Procedure for the purification of biodegradable thermoplastic polymeric particles for medical and/or pharmaceutical use

Abstract

Procedure for the purification of biodegradable thermoplastic polymer particles for medical and/or pharmaceutical use without the use of organic solvents, as well as the particles obtained themselves, and the use of polymeric particles obtained by this procedure to manufacture parenteral administered medicinal products and/or implantable medical devices.

Claims

1-25. (canceled)

26. A solvent-free process for removing extrinsic particles from preformed powdered biodegradable thermoplastic polymer, the process comprising the steps of a) providing powdered biodegradable thermoplastic polymer comprising said extrinsic particles; b) heating said powdered polymer to a temperature that is not more than about 5.5° C. above its melting temperature (Tm) to form molten polymer; c) filtering the molten polymer through at least one filter having a pore size of about 5-300 μm; d) cooling the extruded polymer by means of a sterile gas stream to a temperature at least 4.5-5.5° C. below the glass transition temperature (Tg) of the biodegradable thermoplastic polymer; and e) comminuting the cooled polymer to form purified powdered biodegradable thermoplastic polymer free from visible extrinsic particles of a size greater than greater than 150 μm.

27. A purified powdered biodegradable thermoplastic polymer made according to the process of claim 26.

28. A purified powdered biodegradable thermoplastic polymer free from visible extrinsic particles of a size greater than greater than 150 μm.

29. The purified polymer of claim 28, wherein preformed powdered biodegradable thermoplastic polymer has undergone solvent-free melt extrusion/filtration through at least one filter having a pore size of about 5-300 μm to form filtered polymer, wherein the melt extrusion/filtration is conducted at a temperature that is not more than about 5.5° C. above the melting temperature (Tm), and wherein the filtered polymer has been cooled with an inert gas to a temperature of at least 4.5-5.5° C. below the glass transition temperature (Tg) of the polymer.

30. The purified polymer of claim 29, wherein a) the preformed polymer has not been dissolved in solvent during the purification step; b) the purified powdered biodegradable thermoplastic polymer has been sterilized by exposure to beta radiation; and/or c) the purified powdered biodegradable thermoplastic polymer has been comminuted to an average particle size in the millimeter range, micron range, or nanometer range.

31. The purified polymer of claim 30, wherein a) the purified polymer comprises microparticles comprising PLGA or PLA; b) the purified polymer comprises microparticles having a particle size distribution define as D10: in the range of 25-55 μm, D50: in the range of 120-170 μm, and D90: in the range of 300-375 μm; c) the purified polymer comprises biodegradable thermoplastic polymer; d) the purified polymer has a bulk density of 0.10 to 9.0 g/cm.sup.3; d) the purified polymer has a compacted density of 0.13 to 12.0 g/cm.sup.3; e) the purified polymer has a residual solvent quantity of not more than 0.00%, in particular not more than 0.000%; f) the purified polymer has a pyrogenic load below 1 EU/mg; g) the purified polymer has a microbial load below 300 U.F.C/mg; h) the purified polymer has a particle size distribution of D10 in the range of 25-55 μm, D50 in the range of 120-170 μm, and D90 in the range of 300-375 μm; and/or i) the purified polymer is sterile.

32. A pharmaceutical composition comprising at least one drug, at least one pharmaceutically acceptable excipient, and purified polymer according to claim 27.

33. A dosage form comprising the pharmaceutical composition of claim 32.

34. A medical device comprising the purified polymer according to claim 27.

35. A method of treating a disease, disorder or condition, the method comprising administering to a subject in need thereof one or more doses of the pharmaceutical composition according to claim 32.

36. A method of treating a disease, disorder or condition, the method comprising administering to or implanting in a subject in need thereof one or more medical devices according to claim 34.

37. A pharmaceutical composition comprising at least one drug, at least one pharmaceutically acceptable excipient, and purified polymer according to claim 28.

38. A method of treating a disease, disorder or condition, the method comprising administering to a subject in need thereof one or more doses of the pharmaceutical composition according to claim 37.

39. A medical device comprising the purified polymer according to claim 28.

40. A method of treating a disease, disorder or condition, the method comprising administering to or implanting in a subject in need thereof one or more medical devices according to claim 39.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0058] FIG. 1 depicts a diagram that represents the solidification and cooling process of non-crystalline and partially crystalline thermoplastic polymers with specific volume change with temperature. FIG. 1 shows that there is a decrease in the specific volume with the decrease in temperature that presents a change of slope at a characteristic temperature of the material that is called the glass transition temperature, Tg, above which the polymer exhibits a viscous behavior (rubbery, elastic) and below which the polymer exhibits a brittle glass behavior.

[0059] FIG. 2 depicts a photograph taken with a dry binocular microscope, of a sample of Lactel® particles (Durect® PLGA) as received from the supplier for the beginning of the procedure object of the present invention. This image shows the presence of cellulose fibers in all polymer particles.

[0060] FIG. 3 depicts a photograph taken with a binocular microscope, of a sample of Lactel® particles (Durect's® PLGA) subjected to dissolution in an acetone solution. This image shows the presence of fibers or extrinsic particles in the solution.

[0061] FIG. 4 depicts an IR spectrophotometric image of the nature of the extrinsic particles obtained after the solution of Durect's® PLGA that were in suspension. It was determined that the extrinsic particles are mostly cellulose and polyester.

[0062] FIG. 5 depicts particles obtained after the process of the present invention with a degree of purity of at least 95% with respect to the starting polymeric particles. As can be clearly seen, there is no extrinsic particle.

[0063] FIG. 6 depicts a photograph of a solution of the particles, in acetone, obtained after the process of the present invention with a degree of purity of at least 95% with respect to the polymeric particles of departure. As can clearly be seen, no extrinsic particle is observed.

[0064] FIG. 7 depicts a photograph of sample microparticles obtained after carrying out the procedure of example 3. This image shows the total absence of extrinsic particles, presenting a degree of purity of at least 95% with respect to the starting polymeric particles. As can be clearly seen there is no extrinsic particle, and the sample of microparticles is totally homogeneous.

DETAILED DESCRIPTION OF THE INVENTION

[0065] As used in this description, it should be understood that, unless otherwise specified, the following terms have the following meanings:

[0066] “Biodegradable” refers to a material that can be degraded or metabolized within the body, so that it is generally not removed intact.

[0067] “Biomaterial” includes all materials suitable for contact with body tissues for specific therapeutic, diagnostic, or preventive purposes. These materials must be biocompatible.

[0068] “Biocompatible” means a material that does not cause any significant adverse response from the physiological environment following interaction with tissues and body fluids and must sometimes biodegrade into non-toxic components, either chemically or physically, or a combination of both.

[0069] “Particles” according to the present invention, refers to particulate systems of various shapes with a particle size ≥1 mm. For the purpose of the present invention, the term “particle” includes any amorphous or defined particle of polymeric origin, such as granules, pellets, agglomerates, aggregates, among others. The particles are used as a final product, or as intermediate products of the manufacturing process.

[0070] “Extrinsic particles” according to the present invention, means visible particulate systems of a different nature than the starting polymeric materials, which are detectable when such polymeric materials are subjected to dissolution in a medium in which they are completely solubilized. That is, those particulate systems insoluble in a medium in which the starting polymeric material is totally soluble. This definition shall include any amorphous or defined particle of polymeric origin, such as fibers, granules, pellets, agglomerates, aggregates, among others. They may be organic or inorganic in composition.

[0071] “Granules” means formulations consisting of agglomerates of particles or powders of small size, which may be spherical or irregular in shape.

[0072] “Pellet” means a material that is compacted in the form of small spheres or cylinders by processes such as compaction, extrusion and/or spheronization (melting of the solid mass, wetting of the dry mass, extrusion of the wet or melted mass and rotation of the extruded by spheronization and subsequent drying).

[0073] “Microparticles” are spherical or non-spherical particles, with average diameters between 100 and 150 μm, preferably an average diameter of 125 μm. This group includes microcapsules, which are defined as vesicular systems in which the drug is confined in a cavity surrounded by a single membrane (usually polymeric); and microspheres, which are matrix systems in the form of spherical particles between one and several tens of microns, without a distinction between shell and core, in which the drug is dissolved or dispersed within a matrix consisting of the support materials, usually biocompatible polymers and with a large spectrum of release rates and degradative properties.μ

[0074] “Nanoparticles” are submicron particulate systems (<1 μm). According to the process used to prepare nanoparticles, nanocapsules or nanospheres can be obtained, these being morphological equivalents of microcapsules and microspheres, respectively.

[0075] “Tg” or “glass transition temperature” means the temperature at which a thermodynamic pseudotransition occurs in glassy materials. As can be seen in FIG. 1, it is an intermediate point of temperature between the molten state (Tm) and the rigid state of the material. Tg control is important, because when thermoplastics solidify from the liquid state, they can form a non-crystalline solid or a crystalline solid. Regarding the solidification and slow cooling of non-crystalline or semi-crystalline thermoplastics, there is a decrease in the specific volume with the decrease in temperature that presents a change of slope at a temperature characteristic of the material that is called the glass transition temperature, Tg, above which the polymer presents a viscous behavior (rubbery, elastic), and underneath a brittle glass behavior. This rapid decrease is due to the packing of the polymer chains in the crystalline regions of the material, since the structure of the material is composed of crystalline regions immersed in an amorphous matrix of sub-cooled liquid, which below Tg passes to the vitreous state, leaving the structure formed by crystalline regions immersed in an amorphous vitreous matrix.

[0076] “Tm” means the melting temperature (Tm), which is the temperature at which the phase transition from solid to liquid or molten at normal atmospheric pressure occurs.

[0077] Exemplary melting temperature and glass transition temperature of some polymers are set forth below.

TABLE-US-00001 Glass- Degradation Melting Transition Modulus Time Polymer Point (° C.) Temp (° C.) (Gpa).sup.a (months).sup.b PGA 225-230 35-40 7.0  6 to 12 LPLA 173-178 60-65 2.7 >24 DLPLA Amorphous 55-60 1.9 12 to 16 PCL 58-63 (−65)-(−60) 0.4 >24 PDO N/A (−10)-0 .sup.    1.5  6 to 12 PGA-TMC N/A N/A 2.4  6 to 12 85/15 DLPLG Amorphous 50-55 2.0 5 to 6 75/25 DLPLG Amorphous 50-55 2.0 4 to 5 65/35 DLPLG Amorphous 45-50 2.0 3 to 4 50/50 DLPLG Amorphous 45-50 2.0 1 to 2 .sup.aTensile or flexural modulus. .sup.bTime to complete mass loss. Rate also depends on part geometry.

[0078] By purification “dry” (or dry purification or solvent-free purification) is meant a process of purification of polymeric particles in which neither water nor organic solvents is used in any of the steps of the process of the invention. This aspect is essential of the present invention because it allows for the preparation of purified particles with essentially the same structural (physicochemical) properties as those of the starting particles.

[0079] “Sterile conditions” is intended to mean environmental, equipment, installation, room and work conditions that are suitable for obtaining a non-pyrogenic product with a low microbial load; “non-pyrogenic” means a product with a pyrogenic load below 1 EU/mg (nontoxic units per milligram), and “low microbial load” means a product with less than 300 U.F.C/mg (colony-forming units per mg).

[0080] The process of the present invention is suitable for use with thermoplastic polymers (both homopolymers and copolymers) for medical use, non-parenteral, or parenteral use. Exemplary thermoplastic polymers include lactic acid polymers (L,D,DL), glycolic polymers, ε-caprolactone such as poly polymer (L-lactic), poly (D-lactic), poly (DL-lactic), polyglycolic, poly (ε-caprolactone), copolymers of L-lactic/S-lactic, L-lactic/DL-lactic acids, L-lactic/DL-lactic, L-lactic/glycolic, DL-lactic/glycolic or L-lactic/ε-caprolactone, PC (polycarbonate), PE (polyethylene), PEEK (polyether ketone), PEI (polyetherimide), PES (polyethersulfone), POM (polyoxymethylene), PP (polypropylene), PPS (polyphenylene sulfide), PPSU (polyphenylsulfone), PS (polystyrene), PSU (polysulfone), PTFE (polytetrafluoroethylene) and UHMWPE (ultra-high molecular weight polyethylene), and other known thermoplastic polymers.

[0081] The purified polymeric particles and/or microparticles of biocompatible biodegradable polymers made according to the invention exhibit a purity level of at least 95%, preferably at least 97% and more preferably 99%, without fibers or without particles of a nature different from that of the polymer of choice.

[0082] Preferably, the polymers, of which the particles to be purified are made, are selected from the group consisting of homopolymer particles and copolymers of lactic acid (L, D, DL), glycolic and/or ε-caprolactone such as poly polymer (L-lactic), poly (D-lactic), poly (DL-lactic), polyglycolic, poly (ε-caprolactone), copolymers of L-lactic/S-lactic acids, L-lactic/DL-lactic, L-lactic/glycolic, DL-lactic/glycolic DL, DL-lactic/glycolic or L-lactic/ε-caprolactone, PC, PE, PEEK, PEI, PES, POM, PP, PPS, PPSU, PS, PSU, PTFE, UHMWPE, and any combination thereof.

[0083] Although not limited to any particular bulk density, the bulk density (ρ.sub.b) of polymeric particles obtained by the process of the present invention may be, for example, in the range of 0.10 g/cm.sup.3 to 9.0 g/cm.sup.3, and the compacted density (ρ.sub.t) of the same can be, for example, in the range of 0.13 to 12.0 g/cm.sup.3.

[0084] The bulk density (ρ.sub.b) of polymeric particles obtained by the process of the present invention and the compacted density (ρ.sub.t, of “tap or tapped density”) can be determined by methods and using apparatus known in the prior art. For example, as described in document WO2015/028060. In particular, Method 1 indicated by the United States Pharmacopeial Convention (USP<616>) or Method 1 indicated by European Pharmacopoeia (Ph.Eur. 7.0/2010: 2.9. 3(4).

[0085] Residual solvents are determined by methods known in the prior art, for example, according to ICH Q3C (R6) on impurities: Guideline for Residual Solvents of the European Medicines Agency (EMA/CHMP/ICH/82260/2006), published on Aug. 9, 2019. In particular, the residual quantity of specific solvents is below the limits indicated in said guide.

[0086] The absence of visible extrinsic particles can be easily determined by observing a sample of the particles under a microscope, for example, using a binocular microscope, or using infrared (IR) spectrophotometry, which allows to determine the presence of components of a chemistry different from that of biodegradable polymeric particles.

[0087] The polymeric particles obtained can be typically sterile, also referred to as pyrogen-free and/or having low microbial load; “non-pyrogenic” is understood as a product that has a pyrogenic load below 1 EU/mg (endotoxic units per milligram) and by “low microbial load” the product having less than 300 u.f.c/mg (colony forming units per milligram), determined by methods known in the art, in particular according to the United States Pharmacopeial Convention respectively by USP <85> Bacterial Endotoxins Test and USP <61> Microbial Enumeration Tests.

[0088] In specific embodiments, the polymer particles of the invention can have a microbial load of less than 100 u.f.c/g, and a pyrogen load of less than 0.05 EU/mg. These charges can be obtained, for example, after sterilizing the polymer by Beta radiation with a dose equal to or greater than 25 kGy. In addition, the process described herein may comprise an additional sterilization step performed after step any comminuting step, whereby the polymeric particles are sterilized with a dose of Beta radiation equal to or greater than 25 kGy.

EXAMPLES

[0089] The following specific examples provided herein serve to illustrate the nature of the present invention. These examples are included for illustrative purposes only and are not to be construed as limitations on the invention claimed herein.

[0090] Thermoplastic polymers such as PLGA (lactic or glycolic acid) and PLA (polylactic acid) have been used in these examples.

[0091] The determination of bulk density (ρ.sub.b) and compacted density (ρ.sub.t) has been carried out by method 1 indicated by the United States Pharmacopeial Convention (USP<616>) or method 1 indicated by European Pharmacopoeia (Ph.Eur. 7.0/2010: 2.9.34) using the SOTAX TD1 equipment.

[0092] The determination of pyrogenic load (EU/mg, endotoxic units per milligram) and microbial load (u.f.c./mg, colony forming units per milligram) has been carried out in accordance with the United States Pharmacopeial Convention respectively by USP <85> Bacterial Endotoxins Test and USP <61> Microbial Enumeration Tests.

Example 1. Purification Procedure of the Thermoplastic Polymer PLGA

[0093] In this example, the aim is to purify polymeric particles of PLGA 50/50 of the Durect® brand (in particular Lactel DL-PLG (B6010-1): ester termination, intrinsic viscosity (IV) of 0.26-0.54 dL/g and apparent and compacted densities of the unpurified polymer respectively of 0.64 and 0.84 g/cm.sup.3).

[0094] Before starting, a sample of the commercial polymer particles to be purified is analyzed under the microscope, in order to assess the degree of visible particles outside the polymer (extrinsic) to be eliminated. FIGS. 2 and 3 depicts images taken with a binocular microscope where fibers larger than 100 μm with a morphology very different from the PLGA particles that are intended to be purified can be seen. The images clear demonstrate that purchased PLGA particles (pharmaceutical grade) are not really suitable for parenterally administration and require an additional purification process.

[0095] The morphologically different extrinsic particles were analyzed by FTIR spectroscopy. It was found that the extrinsic particles were for the most part cellulose fibers (FIG. 4). The particles were then subjected to the dry purification process of the invention.

[0096] The purification process begins with an extrusion stage that takes place inside a reactor. Before starting with the purification process, all equipment and materials to be used are clean and sterile. To do this, first, either proceed to perform a sterilization of all the equipment with nebulized or vaporized hydrogen peroxide or mixture of hydrogen peroxide with peracetic acid or proceed with a disinfection of all equipment with disinfectants known in the state of the art. Additionally, in the case of injectable pharmaceutical grade products, all rooms and equipment associated with the process should be sterile.

[0097] Thus, unpurified polymer particles are placed into the reactor, which is then closed and pressurized with an inert gas such as nitrogen. Next, the polymer is heated using a gradual temperature gradient of about 2° C./min±10% from room temperature. When the particles have partially melted, the agitation in the reactor is started with blades, and the agitation is continued until a temperature above the melting temperature (Tm) of the polymer is reached, that is, a temperature in a range of 20-70° C.±10%. Once these conditions are reached, the agitation is stopped, and the reactor is depressurized while maintaining the temperature. The reactor is then pressurized with nitrogen. After this, the discharge valve is opened so that the molten PLGA flows from the reactor through a filter with an average pore size of about 100 μm. By way of this filtration, contaminant (extrinsic) particles that have not been melted in the polymer mass are removed, The polymer mass is then cooled by way of a sterile inert gas stream to a temperature of at least 4.5 to 5.5° C. below Tg. The cooled polymer is then comminuted to provide polymeric particles with a particle diameter 3.mm.

[0098] Finally, a sample of the purified particles is and analyzed with the microscope. The results indicated the cellulose fibers are no longer present in the initial commercial sample (FIGS. 5 and 6).

[0099] The purified PLGA has a specific density identical to that of the unpurified polymer. In particular, the purified PLGA has bulk and compacted densities identical to those of the unpurified starting polymer. The bulk density of the particles obtained is 0.64 g/cm.sup.3 and the compacted density is 0.84 g/cm.sup.3, both the same as those of the starting polymeric product.

[0100] In addition, due to the absence of solvent use in the purification process, the particles obtained do not contain a residual amount of solvent. The amount of residual solvents is below the detection limits, and the total amount of residual solvents is 0.000%, since it is based on a polymer not previously purified with solvents and is therefore below 0.1% the most restrictive limit for class 3 solvents of the guide: ICH Q3C (R6) on impurities: Guideline for Residual Solvents of the European Medicines Agency (EMA/CHMP/ICH/82260/2006), published on Aug. 9, 2019.

[0101] The pyrogenic load of the particles obtained is below 1 EU/mg, and the microbial load of the particles obtained is below 300 u.f.c/mg. After sterilizing the particles obtained by Beta radiation equal to or greater than 25 kGy, the microbial load of the particles obtained is below 100 CFU/g, and the pyrogen count is below 0.05 EU/mg.

Example 2. Thermoplastic Polymer Particle Purification Procedure PLA

[0102] In this example, the aim is to purify polymeric PLA particles of the Resomer® brand. Before starting, a sample of the commercial polymer particles to be purified is analyzed under the microscope, in order to assess the content of visible extrinsic particles to be removed. Fibers (extrinsic particles) larger than 100 μm with a morphology very different from the PLA particles that are intended to be purified were observed. The image showed a clear indication that the purchased PLA particles (pharmaceutical grade) are not really suitable for parenteral administrations, so they require an additional purification process.

[0103] The extrinsic particles were analyzed by FTIR spectroscopy, where they were found identified as cellulose fibers. The particles were then subjected to the dry purification process of the invention, similar to that of Example 1.

[0104] To begin the purification process, the polymer particles are added to the reactor, which is then closed and pressurized with an inert gas such as nitrogen. Next, the polymer is heated using a gradual temperature gradient. Once the PLA particles have partially melted, the particles are agitated with a propeller until a temperature of at least 5° C.±10% above the melting temperature (Tm) of the polymer is reached. The Tm in each case is determined according to the nature and composition of the polymer, and the Tm in general terms is typically between 50° C. and 300° C., and more particularly between 50° C. and 180° C. Once these conditions are reached, the agitation is stopped, and the reactor is depressurized. The reactor is then pressurized with nitrogen. After this, the discharge valve is opened so that the molten PLA flows from the reactor through a filter with an average pore size of 100 μm. By wat of this filtration, contaminant particles that have not been melted in the polymer mass are eliminated, thereby provide a purified PLA with a specific density identical to that of the unpurified polymer.

[0105] The polymer mass is then cooled with a sterile air stream to a temperature of at least 4.5 to 5.5° C. below Tg. The cooled polymer is then comminuted to reach a particle diameter ≥1 mm.

[0106] Finally, a sample of the comminuted particles is taken after the purification process and observed again under the microscope. The results demonstrate that the cellulose fibers from the initial commercial sample, as shown in example 1, are no longer present.

Example 3. Purification Procedure for Polymeric Microparticles

[0107] For this example, a sample of particles obtained after the procedure of examples 1 and 2 is taken and then the following steps are carried out. The particles are vacuum dried for at least 10 hours at room temperature. The particles are then ground or sieved to form microparticles having an average diameter between 100 and 150 μm. The sieving or grinding (micronization) is carried out by means of a system of in-line blades that provides dry powder with an optimal dispersion of particle sizes, e.g. D10: about 25-55 μm; D50: about 120-170 μm; D90: about 300-375 μm.

[0108] A sample of the micronized particles is analyzed under the microscope. The results (FIG. 7) demonstrate absence of the cellulose fibers observed in initial commercial sample.

Comparative Examples

Comparison of Density of Products Purified by Prior Art Methods and Unpurified Products:

[0109] This example compares the bulk and compacted density of a solvent-purified commercial polymer (45 RESOMER RG 503 H GMP and 26 RESOMER RG 504 H GMP), and another commercial polymer with identical unpurified characteristics (RESOMER®®® Select 5050 DLG SE-Mill).

TABLE-US-00002 Intrinsic Viscosity (IV) Polymer Purification (dL/g) ρ.sub.b (g/cm.sup.3) ρ.sub.t (g/cm.sup.3) RESOMER ® Purified per 0.45-0.60 0.64 0.84 Select 5050 the invention DLG SE-Mill 45 RESOMER ® Purified with 0.33-0.44 0.09 ± 0.02 0.11 ± 0.02 RG 503 H GMP solvents 26 RESOMER ® Purified with 0.45-0.60 0.09 ± 0.02 0.10 ± 0.01 RG 504 H GMP solvents

[0110] As shown in the table, purification using solvents results in a very low bulk and compacted density compared to the same unpurified product.

[0111] On the other hand, a polymer of similar characteristics purified with the method of the present invention results in a polymer with the same density characteristics as the starting product (Example 1).

Residual Amount of Solvent from State-of-the-Art Products, Purified by Solvent-Using Methods:

TABLE-US-00003 Polymer Residual Solvents (Sigma-Aldrich) Purification (GLC-HS) Resomer ® Purified with solvents 23 PPM TOLUENE RG 502 H 0.01% ACETONE 0.02% TOTAL

[0112] As can be seen, the residual amount of solvents is much higher than that of polymeric particles obtained by the process of the invention (0.00% in Example 1).