Method for producing shaped polymeric microparticles

Abstract

Method for producing shaped polymeric microparticles of non-spherical shape, comprising the steps of: placing one or more microparticles of substantially spherical shape in a respective micro-cavity of a mold having the desired non-spherical shape; subjecting said microparticles to softening by exposure to a solvent or mixture of solvent/non-solvent, in the liquid or vapor state, adapted to plasticize the polymeric material constituting said microparticles, and possibly assisting the solvent plasticization process by heat treatment, not excluding the possibility, in less critical cases in terms of conservation of the microstructure, of carrying out heat treatment exclusively, at a temperature not exceeding 40% of the glass transition temperature of the polymer material; and removing said microparticles from the mold cavities.

Claims

1. Method for producing non-spherical polymeric microparticles having a microporous structure, comprising the steps of: providing a plurality of polymeric microparticles, each microparticle having a microporous structure and having a substantially spherical shape filled with a drug or a biomolecule; placing each microparticle in a respective micro-cavity of a mould comprised of multiple non-spherical shaped micro-cavities; softening each microparticle by exposure to a solvent or mixture of solvent and non-solvent, in a vapour state at a temperature below 60 C. or exclusively by heat treatment at a temperature not exceeding 40% above the glass transition temperature thereby plasticizing the polymeric material constituting said microparticle; consolidating the thus obtained plasticized microparticle, and removing each plasticized non-spherical microparticle from the respective mould micro-cavity, wherein the said plasticized non-spherical microparticle has maintained said microporous structure; whereby degradation of said drug or biomolecule in said plasticized non-spherical microparticle is avoided.

2. Method according to claim 1, comprising the step of subjecting said microparticles to a pressure in the respective mould micro-cavities prior to removal from said mould micro-cavity.

3. Method according to claim 1, characterized in that the softening of the particles is caused by localized application in the mould micro-cavity of a solvent or a mixture of solvent and non-solvent in a vapour state, at a temperature below 40 C.

4. Method according to claim 1 for deforming microparticles having a size from 2 m to 600 m in diameter.

5. Method according to claim 1, wherein said micro-cavities have a base with a structured surface such that the shaped microparticles have a corresponding surface structure.

6. Method according to claim 1, wherein said shaped microparticles are formed by a biodegradable or biocompatible thermoplastic polymer.

7. Method according to claim 1, wherein said shaped microparticles comprise polylactic acid) (PLA), polylactic-co-glycolic acid) (PLGA), polycaprolactone (PCL) or gelatine.

Description

(1) In the appended drawings,

(2) FIG. 1 is a schematic illustration of the mould apparatus used in the method according to the invention;

(3) FIG. 2 is a schematic illustration of a vaporizing device;

(4) FIGS. 3a and 3b are photographs illustrating microparticles produced by the method of Example 1;

(5) FIGS. 4a and 4b show confocal microscope images of porous microparticles, before and after the forming process respectively; and

(6) FIG. 5 is a photograph produced by a scanning electron microscope showing shaped microspheres produced in Example 2.

(7) For the application of the method according to the invention, an apparatus of the type shown schematically in FIGS. 1 and 2 was used.

(8) This apparatus comprises a mould 2, having a plurality of mould microcavities 4. The mould may be made of various materials and may be produced by various suitable methods such as lithography, RIE or other technologies. In the tests that were conducted, a mould made of PDMS was used, produced in two stages using the replica moulding technique.

(9) Initially, a reverse mould was produced with structures in relief, having the shape of the mould cavities to be provided, for example prismatic shapes with cross-shaped, triangular, rectangular bases, or cylindrical disc shapes.

(10) The reverse mould was produced using a silicon substrate with microstructures of SUB, formed by means of a 2D laser system. The relief structures had a volume of about 4.210.sup.6 m.sup.3, corresponding to the volume of the microparticles to be produced.

(11) For the production of the mould, PDMS in the liquid state (Sylgard 184), previously mixed with a cross-linking agent in proportions by weight of 1:10, was poured on to the silicon/SU8 substrate and cured in an oven at 80 C. for 2 hours. The hardened PDMS mould was then easily separated from the reverse mould made of PMMA.

(12) To enable an automated process to be provided, the apparatus used also comprises a micromanipulator 6 adapted to pick up a plurality of microspheres simultaneously and enable them to be deposited in the mould cavities 4.

(13) By way of example, the micromanipulator device comprises a body defiling a suction chamber within it and having a lower wall with a plurality of holes communicating with said suction chamber and arranged in a matrix with an interval corresponding to the intervals of the mould cavities 4 formed in the mould.

(14) A thin rigid tube or suction needle 8, the passage of which has a smaller diameter than that of the microspheres to be picked up and deposited, is connected to each hole. The upper wall of the body of the micromanipulator has a single hole to which is connected in a sealed way a manifold 10, formed by a thin tube or needle, which in turn can be connected to a vacuum pump.

(15) When the vacuum pump has been started, the micromanipulator can be used to pick up a plurality of microspheres and enable them to be deposited in the mould cavities, after the vacuum pump has been stopped.

(16) In order to avoid phenomena of aggregation of the microparticles due to electrostatic interactions that may occur, depending on the plastic material from which the particles are made, and in order to ensure that a single microsphere is retained at each suction hole, a small flow of air can be used, or a brushing operation can be carried out before the vacuum pump is stopped.

(17) The same micromanipulator can be used to supply vapours of the solvent and plasticizer mixture, using a carrier gas such as nitrogen if necessary, in a localized manner on the microspheres or in the vicinity of the microspheres positioned in each mould cavity.

(18) In order to generate a flow of solvent vapour, a conventional bubble vaporization apparatus 12 may be used, with a heating jacket 18, of the type shown schematically in FIG. 2. In this apparatus 12, a carrier, for example nitrogen, is fed to a porous partition 14 immersed in the liquid solvent solution 16. The solvent vapour that is generated may, as mentioned, be fed to the micromanipulator.

EXAMPLE 1MICROSPHERES OF D,L-LACTIC-CO-GLYCOLIC ACID (PLGA) SOFTENED WITH A MIXTURE OF DIMETHYL CARBONATE (DMC) AND ETHANOL IN THE VAPOUR STATE

(19) PLGA is known to be a polymer that is rapidly dissolved in DMC. On the other hand, ethanol does not dissolve PLGA.

(20) Microspheres of PLGA (Resomer 504H) with a volume of 4.210.sup.6 m.sup.3 were produced in advance by means of a suitable membrane system with a degree of porosity comparable to that of the spherical microparticles to be produced (Micropore System).

(21) Each microsphere was placed in a respective PDMS mould cavity (that is to say, one microsphere in one cavity), using the micromanipulator 6, as shown in FIG. 1. The mould was then positioned on a flat support with its flat lower wall facing the flat surface of the support.

(22) A liquid solution of DMC and ethanol (DMC:EtOH, 2:1, v:v) was then vaporized, using a vaporization apparatus as described above, on to the microspheres placed in the cavities. After two minutes of vapour flow, a glass slide was placed in contact with the plasticized microspheres to improve the forming and for the purpose of removing the shaped microspheres from the mould.

(23) The method was carried out at ambient temperature (about 25 C.) and ambient pressure.

(24) FIGS. 3a and 3b show some of the microparticles obtained by using moulds with cavities of different shapes.

(25) The method described above was repeated using microspheres having a porous internal structure.

(26) FIGS. 4a and 4b are confocal microscope images which show how the porosity is maintained after forming, by using porous microparticles loaded with a chromophore.

EXAMPLE 2MICROSPHERES OF POLYMERIC GELATINE PLASTICIZED WITH WATER IN THE LIQUID STATE

(27) MICROSPHERES OF GELATINE POLYMER WITH A VOLUME OF 65.510.sup.6 M.sup.3, SOLUBLE IN WATER, WERE prepared by the known single emulsion method.

(28) The procedure described in Example 1 was repeated, but the microspheres were softened by using water as the solvent in the liquid state. The water, at a temperature below 50 C., was injected through a syringe and allowed to evaporate partially. After 15 minutes in this condition, a glass slide was placed in contact with all the plasticized microspheres, to improve the shaping and for the purpose of removing the microspheres from the mould.

(29) FIG. 5 shows shaped microspheres produced according to this example with various geometries. The high degree of faithfulness of the geometry of the shaped microparticles to the geometry of the mould cavity should be noted. Additionally, the shaped microparticles are separated from each other; that is to say, they are not interconnected.