEROSOL: colloid in which droplets of a second fluid are dispersed in a gas (e.g. atmospheric air or nitrogen).
POLYMERIC SOLUTION: polymeric fluid in form of a homogeneous liquid blend wherein a gelling polysaccharide is molecularly dispersed in an appropriate solvent, such as an aqueous solvent.
CATIONIC SOLUTION: cationic fluid in the form of a homogeneous liquid blend wherein a cation is molecularly dispersed in a suitable solvent, such as an aqueous solvent.
As shown in
The curing time of the dosage forms within the maturation chamber will advantageously be adjustable by appropriately sizing the linear extension of the maturation chamber defined by the internal body, which may also not be rectilinear, and the rotation speed of the same internal body, and thus the opening/closing interval of the chamber outlet 313c. The shape and size of the chamber outlet 313c and the correlative aperture on the separation element can also be selected to achieve the desired maturation time.
It is therefore apparent how the rotating internal body, that defines at least one maturation chamber, allows the maturation time to be adjusted and the implementation of a substantially continuous process of formation and curing of the dosage forms in a simple and adaptable manner.
Referring to
For this purpose, the serially arranged separation disks and/or internal bodies are rotated in phase with each other, or in any case according to a rule that determines the desired curing time in the different maturation chambers and the subsequent passage of fluid with dosage forms from a maturation chamber to the subsequent one or to the outlet.
Preferably, this is achieved by means of a transmission shaft 312 which passes through a circular opening of the separation disks 1311 and internal bodies 1313, and is integral with the one and/or the others which are intended to be rotated.
The shaft 312 can be rotated by any mechanism that is able to set its rotation speed with precision, such as an electric gear motor. This transmission shaft may be hollow and preferably have on its surface one or more circular openings of variable diameter whose function will be clarified later.
According to a further preferred embodiment, one or more internal bodies of the maturation device may be rotated by means of magnetic or electromagnetic actuation devices. For example, the rotating body can be configured to have an internal magnetic portion, and the body rotation can be controlled by magnetic transmission means located for example outside the drum, or inside one or more of the separation elements.
The maturation device may be arranged with the drum 1310 vertically oriented, or at an angle greater than 5° relative to a horizontal plane, orthogonal to the gravitational acceleration direction. The drum can have, for example, cylindrical, conical or conical frustum shape, and preferably have on its surface one or more variable-width openings or meshes 1310a with defined cut-off (
The drum and/or one or more internal bodies may have an ellipsoidal, oblate spheroidal, prolate spheroidal shape and/or an ellipsoidal frustum, oblate spheroidal frustum, prolate spheroidal frustum section part.
One or more sets of separating disks 1311 may be integral and perpendicular to the inner walls of the drum 1310. Such disks are, for example, circular with at least an axial passing-through region, for example corresponding to a circular part with an angle in the centre between 5 and 45 degrees, or for example of polygonal, circular or semi-circular shape (
In general, a device of the invention with rotating internal body can be configured so that, when the downstream outlet of a maturation chamber of the body is in the open condition to allow the downstream flow of the fluid containing dosage forms, the upstream inlet of the same chamber is not in fluid communication with the inlet of the drum, and/or when the upstream input of a maturation chamber is in fluid communication with the inlet of the dosage forms in the maturation device, the downstream outlet of the chamber is in the closed condition, so as to allow an optimal filling of the maturation chamber. Such configuration can be obtained by a suitable orientation of the maturation chamber, by a suitable size of the drum inlet in relation to the maturation chamber inlet, by a suitably shaped separation element between the drum inlet and the first internal body, or by a combination of these elements.
This configuration can also be extended to the fluid communication between maturation chambers of subsequent internal bodies separated by separation elements, previously and subsequently described as an example in relation to preferred embodiments.
Referring now to
All embodiments of the internal body that exhibit a plurality of maturation chambers are preferred because they allow an increased production capacity proportional to the number of maturation chambers.
A separation disk 1311 has a shape corresponding to the drum section, with an empty region 1311a shaped according to an aperture at least partially overlapping, and preferably corresponding to the cross-sectional shape of the grooves 1313a of the internal body 1313 (in the example, a circle arc) to determine the opening condition of the respective chamber when the relative rotation of the body with respect to the disk determines the alignment of the outlet of a maturation chamber with the open region of the same separation disk.
The transmission shaft 312 is inserted coaxially to the internal body 1313 and to the disk 1311, and is integral with one or the other to rotate the body or disk.
The chambers can be defined on the external peripheral surface of the internal body (
The body 1313 is able to rotate and is for this purpose integral with the drive shaft 312, which crosses it through the centre of the circumference of the two bases. Preferably, there are openings and/or ducts establishing a communication between the inside of the shaft and the maturation chambers of the inner body 1313.
The rotating body 1313 is axially adjacent to respective separation disks 1311. The arrangement of the disks and the rotating body is designed to ensure intimate contact between the two bases of the rotating body and a base of the disks adjacent thereto.
Referring to
A particularly preferred form is shown in
It is not necessary that an internal body of the device is comprised of a single piece. According to a variant embodiment, the internal body may be formed by a plurality of parts that can be assembled, preferably consisting of axially extending segments suitable to be coupled along respective contact surfaces for the formation of the internal body. This can allow for an easier assembly and/or construction of the device.
According to a further preferred variant, between the parts contact surfaces forming the internal body, it is possible to insert elastic elements capable of generating a force that drives the parts of the rotating body against the internal walls of the drum, ensuring a greater fluid tightness between body and drum.
With reference to
The pre-treatment chamber 206 is associated with a group 207 for providing an aerosol of a fluid within the pre-treatment chamber (206) suitable to determine at least a superficial pre-consolidation of the falling droplet of the first fluid A, i.e. a first polymerization/crosslinking reaction at least on the outer surface of the falling drop within the pre-treatment chamber 206.
Preferably, and in the described exemplary embodiment, said fluid dispensed in the form of an aerosol is the same second fluid B provided in the forming chamber bath. It may possibly be advantageous to dispense aerosol of a similar fluid formulated with a different appropriate reagent concentration and/or viscosity to facilitate aerosol generation, and the choice of a suitable formulation will be within the reach of the technician.
In the illustrated example, the pre-treatment chamber 206 comprises suitable mechanisms 207 for producing an aerosol of a second fluid B, in the example a cationic solution.
The aerosol production group 207 may comprise at least one atomization system able to dispense the second fluid B in the form of finely divided droplets within chamber 206.
With reference to
The nebulizer 2071 further comprises a duct 2071c whose outlet is located at the atomizer aerosol feeding nozzle 2071a and which is suitable to be fed with a gas (e.g. air or nitrogen). Said gas, emitted by the outlet at the feeding nozzle 2071a, breaks the flow of fluid B at the end of the nozzle 2071a, generating a finely divided spray cone and then a second fluid B aerosol.
With ongoing reference to
According to a preferred embodiment, a coil stirring system 209 is located at the centre of the forming/bath containing chamber, for example supported and actuated by an arm extending from the lateral surface of the chamber;
The feeding pump of the dispensing unit is preferably of the Archimedean screw type, which allows optimum feed flow management, and, unlike other systems, allows dispersed systems to be discharged without damaging the dispersed substances in the first fluid A (e.g. cells, easily breakable).
With this configuration, and assuming the dripping of a first polymeric fluid A into a second cationic fluid B bath with a single nozzle, the machine operates as follows:
The pre-dosage form obtained in the pre-treatment chamber allows the droplets not to deform upon impact with the bath of the second fluid B; moreover, since they have a superficial shell of crosslinked polymer obtained by pre-treatment, they do not adhere to one another;
The axially pass-through apertures located on the separation disks are preferably angularly offset with respect to each other. The transmission shaft or alternative drive means rotate the rotating bodies around their longitudinal axis (and possibly one or more designated separation elements), and the rotation of the rotating body more adjacent to the inlet 1310b involves the opening of the communication between the conveying structure and one of the maturation chambers of the first rotating body. Said chamber is then filled with the second fluid B (for example, a cationic solution) and with dispersed uncured dosage forms, which flow from the chamber 208 to a maturation chamber of the first body 1313.
At the inlet 1310b, which connects the uncured dosage forms forming chamber 208 with one of the maturation chamber of the first internal body, the drum preferably has an aperture or grid 1310a on its surface, or a set of calibrated apertures connected to the recirculation system 214. With this preferred configuration, a communication is established between the maturation chamber, the recirculation system 214 and the forming chamber 208. A flow of second fluid B, which loads the chamber with dosage forms faster than by simple fall by gravity, is thereby generated and feeds the maturation chamber through the funnel 208a.
This structure of the maturation device 1300 prevents contact of the material present in a chamber with the material located in an adjacent chamber, ensuring a controlled maturation time for each set of dosage forms.
The structure is modular and hence there may be an appropriate number of internal bodies with chambers and respective separation disks placed in series from upstream to downstream within the external drum. Different sections of the drum can be suitably shaped and contain internal bodies and separation elements of different shape.
The second fluid B bath, which contains the dosage forms, moves from one chamber to another following the inclination of the drum under the effect of gravity, or by the injection of gases or liquids that can wash the entire inner surface of an emptying maturation chamber through the possible openings (
Depending on the shape of the internal body and the respective maturation chambers, the openings or grids 1310a with a defined diameter on the surface of the drum 1310 and/or the openings on the transmission hollow shaft allow for additional compounds to be added to the curing dosage forms inside the maturation chambers. For example, solutions of other polymers may be added to perform a coating, air or nitrogen can be blown to keep the maturation dosage forms in a stirred condition, and increasing the pressure in the maturation chamber by speeding up the transfer to the following one. Such openings can also be used to remove the second fluid B from the maturation chamber to allow its drying or the addition of other fluids.
According to a further aspect, one or more separation elements can be configured with a solid region having a series of holes in fluid communication with the outside of the drum. In such holes, it is possible to blow a gas to keep the polymeric curing forms in a stirred condition inside a closed chamber from the solid region of the separation element, or to add one or more liquids during maturation. A rotating internal body can also have openings that connect a shaft cavity with the maturation chambers for air insufflation or fluid circulation.
At the end of the path within the drum 310, the dosage forms will have completed their maturation period and can be harvested and treated as needed.
In a variant embodiment shown in
In the case of the production of floating systems, it is particularly useful to use rotating bodies with baffles and divisors with V-shaped openings, as shown in
According to further preferred embodiments, the external drum can be conical or conical frustum or have one or more conical or conical frustum sections. One or more internal bodies may also be conical or conical frustum, or be formed with one or more conical or conical frustum sections.
In a variant embodiment shown in
Between the first separation element 4311 and the outlet there may be further internal bodies, for example with a conical frustum shape and having the same orientation of the drum, and respective separation elements.
Preferably, the outlet 4310c is connected with an extraction device, constituted in the example by an Archimedean screwfeeder 4316 with an axial extension preferably forming an angle between 5 and 700 with respect to the longitudinal direction parallel to the axis of the drum. In the case of sinking dosage forms, these are transferred by gravity to the maturation chambers. The rotation of the last internal body determines the opening of the chamber outlet of one of the internal body chambers towards the outlet 4310c, and the subsequent transfer of Fluid B comprising the uncured dosage forms to the coil 4316, which allows its transfer to another site where dosage forms can be retrieved and/or treated as needed. The size and positioning of the rotating internal body allow a proper maturation of the dosage forms and a controlled filling of the coil that would otherwise be filled with fluid B to the same level of the maturation chamber due to the principle of communicating vessels.
It is eventually possible to apply the recirculation system 214 by generating a continuous stream of second fluid B which charges the exposed maturation chambers with dosage forms faster than by simple gravity fall.
A possible variant embodiment of the feeding group of first fluid A in form of droplets provides that the fluid is fed to a spray dispensing system capable of delivering the first Fluid A in the form of finely divided droplets. In this case, two-way atomizers 2071 or previously described atomizers 2072 with reference to
With reference to
It is possible to associate to said variant embodiment of group 2073 with a vent opening in pre-treatment chamber 206, so as to allow an optimum compensation of the pressure created in this pre-treatment chamber 206. It is possible to associate this vent opening with any pneumatic pump such as to blow and/or draw gas so as to generate negative or positive pressure in the pre-treatment chamber.
The reduction of the partial pressure of the gas/liquid interface favours the evaporation of fluid B, resulting in increased presence of fluid molecules B in the pre-treatment chamber. The use of negative pressure may be particularly advantageous in combination with the use of an aerosol-dispensed fluid in which volatile substances (e.g. ammonia or glutaraldehyde, in the case of chitosan as a gelling agent) are dissolved, to improve/accelerate the consolidation effect of the surface of each droplet dispensed by the dispensing unit 102. With ongoing reference to
A transport/dilution gas is introduced from a second duct 2074c, said gas being capable of spreading the droplets formed within the pre-treatment chamber 206 through a discharge duct 2074d which flows into the pre-treatment chamber 206.
The first duct is preferably connected to the containing chamber 208, but may also be connected to a different container from which the second fluid B to be fragmented into droplets is fed.
Any embodiment of a production unit of an aerosol of a suitable fluid in the pre-treatment chamber may be associated with the vent opening, possibly connected to any pneumatic pump so as to blow and/or draw gases to generate a negative or positive pressure in the pre-treatment chamber.
A skilled technician will be able to integrate in the same machine two or more of the different embodiments of the aerosol production group in the pre-treatment chamber described above, to provide a particularly heterogeneous aerosol or to provide a machine structure suitable for fluids of different nature. A skilled technician will also be able to provide means for switching the operation of the machine to exclude one or more of said different elements of the aerosol production group.
It is also apparent that, although the invention has been described with reference to an aerosolized fluid in the pre-treatment chamber corresponding to the second fluid B provided in the form of a bath in the formation chamber, or comprising the same crosslinking/polymerizing structuring substance, the invention is not limited in such a way, but it can also be implemented by providing, in the form of an aerosol, any suitable fluid capable of determining the desired superficial consolidation of the droplet passing through the pre-treatment chamber.
It is also within the reach of the technician to appropriately modulate the concentration of a structuring or reactant substance in the fluid to be dispensed in the form of an aerosol, and the viscosity of the latter, according to the desired degree and type of superficial consolidation to be obtained for the pre-dosage forms. Combining multiple processes into one machine is of particular relevance in the pharmaceutical and biological fields where, for example, there may be a need to operate in sterile conditions. The application of sterility protocols to a single machine is particularly advantageous. In addition, reducing the size of this machine results in the reduction of costs and the possibility to use it in biological or pharmaceutical research laboratories.
It is within the reach of the technician skilled in the art to determine the cycle and the execution times of the various phases, as well as the selection of the number of internal bodies and separation elements, the rotation rate of the same, as well as the opening/closing characteristics of the maturation chambers defined by the internal bodies and the features of the separation element openings.
Further configurations are possible wherein multiple drum groups are positioned in parallel, and are possibly connected to each other.
It is therefore apparent how the use of rotating internal bodies with multiple maturation chambers allows for the realization of a compact maturation device adaptable to the spaces available, with high production capacity even in continuous mode.
The use of a drum with side holes or grids allows the use of several production techniques in a single apparatus. For example, removal of the gelling bath and addition of further compounds or drying.
The different embodiments of internal bodies allow for an efficient production of dosage systems with different densities.
It is also apparent that a single maturation device can be provided in the form of a kit that can be assembled with a drum and various internal body configurations and separation disks, selectable from the kit according to the actual production needs and interchangeable according to changes in the dosage form format and/or the production process.
It is also apparent how the use of the screw pump in the first fluid A supply system allows the transfer of the dispersions whose dispersed phase is fragile or may be damaged by other transfer systems, while maintaining an optimum flow control.
The Archimedean screw type pump and the dispensing unit allow the delivery of fluids whose physical stability, intended as homogeneity and absence of sedimentation, is limited. This is the case, for example, of dispersed systems with high size (seeds) or high density (metals) that involve a quick separation of the phases.
The aerosol production system 207 provides a pre-form to the dosage forms. The pre-form stabilizes the dosage form with the consequent possibility of increasing the process speed, while synergistically ensuring more spherical form of the produced dosage forms and a reduced incidence of agglomeration of two or more dosage forms in formation. This is particularly effective when the aerosol 207 is used in combination with the electrostatic dripper 105 and a vibratory motion, so that well-rounded and separate droplets are obtained that maintain their spherical shape due to the pre-treatment with the aerosol.
The machine with supply/delivery and forming groups allows a greater hourly delivery of uncured dosage forms towards a maturation device.
The recirculating system 214 applied to any of the machine/device configurations allows a higher loading speed of the maturation chambers with a subsequent increased production speed.
It is also apparent how the maturation device of the invention in its multiple configurations, although described in relation to an application in which the first fluid is a polymeric fluid and the second fluid is a cationic fluid, is applicable to any production equipment of a chemical reaction product in the presence of a fluid, wherein it is necessary for said reaction to occur over a certain amount of time in order to execute a maturation process with the desired product characteristics (for example, radical polymerization or chitosan crosslinking with glutaraldehyde).
The subject matter of the description also includes a process for the formation of seamless polymeric dosage forms comprising the steps of
In such a process, said first fluid A and second fluid B can be selected between a fluid containing a structuring substance, preferably a polymeric fluid, and a fluid containing a polymerizing/crosslinking reagent of said structuring agent, preferably a cationic fluid, wherein the second fluid is a fluid containing a polymerizing/crosslinking reagent of the structuring substance of the first fluid if the latter is a fluid containing a structuring substance, and vice versa.
The process may preferably comprise the further steps of
The preferred characteristics of the maturation device and of a dosage form production machine described with reference to
For example, the feed characteristics of the first fluid to be dispensed described with reference to the exemplary machines of
Similarly to what has been described above, a second fluid B extracted from the maturation device can be recirculated to the forming chamber by means of a series of pipes connecting the maturation device to a liquid pump which is connected by another pipe to the containing chamber of the forming bath of the dosage forms.
The production of an aerosol in the pre-treatment chamber can be performed by means of one of the systems described above, such as a system for spraying or injecting a gas into the second fluid B bath contained in the forming chamber.
The first and/or second fluid may be selected from those previously listed in relation to the embodiments of the present invention.
This further described process can advantageously be implemented in continuous mode.
Although described in the context of some embodiments and some preferred examples of implementation of the invention, it is understood that the scope of protection of this patent is determined solely by the following claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 102016000083055 | Aug 2016 | IT | national |
| 102016000083078 | Aug 2016 | IT | national |
| 102016000083121 | Aug 2016 | IT | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IB2017/054782 | 8/4/2017 | WO | 00 |
| Publishing Document | Publishing Date | Country | Kind |
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| WO2018/025232 | 2/8/2018 | WO | A |
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| 20190184357 A1 | Jun 2019 | US |
