WO2006095372A1 - Process for producing polymeric membranes loaded with active ingredients - Google Patents

Process for producing polymeric membranes loaded with active ingredients Download PDF

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Publication number
WO2006095372A1
WO2006095372A1 PCT/IT2005/000642 IT2005000642W WO2006095372A1 WO 2006095372 A1 WO2006095372 A1 WO 2006095372A1 IT 2005000642 W IT2005000642 W IT 2005000642W WO 2006095372 A1 WO2006095372 A1 WO 2006095372A1
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solution
suspension
process according
supercritical
polymer
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PCT/IT2005/000642
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French (fr)
Inventor
Ernesto Reverchon
Stefano CARDÉA
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Universita' Degli Studi Di Salerno
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
    • B01D67/0002—Organic membrane manufacture
    • B01D67/0009—Organic membrane manufacture by phase separation, sol-gel transition, evaporation or solvent quenching
    • B01D67/0011—Casting solutions therefor
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
    • B01D67/0002—Organic membrane manufacture
    • B01D67/0009—Organic membrane manufacture by phase separation, sol-gel transition, evaporation or solvent quenching
    • B01D67/0016—Coagulation
    • B01D67/00165—Composition of the coagulation baths
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
    • B01D67/0002—Organic membrane manufacture
    • B01D67/0009—Organic membrane manufacture by phase separation, sol-gel transition, evaporation or solvent quenching
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
    • B01D67/0002—Organic membrane manufacture
    • B01D67/0009—Organic membrane manufacture by phase separation, sol-gel transition, evaporation or solvent quenching
    • B01D67/00091—Organic membrane manufacture by phase separation, sol-gel transition, evaporation or solvent quenching by evaporation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
    • B01D67/0002—Organic membrane manufacture
    • B01D67/0009—Organic membrane manufacture by phase separation, sol-gel transition, evaporation or solvent quenching
    • B01D67/0016—Coagulation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/08—Hollow fibre membranes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/14—Dynamic membranes
    • B01D69/141—Heterogeneous membranes, e.g. containing dispersed material; Mixed matrix membranes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/08—Polysaccharides
    • B01D71/12—Cellulose derivatives
    • B01D71/22—Cellulose ethers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/40—Polymers of unsaturated acids or derivatives thereof, e.g. salts, amides, imides, nitriles, anhydrides, esters
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/40—Polymers of unsaturated acids or derivatives thereof, e.g. salts, amides, imides, nitriles, anhydrides, esters
    • B01D71/401—Polymers based on the polymerisation of acrylic acid, e.g. polyacrylate
    • B01D71/4011—Polymethylmethacrylate
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/24—Formation of filaments, threads, or the like with a hollow structure; Spinnerette packs therefor
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/24—Formation of filaments, threads, or the like with a hollow structure; Spinnerette packs therefor
    • D01D5/247—Discontinuous hollow structure or microporous structure
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2323/00—Details relating to membrane preparation
    • B01D2323/08—Specific temperatures applied
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2323/00—Details relating to membrane preparation
    • B01D2323/10—Specific pressure applied
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2323/00—Details relating to membrane preparation
    • B01D2323/219—Specific solvent system
    • B01D2323/225—Use of supercritical fluids
    • B01J35/59—

Definitions

  • This invention is related to a process for the production of polymeric membranes loaded with active ingredients. More specifically, the invention concerns the production of membranes, i.e. porous structures, containing one or more active principles homogenously distributed inside the membrane, by means of a supercritical fluid assisted phase inversion process.
  • a membrane is a porous structure with open cells, wherein "open” means that the cells of the structure are interconnected.
  • Membranes are mostly formed by polymers or biopolymers and can contain one or more active ingredients (for example, pharmaceutical compounds) inside the structure.
  • the liquid-liquid phase inversion process is currently used for polymeric membranes preparation. This method is based on the interaction between a polymer solution and a liquid solvent that is a non-solvent for the polymer, whereas it is miscible with the solvent of the solution. The contact between the solvent and the non-solvent causes the formation of two phases, a polymer lean phase and a polymer rich phase. At the end of the process, a porous polymeric matrix characterized by open cells and a solvent plus non- solvent mixture are obtained.
  • a method to generate porous polymers containing a solute is dis- closed in the international patent application WO 03/064509.
  • a forced phase separation (coacervation) process is described: the polymer is solubilized in a solvent; then, a solute (insoluble in the solvent) is added to the solution until a stable suspension is formed.
  • a second liquid solvent, in which both the polymer and the solute particles are insoluble, is added to the sus- pension.
  • the mixture is vigorously stirred and the polymer precipitates with the solute encapsulated inside.
  • the polymer is reduced to granules and dried.
  • the product obtained has to be treated in turn with a leaching process (to obtain porous granules) or with a melting extrusion process to obtain porous structures (starting from the particles obtained in the previous steps of the process).
  • a supercritical fluid is characterized by a density and a solvent power similar to the one of liquids and a diffusivity similar to gases. Moreover, these characteristics can be easily modulated by changing pressure and temperature.
  • Dense gas phase inversion is described in the patent US 5422377.
  • the authors disclose a process for producing microporous polymeric films, not loaded with a solute, in which a dense gas is used. During the process, two phases are formed.
  • a supercritical fluid-assisted phase inversion continuous process for obtaining hollow fiber is described in the Italian patent application RM2004 A000193.
  • the process includes the following steps: a solution formed by one or more polymers and one or more solvents is introduced in an extruder and extruded as a hollow fiber; this fiber falls in a pressurized coagulation bath placed after the extruder, wherein one or more supercritical fluids are flowing.
  • the supercritical fluids cause the phase separation, generating the hollow fiber membrane.
  • An attempt to use a supercritical fluid as antisolvent to obtain the encapsulation of drugs in polymer particles is described in the international patent application WO 2004/091571. The authors present a method to generate polymer particles loaded with nanoparticles of solute.
  • SC-CO2 supercritical CO 2
  • SC-CO2 supercritical CO 2
  • the suspension contacts SC-CO 2 , that extracts the solvent and induces polymer precipitation on the active principles, thus obtaining microcapsules.
  • an object of the present invention is to propose an innovative process assisted by supercritical fluids that allows to obtain both the above- mentioned results.
  • the first step is related to the preparation of the polymer solution, that can contain one or more polymers, as for example polymethyl-methacrilate, ethylcellulose, cellulose acetate, poly-L-lactide, poly- vinyl-alcohol, polysulfone, polyethylene glycol, polycaprolactone, dextran, chitosan, inulin, polyvinylidene fluoride, polyvinyl pyrrolidone, polyethersul- fone, polycarbonate, polyacrylonitrile, polyamide, polyimide, polyethylene, polyether imide, and one or more solvents, such as acetone, dichloromethane, dimethylsulfoxide, chloroform, N-methyl-2-pyrrolidone, dichloroethane, diox- ane, trichloroethane, dichloromethane,
  • solvents such as acetone, dichloromethane, dimethylsulfoxide, chloroform, N-methyl-2-pyrroli
  • the polymer (or polymers) used in the process according to the invention have to be soluble in the solvent or in the mixture of solvents.
  • the polymer concentration the in the solution can vary from 1% to 60% w/w.
  • the process conditions that cause the phase inversion of the solution (or suspension) by SC-CO2, while maintaining the active ingredients inside the structure, are also an object of the present invention. Indeed, in some process conditions the SC-CO2 can have affinity for the solvent but not for the polymer and the active ingredient and, as a consequence, the active ingredient is encapsulated inside the porous structure.
  • the first step of the process according to the invention is the prepara- tion of a solution or suspension formed by one or more liquid solvents, by one or more polymers and by one or more active ingredients.
  • Two cases are possible: in the first case, the active ingredient is soluble in the solvent (or in the mixture of solvents); therefore, a homogeneous solution with three components is formed; in the second case an insoluble active ingredient is used and a suspension of the active ingredient in the polymeric solution is formed.
  • the present invention specifically provides, according to one aspect thereof, a semi-batch process for producing porous polymer flat structures with open cells (membranes) loaded with one or more active ingredients by means of a supercritical CO 2 -assisted phase inversion process, which process comprises contacting supercritical CO2 with a solution, or suspension, formed by one or more polymers, one or more solvents and one or more active ingredients, thereby forming two phases: a polymer-rich phase, from which the membrane is formed, and a polymer-lean phase, from which the cells are formed; then, once a phase separation is obtained, feeding a flow of further CO 2 through the vessel thus eliminating the solvent, or solvents, from the membrane.
  • a supercritical CO 2 -assisted phase inversion process which process comprises contacting supercritical CO2 with a solution, or suspension, formed by one or more polymers, one or more solvents and one or more active ingredients, thereby forming two phases: a polymer-rich phase, from which the membrane is formed, and a polymer-
  • the solution (or suspension) is placed in a tank that is pressurized by CO 2 .
  • Pressure can range from 60 to 300 bar and temperature can range from 25°C to 75°C, although the upper temperature limit depends on the degradation temperature of the active ingredient.
  • the total time required for membrane production can range from 8 minutes to 5 hours.
  • the semi-batch process can be performed using two modes.
  • the first mode consists of three steps:
  • the present invention specifically provides a continuous process for producing porous polymer hollow structures with open cells (membranes) loaded with one or more active ingredients by means of a supercritical CO 2 -assisted phase inversion process, which process comprises extruding a solution, or suspension, formed by one or more polymers, one or more solvents and one or more active ingredients while feeding supercritical CO 2 inside the extruder, thereby obtaining a phase separation and an initial solidification of the membrane, with the formation of a hollow structure bore; then completing the membrane formation and solidification by contacting the extruded hollow structure with a pressurized coagulation bath containing supercritical CO 2 .
  • a hollow fiber membrane is obtained by melt spinning the solution (or suspension) through an annular orifice; the head of the extruder is connected with a coagulation bath in which the supercritical fluid flows.
  • the process consists of two steps:
  • the supercritical CO 2 can also be added inside the extruder, where a partial phase separation (partial solidification) is caused and the bore of the hollow fiber is formed.
  • a partial phase separation partial solidification
  • the supercritical fluid allows to complete the phase separation with solidification of membrane.
  • SC-CO 2 substitutes the organic solvent used in the traditional techniques and allows to complete the process in a shorter time and without post-treatments.
  • the continuous process needs the control of a larger number of parameters: temperature, pressure in the extruder and in the coagulation bath, the CO 2 /polymer solution ratio in the extruder, the fiber speed in the extruder and the residence time of the fiber inside the coagulation bath (leaching time).
  • the temperature can range from 30 0 C to 85 0 C in the extruder, and from 35 0 C to 8O 0 C inside the coagulation bath;
  • the pressure can range from 80 to 350 bar in the extruder, and from 60 to 350 bar in the coagulation bath;
  • the CO 2 /solution (or suspension) ratio can range from 1 to 100 and the fiber speed can range from 10 g/h to 1000 g/h, with a leaching time ranging from 5 minutes to 1 hour.
  • the overall time of the process can vary from 5 min to 5 h; it depends on the modality of process, on the starting mixture, on the working conditions and on the affinity between supercritical CO 2 and the solvent (or mixture of solvents).
  • a polymer membrane loaded with active principles is obtained; the morphology and the mean cell dimension of the membrane depends on the working conditions and can be continuously modulated.
  • the active ingredient is encapsulated in the polymer matrix (when it is soluble in the solvent) or homogenously distributed inside the porous structure as microparticles (when it is insoluble).
  • the proposed process ins employed to produce porous membranes loaded with a catalyst, or one or more pharmaceutically active ingredients, or a dye, or an amino acid or a protein, such as an enzyme.
  • the concerned solution or suspension may contain an amount of solvent(s) between 40% and 99% w/w, an amount of polymer(s) between 1% and 60% w/w and an amount of active ingredient(s) between 1% and 50% w/w.
  • the suspension is prepared using dimethylsulfoxide (DMSO) as sol- vent, in which only PMMA is soluble.
  • the starting solution is prepared with a PMMA content ranging from 10 to 50% w/w in DMSO (preferably from 20 to 30% w/w).
  • DMSO dimethylsulfoxide
  • an amount of amoxicillin from 5 to 50% w/w with respect to the amount of polymer is suspended.
  • This suspension is placed in a tank and put in contact with SC-CO 2 at a temperature between 30 0 C and 6O 0 C and at a pressure between 100 and 300 bar, for a time between 45 and 180 minutes.
  • a PMMA membrane loaded with amoxicillin is obtained; the mean cell diameter ranging between 3 and 60 ⁇ m.
  • the particles of amoxicillin are homogenously distributed inside the polymeric matrix as can be observed from the enclosed Figure 1 , obtained by a scanning electronic microscope (SEM).
  • EXAMPLE 2 Formation of ethylcellulose hollow fiber membrane loaded with diclofenac sodium (an anti-inflammatory drug).
  • a suspension of drug particles in the polymeric solution is formed.
  • the amount of polymer can range from 5 to 40% w/w in chloroform, (preferably between 14 to 28% w/w).
  • an amount of drug between 10 to 50% w/w with respect to the mass of polymer is suspended.
  • the suspension is loaded inside an extruder, extruded at temperatures between 35°C and 65 0 C and at pressures between 80 and 250 bar, with extrusion speeds between 100 and 500 g/h and with a CO 2 /suspension mass ratio between 10 and 80.
  • the fiber enters in a SC-CO 2 coagulation bath, characterized by a pressure ranging between 100 and 230 bar and a temperature between 4O 0 C and 60°C; the leaching time ranges between 30 and 55 minutes.
  • An ethylcellulose hollow fiber membrane with a mean diameter between 0.8 and 50 ⁇ m is obtained.
  • the drug particles are homogenously distributed inside the membrane.
  • EXAMPLE 3 Formation of a flat membrane formed by two polymers, poly-L- lactide (PLLA) and polyethylene glycol (PEG), loaded with flurbiprofen (anti- inflammatory drug).
  • PLLA poly-L- lactide
  • PEG polyethylene glycol
  • polymers and drug are soluble in the solvent used, i.e. dichloromethane (DCM).
  • DCM dichloromethane
  • the solution is prepared with an amount of solvent between 40 and 90% w/w (preferably between 65 and 85% w/w); the remaining part is formed by PLLA (between 50 and 90% w/w), PEG (between 5 and 20% w/w) and flurbiprofen (between 5 and 30% w/w).
  • the working temperature can range from 35 0 C to 70 0 C, the pressure between 100 and 250 bar and time between 25 and 150 minutes.
  • a flat membrane with mean cell diameter between 10 and 100 ⁇ m is obtained with the drug loaded inside.

Abstract

A process for obtaining membranes loaded with one or more active ingredients, consisting of contacting a solution, or suspension, formed by one or more solvents, one or more polymers and one or more active ingredients with supercritical carbon dioxide (SC-CO2). SC-CO2, at suitable process conditions, has a high affinity for organic solvents; therefore, a supercritical fluid solution is formed and a continuous solid structure precipitates. The latter is characterized by interconnected cells (membrane) loaded with the active ingredient initially present in the solution (or suspension). The described process is extremely versatile and allows to obtain membranes with different morphologies, as well as to control the mean cell diameter and porosity.

Description

PROCESS FOR PRODUCING POLYMERIC MEMBRANES LOADED WITH
ACTIVE INGREDIENTS
SPECIFICATION
This invention is related to a process for the production of polymeric membranes loaded with active ingredients. More specifically, the invention concerns the production of membranes, i.e. porous structures, containing one or more active principles homogenously distributed inside the membrane, by means of a supercritical fluid assisted phase inversion process.
As it is known, a membrane is a porous structure with open cells, wherein "open" means that the cells of the structure are interconnected. Membranes are mostly formed by polymers or biopolymers and can contain one or more active ingredients (for example, pharmaceutical compounds) inside the structure.
The liquid-liquid phase inversion process is currently used for polymeric membranes preparation. This method is based on the interaction between a polymer solution and a liquid solvent that is a non-solvent for the polymer, whereas it is miscible with the solvent of the solution. The contact between the solvent and the non-solvent causes the formation of two phases, a polymer lean phase and a polymer rich phase. At the end of the process, a porous polymeric matrix characterized by open cells and a solvent plus non- solvent mixture are obtained.
A method to generate porous polymers containing a solute is dis- closed in the international patent application WO 03/064509. In this document, a forced phase separation (coacervation) process is described: the polymer is solubilized in a solvent; then, a solute (insoluble in the solvent) is added to the solution until a stable suspension is formed. A second liquid solvent, in which both the polymer and the solute particles are insoluble, is added to the sus- pension. The mixture is vigorously stirred and the polymer precipitates with the solute encapsulated inside. Subsequently, the polymer is reduced to granules and dried. The product obtained has to be treated in turn with a leaching process (to obtain porous granules) or with a melting extrusion process to obtain porous structures (starting from the particles obtained in the previous steps of the process).
A similar application is described in the international patent application WO 03/053325. The process can be divided in two steps: a first step in which the polymer solution containing the solute (not soluble in the solvent) is prepared; a second step consisting in the injection of the previously obtained suspension by a syringe in a non-solvent bath (water) having affinity for the solvent. By operating in this manner, porous polymeric particles are formed in which the solute is encapsulated. Both documents mentioned above allow to obtain porous particles containing solute inclusions, but continuous membranes are not obtained in any case.
An example of continuous membranes containing one or more solutes and obtained by a liquid-liquid phase inversion process is reported in the pat- ent application WO 2004/003268. The process described is continuous: a polymer solution formed by one or more polymers with one or more active ingredients suspended inside is extruded, and the liquid phase inversion is induced in the extruder (partially) and in a coagulation bath located downstream the extruder. The authors describe different phase inversion tech- niques: by temperature increase, by evaporation of the solvent from the solution or by means of a liquid non-solvent (for example, water). The tubular membrane obtained presents interconnected cells and contains the active ingredients.
To generate porous polymers, it is also possible to use dense gases or supercritical fluids as non-solvents. A supercritical fluid is characterized by a density and a solvent power similar to the one of liquids and a diffusivity similar to gases. Moreover, these characteristics can be easily modulated by changing pressure and temperature.
For example, in the US patent application US 04/0080070 a process for the formation of porous polymers by means of supercritical fluids is described. In this case, the polymer is placed in a tank, the system is pressurized with a supercritical fluid for a given period of time and then the system is depressurized. A foaming process is obtained, in that the polymer presents a porous structure with closed cells (not interconnected). The limit of this kind of process is the difficulty in obtaining open cell structures (membranes). Moreover, the temperature of the polymer-supercritical fluid system has to be higher than the glass transition temperature of the polymer during the depressuriza- tion step.
Dense gas phase inversion is described in the patent US 5422377. The authors disclose a process for producing microporous polymeric films, not loaded with a solute, in which a dense gas is used. During the process, two phases are formed. Another patent document, i.e. patent application US 03/0064156, presents a similar process. In this case, the authors use a phase inversion batch process assisted by a supercritical fluid. This process is performed in three steps: first, the polymer solution is placed in a tank; second, the supercritical fluid is added, causing the phase separation and the elimina- tion of the solvent from the solution; third, the system is depressurised and the mixture of solvent and supercritical fluid is removed.
A supercritical fluid-assisted phase inversion continuous process for obtaining hollow fiber is described in the Italian patent application RM2004 A000193. The process includes the following steps: a solution formed by one or more polymers and one or more solvents is introduced in an extruder and extruded as a hollow fiber; this fiber falls in a pressurized coagulation bath placed after the extruder, wherein one or more supercritical fluids are flowing. The supercritical fluids cause the phase separation, generating the hollow fiber membrane. An attempt to use a supercritical fluid as antisolvent to obtain the encapsulation of drugs in polymer particles is described in the international patent application WO 2004/091571. The authors present a method to generate polymer particles loaded with nanoparticles of solute. In this case, SC-CO2 (supercritical CO2) contacts the solution and causes the precipitation of both the solute and the drug, generating solute nanoparticles coated with polymers. Another example of this process is reported in patent US 6183783: in this case the authors propose a supercritical coacervation process. After the preparation of the polymeric solution with the active principle in suspension, the suspension contacts SC-CO2, that extracts the solvent and induces polymer precipitation on the active principles, thus obtaining microcapsules.
The above patent documents, related to the loading of polymers with active ingredients by means of supercritical fluids, do not disclose the production of continuous structures (such as membranes), but only the production of loaded micro- or nanoparticles.
Analysing the previous patents, it is evident the difficulty in generating continuous polymeric structures with open cells (that is, membranes) that contain active principles. Indeed, the methods described in the patents mainly produce porous particles containing active ingredients and, in any case, are based on liquid solvents and non-solvents. On the other hand, the use of dense gases or supercritical fluids allows to obtain foams (US 04/0080070) or porous structures (US 5422377, US 03/0064156, RM2004 A000193) consist- ing of the polymer only, or else microporous particles encapsulating the active ingredient (WO 2004/091571 , US 6183783).
The difficulty in controlling, at the same time, the supercritical fluid- assisted phase inversion process and the simultaneous encapsulation of active ingredients did not allow, to date, to obtain the two results at the same time. Therefore, an object of the present invention is to propose an innovative process assisted by supercritical fluids that allows to obtain both the above- mentioned results.
In the present invention, an innovative process to obtain polymeric membranes loaded with one or more active ingredients (for example a drug or a catalyst) is described. The first step is related to the preparation of the polymer solution, that can contain one or more polymers, as for example polymethyl-methacrilate, ethylcellulose, cellulose acetate, poly-L-lactide, poly- vinyl-alcohol, polysulfone, polyethylene glycol, polycaprolactone, dextran, chitosan, inulin, polyvinylidene fluoride, polyvinyl pyrrolidone, polyethersul- fone, polycarbonate, polyacrylonitrile, polyamide, polyimide, polyethylene, polyether imide, and one or more solvents, such as acetone, dichloromethane, dimethylsulfoxide, chloroform, N-methyl-2-pyrrolidone, dichloroethane, diox- ane, trichloroethane, dichloromethane, tetrahydrofuran, methanol, propanol, ethanol.
The polymer (or polymers) used in the process according to the invention have to be soluble in the solvent or in the mixture of solvents. The polymer concentration the in the solution can vary from 1% to 60% w/w. Once a homogenous solution is obtained, the active ingredient is added until a solution, or a stable suspension, is obtained.
The process conditions that cause the phase inversion of the solution (or suspension) by SC-CO2, while maintaining the active ingredients inside the structure, are also an object of the present invention. Indeed, in some process conditions the SC-CO2 can have affinity for the solvent but not for the polymer and the active ingredient and, as a consequence, the active ingredient is encapsulated inside the porous structure.
The first step of the process according to the invention is the prepara- tion of a solution or suspension formed by one or more liquid solvents, by one or more polymers and by one or more active ingredients. Two cases are possible: in the first case, the active ingredient is soluble in the solvent (or in the mixture of solvents); therefore, a homogeneous solution with three components is formed; in the second case an insoluble active ingredient is used and a suspension of the active ingredient in the polymeric solution is formed.
It is also possible to perform the process in two modes: semi-batch mode (with the aim of obtaining loaded flat membranes) and continuous mode (with the aim of obtaining loaded hollow fiber membranes).
Therefore, the present invention specifically provides, according to one aspect thereof, a semi-batch process for producing porous polymer flat structures with open cells (membranes) loaded with one or more active ingredients by means of a supercritical CO2-assisted phase inversion process, which process comprises contacting supercritical CO2 with a solution, or suspension, formed by one or more polymers, one or more solvents and one or more active ingredients, thereby forming two phases: a polymer-rich phase, from which the membrane is formed, and a polymer-lean phase, from which the cells are formed; then, once a phase separation is obtained, feeding a flow of further CO2 through the vessel thus eliminating the solvent, or solvents, from the membrane.
In the semi-batch process, the solution (or suspension) is placed in a tank that is pressurized by CO2. Pressure can range from 60 to 300 bar and temperature can range from 25°C to 75°C, although the upper temperature limit depends on the degradation temperature of the active ingredient. The total time required for membrane production can range from 8 minutes to 5 hours.
The semi-batch process can be performed using two modes. The first mode consists of three steps:
1) a batch step, in which SC-CO2 diffuses in the solution and causes the phase inversion - at the working conditions, SC-CO2 shows affinity with the solvent (or with the mixture of solvents); two phases are formed: a polymer-rich phase, from which the membrane is formed, and a poly- mer-lean phase, that generates the cells;
2) a continuous step, during which SC-CO2 flows trough the tank and eliminates the solvent (or solvents) of the solution (or suspension);
3) a final step, in which the tank is depressurised, which allows to remove CO2 and possible solvent traces from the polymer matrix. The second mode of semi-batch processing consists of two steps:
1) a continuous step, during which SC-CO2 flows through the vessel and diffuses in the solution (or suspension) causing the phase separation;
2) a depressurization step, in which the tank is depressurised, which allows to remove CO2 and possible solvent traces from the polymer ma- trix.
According to a second aspect thereof, the present invention specifically provides a continuous process for producing porous polymer hollow structures with open cells (membranes) loaded with one or more active ingredients by means of a supercritical CO2-assisted phase inversion process, which process comprises extruding a solution, or suspension, formed by one or more polymers, one or more solvents and one or more active ingredients while feeding supercritical CO2 inside the extruder, thereby obtaining a phase separation and an initial solidification of the membrane, with the formation of a hollow structure bore; then completing the membrane formation and solidification by contacting the extruded hollow structure with a pressurized coagulation bath containing supercritical CO2. In the continuous process, a hollow fiber membrane is obtained by melt spinning the solution (or suspension) through an annular orifice; the head of the extruder is connected with a coagulation bath in which the supercritical fluid flows. The process consists of two steps:
1) solution (or suspension) extrusion, in which SC-CO2 can be coextruded as internal bore fluid);
2) coagulation in a pressurized bath containing SC-CO2.
The supercritical CO2 can also be added inside the extruder, where a partial phase separation (partial solidification) is caused and the bore of the hollow fiber is formed. In the coagulation bath the supercritical fluid allows to complete the phase separation with solidification of membrane. In the extruder and in the coagulation bath, SC-CO2 substitutes the organic solvent used in the traditional techniques and allows to complete the process in a shorter time and without post-treatments.
With respect to semi-batch processes, the continuous process needs the control of a larger number of parameters: temperature, pressure in the extruder and in the coagulation bath, the CO2/polymer solution ratio in the extruder, the fiber speed in the extruder and the residence time of the fiber inside the coagulation bath (leaching time). In particular, the temperature can range from 300C to 850C in the extruder, and from 350C to 8O0C inside the coagulation bath; the pressure can range from 80 to 350 bar in the extruder, and from 60 to 350 bar in the coagulation bath; the CO2/solution (or suspension) ratio can range from 1 to 100 and the fiber speed can range from 10 g/h to 1000 g/h, with a leaching time ranging from 5 minutes to 1 hour.
The overall time of the process can vary from 5 min to 5 h; it depends on the modality of process, on the starting mixture, on the working conditions and on the affinity between supercritical CO2 and the solvent (or mixture of solvents). A polymer membrane loaded with active principles is obtained; the morphology and the mean cell dimension of the membrane depends on the working conditions and can be continuously modulated. The active ingredient is encapsulated in the polymer matrix (when it is soluble in the solvent) or homogenously distributed inside the porous structure as microparticles (when it is insoluble).
According to some specific embodiments thereof, the proposed process ins employed to produce porous membranes loaded with a catalyst, or one or more pharmaceutically active ingredients, or a dye, or an amino acid or a protein, such as an enzyme. The concerned solution or suspension may contain an amount of solvent(s) between 40% and 99% w/w, an amount of polymer(s) between 1% and 60% w/w and an amount of active ingredient(s) between 1% and 50% w/w.
With respect to the conventional encapsulation processes, the SC- Cθ2-assisted phase inversion process according to the invention presents various advantages:
1) membranes can be obtained without additional post-treatments, because there are no solvent residues;
2) it is easy to recover the liquid solvent; it is dissolved in supercritical CO2 and can be removed from gaseous CO2 in a separator located downstream the membrane formation vessel;
3) the high versatility of SC-CO2 allows to modulate the morphology and the cell size of the membrane, by changing the operative conditions;
4) CO2 is not toxic, not flammable and cheap. The specific features of the invention, as well as the advantages thereof and its operating mode, will be more evident with reference to the detailed description shown below by way of examples, together with some experimental results obtained by carrying out the invention. One of said experimental results is also illustrated in the enclosed drawings, wherein: Figure 1 shows a scanning electron microscope (SEM) image of a polymethyl methacrylate (PMMA) membrane loaded with amoxicillin obtained by the process according to the invention, in accordance with Example 1. EXAMPLE 1 - Generation of a polymethyl methacrilate (PMMA) flat membrane loaded with amoxicillin (an antibiotic).
The suspension is prepared using dimethylsulfoxide (DMSO) as sol- vent, in which only PMMA is soluble. The starting solution is prepared with a PMMA content ranging from 10 to 50% w/w in DMSO (preferably from 20 to 30% w/w). In this solution, an amount of amoxicillin from 5 to 50% w/w with respect to the amount of polymer is suspended. This suspension is placed in a tank and put in contact with SC-CO2 at a temperature between 300C and 6O0C and at a pressure between 100 and 300 bar, for a time between 45 and 180 minutes.
At the end of the process, a PMMA membrane loaded with amoxicillin is obtained; the mean cell diameter ranging between 3 and 60 μm. The particles of amoxicillin are homogenously distributed inside the polymeric matrix as can be observed from the enclosed Figure 1 , obtained by a scanning electronic microscope (SEM).
EXAMPLE 2 - Formation of ethylcellulose hollow fiber membrane loaded with diclofenac sodium (an anti-inflammatory drug). In this case, a suspension of drug particles in the polymeric solution is formed. The amount of polymer can range from 5 to 40% w/w in chloroform, (preferably between 14 to 28% w/w). In this solution an amount of drug between 10 to 50% w/w with respect to the mass of polymer is suspended. The suspension is loaded inside an extruder, extruded at temperatures between 35°C and 650C and at pressures between 80 and 250 bar, with extrusion speeds between 100 and 500 g/h and with a CO2/suspension mass ratio between 10 and 80.
Once extruded, the fiber enters in a SC-CO2 coagulation bath, characterized by a pressure ranging between 100 and 230 bar and a temperature between 4O0C and 60°C; the leaching time ranges between 30 and 55 minutes. An ethylcellulose hollow fiber membrane with a mean diameter between 0.8 and 50 μm is obtained. The drug particles are homogenously distributed inside the membrane.
EXAMPLE 3 - Formation of a flat membrane formed by two polymers, poly-L- lactide (PLLA) and polyethylene glycol (PEG), loaded with flurbiprofen (anti- inflammatory drug).
In this case, polymers and drug are soluble in the solvent used, i.e. dichloromethane (DCM). The solution is prepared with an amount of solvent between 40 and 90% w/w (preferably between 65 and 85% w/w); the remaining part is formed by PLLA (between 50 and 90% w/w), PEG (between 5 and 20% w/w) and flurbiprofen (between 5 and 30% w/w). The working temperature can range from 350C to 700C, the pressure between 100 and 250 bar and time between 25 and 150 minutes.
A flat membrane with mean cell diameter between 10 and 100 μm is obtained with the drug loaded inside.
The present invention has been disclosed with particular reference to some specific embodiments thereof, but it should be understood that modifications and changes may be made by the persons skilled in the art without departing from the scope of the invention as defined in the appended claims.

Claims

1. A semi-batch process for producing porous polymer flat structures with open cells (membranes) loaded with one or more active ingredients by means of a supercritical CO2-assisted phase inversion process, which process comprises contacting supercritical CO2 with a solution, or suspension, formed by one or more polymers, one or more solvents and one or more active ingredients, thereby forming two phases: a polymer-rich phase, from which the membrane is formed, and a polymer-lean phase, from which the cells are formed; then, once a phase separation is obtained, feeding a flow of further CO2 through the vessel thus eliminating the solvent, or solvents, from the membrane.
2. A continuous process for producing porous polymer hollow structures with open cells (membranes) loaded with one or more active ingredients by means of a supercritical CO2-assisted phase inversion process, which process comprises extruding a solution, or suspension, formed by one or more polymers, one or more solvents and one or more active ingredients while feeding supercritical CO2 inside the extruder, thereby obtaining a phase separation and an initial solidification of the membrane, with the formation of a hollow structure bore; then completing the membrane formation and solidification by contacting the extruded hollow structure with a pressurized coagulation bath containing supercritical CO2.
3. A process according to claim 1 , wherein flat membranes with mean cell diameters ranging from 0.1 to 300 μm are obtained at working conditions between 25°C and 700C of temperature, 60 and 300 bar of pressure, and for a total production time from 8 minutes to 5 hours.
4. A process according to claim 2, wherein hollow fiber membranes with mean cell diameters ranging from 0.01 to 100 μm are obtained at working conditions between 300C and 85°C of temperature, 80 and 350 bar of pres- sure inside the extruder, and between 300C and 8O0C of temperature, 60 and 350 bar of pressure in the coagulation bath, for a leaching time from 5 minutes to 1 hour, with an extrusion speed comprised between 10 and 1000 g/h, and with a supercritical C02/solution (or suspension) ratio comprised between 1 and 100.
5. A process according to any one of claims 1-4, wherein said one or more solvents used in the solution, or suspension, are chosen from the group consisting of: acetone, dichloromethane, dimethylsulfoxide, chloroform, N- methylpyrrolidone, dichloroethane, dioxane, trichloroethane, tetraidrofuran, methanol, propanol, ethanol.
6. A process according to any one of claims 1-5, wherein said one or more polymers used in the solution, or suspension, are chosen from the group consisting of: polymethyl methacrylate, ethylcellulose, cellulose acetate, poly- L-lactide, polyvinyl alcohol, polysulfone, polyethylene glycol, polycaprolactone, dextran, chitosan, inulin, polyvinilidene fluoride, polyvinylpyrrolidone, polyeth- ersulfone, polycarbonate, polyacrilonitrile, polyamide, polyimide, polyethylene, polyether imide.
7. A process according to any one of claims 1-6, wherein said one or more active ingredient used in the solution, or suspension, preparation is a catalyst.
8. A process according to any one of claims 1-6, wherein said one or more active ingredient used in the solution, or suspension, preparation is a drug.
9. A process according to any one of claims 1-6, wherein said one or more active ingredient used in the solution, or suspension, preparation is a dye.
10. A process according to any one of claims 1-6, wherein said one or more active ingredient used in the solution, or suspension, preparation is a protein or an amino acid.
11. A process according to any one of claims 1-10, wherein said solution, or suspension, contains an amount of solvent between 40% and 99% w/w.
12. A process according to any one of claims 1-11 , wherein said solution, or suspension, contains an amount of polymer between 1% and 60% w/w.
13. A process according to any one of claims 1-12, wherein said solution, or suspension, contains an amount of active ingredient between 1% and 50% w/w.
PCT/IT2005/000642 2005-03-10 2005-11-04 Process for producing polymeric membranes loaded with active ingredients WO2006095372A1 (en)

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ITVI20130285A1 (en) * 2013-11-28 2015-05-29 Lucia Baldino PROCEDURE FOR THE PRODUCTION OF POROUS MEMBRANES LOADED WITH ANTIMICROBIAL PRINCIPLES
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