WO2015024759A1

WO2015024759A1 - Process for preparing redispersible powders of water-insoluble, biodegradable polyesters

Info

Publication number: WO2015024759A1
Application number: PCT/EP2014/066586
Authority: WO
Inventors: Rima JABER; Andreas Kirchner; Muhammad Irfan; Uwe WEIDENAUER
Original assignee: Evonik Industries Ag
Priority date: 2013-08-21
Filing date: 2014-08-01
Publication date: 2015-02-26

Abstract

The invention refers to a process for preparing a redispersible powder from a granulate of a water-insoluble, biodegradable polyester including the steps a) mixing a granulate of a water-insoluble, biodegradable polyester with a water- soluble plasticizer with a molecular weight of 100 or more, at a ratio of at least 7.5 parts per weight of the plasticizer per 1 part per weight of the water-insoluble, biodegradable polyester, to give a dispersion or solution, b) mixing the dispersion or solution from step a) with water at a ratio of at least 5 parts per weight of water per 1 part of weight of the dispersion or solution, to obtain an emulsion, c) homogenizing the emulsion from step b) by means of high shear mixing to promote the transfer of the water-soluble plasticizer to the water phase and to precipitate the water-insoluble, biodegradable polyester, d) filtrating the mixture from step c) to gain the filtrated mass, e) re-dispersion the filtrated mass in water by means of high shear mixing f) filtrating the dispersion from step e) to obtain the filtrated mass, g) repeating steps e) and f) for at least one time, h) drying of the final filtrated mass, i) collection of the dried mass as the redispersible powder.

Description

Process for preparing redispersible powders of water-insoluble,

biodegradable polyesters

Field of the invention

The invention is concerned with a process for preparing a redispersible powder from a granulate of a water-insoluble, biodegradable polyester

Technical Background

US 2004/01 15277A1 describes a method for preparing microparticles for delayed release of an active ingredient, wherein a) a composition of the active ingredient is added to an organic solution of a polymer and dispersed therein, b) the emulsion or dispersion produced in a) is added to an outer phase and dispersed therein, whereby the temperature of the outer phase is between 0° C and 20° C, and c) the organic solvent is removed by subjecting the dispersion or emulsion produced in b) to a pressure less than 1 ,000 mbar, or by conducting an inert gas into the dispersion or emulsion produced in b). The polymers of the microparticles gained may be for instance of the polylactic-glycolic acid type.

WO 2007/025441 A1 describes a method to prepare polysaccharide glassy particles without using organic solvents and surface active agents. The polysaccharide solution is as a dispersed phase mixed with another water soluble polymer solution, e.g. PEG, PEO, PVP or PVA, as a continuous phase. Both solutions are immiscible at a temperature below room temperature but above its freezing point to form an aqueous-aqueous emulsion. The emulsion is then freeze-dried to give a powder. The freeze-dried powder is washed to remove the continuous phase. The resulting polysaccharide glassy particles have diameters of less than 10 microns, preferably less than 5 microns. The polysaccharide glassy particles may be useful for loading protein therapeutics and may be further dispersed in matrices like PLGA sheets or scaffolds and the like. Ali, M. A. and Lamprecht, A., Int.J.Pharm 456 (2013) 135-142 "Polyethylene glycol as an alternative polymer solvent for nanoparticle preparation" describe the formation of EUDRAGIT® RL and poly-lactide-co-glycolide (PLGA) nanoparticles by dissolving the EUDRAGIT® RL or the PLGA polymers in polyethylene glycol (PEG).

Nanoparticles with diameters ranging from 80 to 400 nm are obtained. After washing wet PLGA particles are below 100 or 125 nm (table 2). Bovine serum albumin (BSA) and lysozyme are encapsulated as model proteins. The encapsulation efficiencies with BSA and EUDRAGIT® RL with about 60 - 70% are higher compared to PLGA with about 20 - 40%. This modified solvent displacement (MSD) method uses as described 3 ml PEG 400 to a diffusing phase as carrier for the EUDRAGIT® RL or the PLGA. A dispersing phase, 15 ml water, was used as a carrier for the model proteins and could be added dropwise and mixed under magnetic stirring at 900 rpm or by ultrasound. Polyvinylalcohol (1 %, w/v) was contained as a stabilizer in the dispersing phase. Stirring was continued for 6 h with continuous investigation of the particle size. Washing of the nanoparticle dispersion was carried out by dialysis. All particle characterizations were done in the wet stage. No dry polymer material was generated by this method.

Objects of the invention

The polymerization products of water-insoluble, biodegradable polyesters, such as poly-lactide-co-glycolide copolymers are usually obtained from precipitation processes as a wet polymer mass which has been washed and dried first. The dried polymer masses are often not available in a readily in water redispersible form. In many cases such a polymer mass has more or less the form of a lump, a clot or a nugget which may be comminuted to granules of often only very in-homogenous structure and size, which are not easy to process further. Such further processing may be done by employing organic solvents. However this is often problematic when active pharmaceutical ingredient shall be encapsulated in nanostructured particles. Poor loading and reduction of biological activity may encounter.

Ali, M. A. and Lamprecht, A., Int.J.Pharm 456 (2013) 135-142 "Polyethylene glycol as an alternative polymer solvent for nanoparticle preparation" describes the formation of EU DRAG IT® RL and poly-lactide-co-glycolide (PLGA) nanoparticles by avoiding organic solvents and dissolving the EUDRAGIT® RL or the PLGA polymers in polyethylene glycol (PEG). The nanoparticles achieved by this process are however far too small in size to be able to result in suitable redispersible powders.

Furthermore poly-lactide-co-glycolide (PLGA) nanoparticles of such small size show only poor loading degrees of model substances such as BSA. Furthermore the method of Ali et al. uses a dialysis process for washing and concentration which results only in particle suspensions in the wet form.

It was an object of the present invention to provide a process for preparing readily in water redispersible powders from water-insoluble, biodegradable polyesters. It was also an object to provide a process for preparing readily in water redispersible powders from water-insoluble polymers with included or encapsulated active pharmaceutical ingredients, preferably with active pharmaceutical ingredients which are thermo-sensitive or water-insoluble. The encapsulation process should also lead to efficient loading degrees.

Details of the invention

The invention discloses a process for preparing a redispersible powder from a granulate of a water-insoluble, biodegradable polyester including or comprising or consisting of the steps a) Mixing, preferably high shear mixing for 1 - 10, 2 - 5 minutes, a granulate of a water-insoluble, biodegradable polyester with a water-soluble plasticizer with a molecular weight of 100 or more at a ratio of at least 7.5 parts per weight of the plasticizer per 1 part per weight of the water-insoluble, biodegradable polyester, to give a dispersion or solution,

In the case of the encapsulation of an active pharmaceutical ingredient (API) it should be mixed with the dispersion or solution.

A granulate as used in step a) may comprise usually irregular formed particles which in some cases may form agglomerates or even large lumps. In the case of more regular formed particles the granulate may be roughly characterized with a mean particle size in the range of 200 μηη - 5 mm, preferably in the range of 500 to 2 mm (determination possible by laser diffraction or by analytical sieving). b) mixing the dispersion or solution from step a) with water at a ratio of at least 5, preferably 5 - 100, preferably 8 - 20 parts per weight of water per 1 part of weight of the dispersion or solution, to obtain an emulsion. c) homogenizing the emulsion from step b) by means of high shear mixing to promote the transfer of the water-soluble plasticizer to the water phase and to precipitate the water-insoluble, biodegradable polyester. High shear mixing in step b) may be defined in that sufficient shear forces are applied to the emulsion to promote the transfer of the water-soluble plasticizer to the water phase to a degree of at least 80, 90, 95, 99 or 100 % by weight within the time of application. The time of application of the high shear mixing may be 1 - 20, 2 - 12, 3 - 10 or 3 - 8 minutes. d) filtrating the mixture from step c) to gain the filtrated mass. e) redispersion of the filtrated mass in water by means of high shear mixing. High shear mixing in step e) may be defined in that sufficient shear forces are applied to redispers the filtrated mass in water within the time of application to give an opaque and/or foggy dispersion, where no or almost no more solid particles are detectable by the naked eye. The time of application of the high shear mixing may be 1 - 20, 2 - 12, 3 - 10 or 3 - 8 minutes. f) filtrating the dispersion from step e) to obtain the filtrated mass, g) repeating steps e) and f) for at least one time, h) drying, preferred freeze drying, of the final filtrated mass. i) Collection of the dried mass as the redispersible powder. The redispersible powder may be directly obtained from the filtrated mass which collapses to the powder. Usually there is no need for milling or other further comminution in step i).

The redispersible powders from step i) may be more or less uniform sometime spherical or irregular shaped and may be preferably characterized by powder particles that may have a particle size distribution respectively a particle size d(0.5) value (laser diffraction) in the range of 0.1 - 1 .5 μηη , preferably from 0.1 - 1 , 0.2 - 0.8 μηη , more than 0.4 and up to 1 .5 μηη , 0.5 - 1 μηη , 0.6 - 0.95 μηη , 0.7 - 0.9 μηη . d(0.9) values may be in the range of 10 - 250 μηη or 0.1 - 2 mm.

The redispersible powder from step i) should preferably contain any or only very small amounts (< 1 .000 or <100 ppm), traces or no or almost detectable amounts of the water-soluble plasticizer.

The process steps, except for instance freeze drying, may be carried out at room temperature (20 - 25 °C, about 22 °C or 22°C).

Water-insoluble, biodegradable polyester

The water-insoluble, biodegradable polyester is preferably a polylactic acid, a polyglycolic acid, a poly-caprolactone, a lactic acid-glycolic acid copolymer, a lactic acid-glycolic acid-polyethylene blockcopolymer, a lactic acid-glycolic acid- caprolactone terpolymer, a lactic acid-caprolactone copolymer, a poly dioxanone or a lactic acid-trimethylene carbonate copolymer or blends thereof.

The water-insoluble, biodegradable polyester polymer is preferably selected from lactic acid polymers (polylactic acid) or copolymers. The term "lactic acid polymers or copolymers" shall mean polymers comprising polymerized monomer units, preferably at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70 % by weight or up to 100 % of polymerized lactic acid or lactide units. A lactide is a cyclic diester of lactic acid. The term lactide shall mean L-lactide, D-lactide, D,L-lactide or meso-lactide. Suitable comonomers that may be polymerized with the lactic acid or lactide respectively are glycolide, epsilon- caprolactone, trimethylene carbonate or dioxanone. Lactic acid polymers or copolymers may include also a AB- or ABA-blockcopolymer containing an A-Block selected from polylactic acid polymers or copolymers and a B- Block selected from a polyethylenglycol polymer.

The water-insoluble, biodegradable polyester polymer is preferably selected from lactic acid polymers or copolymers synthesized from monomer components or from a mixture of monomer components selected from the group consisting of a) to I): a) D- and L-lactide,

b) L-lactide and glycolide,

c) D, L-lactide and glycolide,

d) L-lactide and epsilon-caprolactone,

e) L-lactide and dioxanone,

f) L-lactide and trimethylene carbonate,

g) L-lactide, D-lactide, meso-lactide or D, L-lactide,

h) L-lactide,

i) DL-lactide,

j) statistically distributed monomer units of L-lactide, D-lactide, meso-lactide or DL-lactide and epsilon caprolactone,

k) statistically distributed monomer units of L-lactide, D-lactide, meso-lactide or DL-lactide and dioxanone,

I) statistically distributed monomer units of L-lactide, D-lactide, meso-lactide or DL-lactide and trimethylene carbonate.

These kind of lactic acid polymers or copolymers are biodegradable polyester polymers and well known in the art for example from EP1468035, US6706854, WO2007/009919A2, EP1907023A, EP2263707A, EP2 47036, EP0427 85 or US5610266. A preferred lactic acid polymer is poly(D,L-l_actide). The inherent viscosity ([dL/g] 0.1 % in CHCI3, 25 °C) may be in the range 0.2 to 0.4, most preferred from 0.25 to 0.35 dL/g (RESOMER® R 203 H).

Other suitable water-insoluble, biodegradable polyester polymers are for instance:

RESOMER® 202H is a poly(D,L-lactide) polymer with an inherent viscosity in the range of 0.16 - 0.24, for instance 0.23 dL/g.

RESOMER® 202S is a poly(D,L-lactide) polymer with an inherent viscosity in the range of 0.16 - 0.24 or instance 0.22 dL/g.

RESOMER® RG503 is a poly(D,L-iactide-co-glycolide) 50:50 copolymer with an inherent viscosity in the range of 0.32 - 0.44, or instance 0.43 dL/g.

RESOMER® RG503H is a poly(D,L-lactide-co-glycolide) 50:50 copolymer with an inherent viscosity in the range of 0.32 - 0.44, or instance 0.35 dL/g.

RESOMER® RG502H is a poly(D,L-lactide-co-glycolide) 50:50 copolymer with an inherent viscosity in the range of 0.16 - 0.24, for instance 0.2 dL/g.

RESOMER® RG502 is a poly(D,L-lactide-co-glycolide) 50:50 copolymer with an inherent viscosity in the range of 0.16 - 0.24, for instance 0.22 dL/g.

RESOMER® RG505 is a poly(D,L-lactide-co-glycolide) 50:50 copolymer with an inherent viscosity in the range of 0.61 - 0.74.

RESOMER® RG 653H is a poly(D,L-lactide-co-glycolide) 65:35 copolymer with an inherent viscosity in the range of 0.32 - 0.44, or instance 0.37 dL/g.

RESOMER® RG 752H is a poly(D,L-lactide-co-glycolide) 75:25 copolymer with an inherent viscosity in the range of 0.14 - 0.22, or instance 0.2 dL/g. RESOMER® RG 756S is a poly(D,L-lactide-co-glycolide) 75:25 copolymer with an inherent viscosity in the range of 0.71- 1 .0 dL/g.

RESOMER® 858S is a poly(D,L-lactide-co-glycolide) 85:15 copolymer with an inherent viscosity in the range of 1 .3 - 1 .7 dL/g.

RESOMER® types with an "S" carry an ester end group, while RESOMER® types with an Ή" carry an acid end group.

The biodegradable polyester is preferably used in the form of a granulate. The granulate particle may have a mean particle size, preferably a spherical size, in the range of above 0.5 or above 1 mm, for instance in the range from 1 to 5 mm, preferably, in the range from 1 .5 μηη to 3 mm. The mean particle size of the granulate may be determined by sieving. A certain mean particle size of a certain value or range as stated above means that at least 70 % or preferably at least 80 %, or 70 to 100 % by weight of the granulate mass is in the sieved fraction for this certain value or range.

The water-soluble plasticizer with a molecular weight of 100 or more, preferably 180 or more, more preferred 200 or more may be a polyethylene glycol, preferably a polyethylene glycol with a molecular weight (M_w) of 100 to 2000, preferably of 200 to 1000. The water-soluble plasticizer may be solid , waxy or preferred liquid at room temperature. The inventors found that water-soluble plasticizers with a molecular weight of less than 100 like glycerine (molecular weight 92.1 ) or propylene glycol (molecular weight 76.1 ) are not suitable for the purposes of the invention.

The high shear mixing is preferably performed by an Ultraturrax® or by more preferably by Microfluidizer® equipment.

Plasticizer

Plasticizers are substances that modify the physical properties of polymers, such as thermoplastic polymers or biodegradable polyesters. Plasticizers usually soften and are improving the flexibility of polymers.

Stabilizer

Stabilizers are chemical compounds which are added to a metastable system, to prevent the transition to a lower energy state. These conversions can be triggered by different factors e.g. elevated temperature. A stabilizer may have the function of preventing a dispersion to coagulate and may promote a fine distribution of dispersed particles. An example for a stabilizer in the sense of the invention is polyvinyl alcohol (PVA) or a polyoxamer, for instance Pluronic®. mulsifier

An emulsifier may be defined as a molecule or a substance comprising a balance of hydrophilic and hydrophobic (lipophilic) properties. This may also be called an amphiphilic property. Emulsifiers may be characterized by their HLB values (HLB stands for hydrophilic-lipophilic balance)

The HLB, introduced by Griffin in 950, is a measure of the hydrophilicity of lipophilicity of non ionic surfactants. It may be determined experimentally by the phenol titration method of Marszall; cf. "Parfumerie, Kosmetik", Volume 60, 1979, pp. 444-448; further literature references are in Rompp, Chemie-Lexikon, 8^th ed. 1983, p. 1750. See also, for example, US 4 795 643 (Seth). An HLB (hydrophilic/lipophilic balance) can be determined exactly only for nonionic emulsifiers. For anionic emulsifiers, this value may be determined arithmetically but is virtually in most cases above or well above 20.

Stabilizer and Emulsifier

The water phase of step b) may comprise a stabilizer or an emulsifier or both.

Suitable amounts for the stabilizer may be 0.01 - 2, preferably 0.05 - 1 % by weight. Suitable amounts for the emulsifier may be 0.01 - 2, preferably 0.05 - 1 % by weight. This has the advantage that finer particles can be obtained in the final step i), preferably the powder particles that may have a particle size value of d(0.5) (laser diffraction) in the range of 0.5 - 1 , 0.6 - 0.95, 0.7 - 0.9 pm.

It is also possible that the water phase of step b) may comprise any stabilizer or any emulsifier. In this case the powder particles that may have a particle size value of d(0.5) (laser diffraction) in the range of more than 1 - 1 .5 μηη .

A suitable stabilizer may be a polyvinylalkohol (PVA) or a polyoxamer, for instance a polyoxamer of the polyoxyethylen-polyoxypropylene-polyoxyethylen-type, such as Pluronic® F68. A suitable emulsifier may be a polyoxyethylen-sorbitan ester such as

polyoxyethylen(20)-sorbitan-monooleat (lUPAC, Tween® 80), polyoxylated castor oil (Cremophor® EL) or sodium dodecyl sulphate.

Active pharmaceutical ingredient (API)

The process disclosed herein may be characterized in that an active pharmaceutical ingredient (API) is added in step a). The active pharmaceutical ingredient may be a peptide or a protein. The process disclosed herein is preferably suitable for active pharmaceutical ingredients which are intended to be sustained over a certain period of time.

The process disclosed in here is further preferably suitable for active pharmaceutical ingredients with a water solubility less than 14, 12, 10, 8, 6, 4 or 2 g/l (at 23 °C). For these active pharmaceutical ingredients inclusion or encapsulation rates in the final (in water) redispersible powder in the range from 5 to 90, 20 to 80, 25 to 70 or 30 to 60 % may be obtained. Examples for active pharmaceutical ingredients which are highly suitable for the purposes of the invention may be Risperidone or Olanzapine.

Active pharmaceutical ingredients (API) with a water solubility of 14 g/l or more are usually not suitable for the purposes of the invention because they are washed out almost completely with the water phase. An example for an active pharmaceutical ingredient which is not suitable for the purposes of the invention is paracetamol.

The process disclosed in here is suitable for active pharmaceutical ingredient which is thermo-labile such as proteins or peptides, preferably proteins or peptides with a water solubility less than 14, 12, 10, 8, 6, 4 or 2 g/l (at 23 °C). Definitions and analytical methods

Particle sizes

Granulate

A granulate in the sense of the invention as used in step a) may comprise usually irregular formed particles which in some cases may form agglomerates or even large lumps. In the case of more regular formed particles the granulate may be roughly characterized with a mean particle size in the range of 200 μηη - 5 mm, preferably in the range of 500 pm to 2 mm (determination possible by laser diffraction or by analytical sieving).

Powder/Redispersible Powder

A powder is more regular than a granulate. Powders may be more or less uniform sometime spherical or irregular shaped and may be preferably characterized by powder particles that may have a particle size distribution or a particle size d(0.5) value (laser diffraction) in the range of 0.1 - 1 .5 pm, preferably from 0.1 - 1 , 0.2 - 0.8 pm, more than 0.4 and up to 1 .5 pm, 0.5 - 1 pm, 0.6 - 0.95 pm, 0.7 - 0.9 pm. d(0.9) values may be in the range of 10 - 250 pm or 0.1 - 2 mm.

Powders of such size are very suitable for the redispersion of the water-insoluble, biodegradable polyester in water. Powder of smaller size may give problems with the safe handling because of their potential hazardous dust formation and because of their tendency to form irregular aggregates in water which are not well dispersible. Powders of larger size are usually not readily dispersible and tend to the formation of remaining not redispersed pieces and bits.

A redispersible powder from a granulate of a water-insoluble, biodegradable polyester in the sense of the present invention shall mean powder particles that can be dispersed respectively redispersed in water instantly on contact with the water or at least under gentle stirring or gentle agitation within a few seconds or at least within 1 - 10 or 2 - 5 minutes creating an opaque and/or foggy suspension. Usually almost no or no more solid particles are detectable by the naked eye in that opaque and/or foggy suspension.

A minimum d(0.5) particle size value for a redispersible powder may be in the range of at least 100, at least 200 or more than 400 nm.

A maximum d(0.5) particle size value for a redispersible powder may be in the range of not more than 5, 4, 3, 2 or not more than 1 pm or not more than 900, 800 or 700 nm.

Water-insoluble, biodegradable polyester

The term water-insoluble, biodegradable polyester in the sense of the invention are biodegradable polyesters which do not dissolve in water over of the whole range of pH 1 - 14.

The term biodegradable as used herein refers to polyester polymers that dissolve or degrade within a period of time that is acceptable in a desired application, which is usually an in-vivo therapy, typically less than about five years, less than about one year, once exposed to a physiological solution between about pH 6 - 8 and a temperature between about 25 - 40 °C.

The term "biodegradable polyester" means also that the polyester is after

implantation or injection in the human body or in the body of an animal in contact with the body fluids broken down into oligomers in a slow hydrolytic reaction. Hydrolysis end products such as lactic acid or glycolic acid are metabolized into carbon dioxide and water. Other exchangeable expressions for the term "biodegradable polyester" which are often used are "resorbable polyester" or "bio-resorbable biodegradable polyester" or "adsorptive polyester". Inherent viscosity

The determination of the inherent viscosity is preferably performed in an Ubbelohde viscometer (preferably type 0c) at 25 + 0.1 °C utilizing a sample concentration of 0.1 % dissolved in chloroform.

High-shear mixer

The terms high-shear mixer, high-shear mixing or high-shear homogenisation are well known to a skilled person in the field of pharmacy or galenics.

A definition for a term high-shear mixer may be found for instance in Wikipedia (http:/en. wikipedia.org/wiki/Highshear mixer) :

A high-shear mixer disperses, or transports, one phase or ingredient (liquid, solid, gas) into a main continuous phase (liquid), with which it would normally be

immiscible. A rotor or impellor, together with a stationary component known as a stator, or an array of rotors and stators, is used either in a tank containing the solution to be mixed, or in a pipe through which the solution passes, to create shear. A high-shear mixer can be used to create emulsions, suspensions, lyosols (gas dispersed in liquid), and granular products. It is used in the adhesives, chemical, cosmetic, food, pharmaceutical, and plastics industries for emulsification,

homogenization, particle size reduction, and dispersion.

A well-known and broadly used type of a high-shear mixer is for instance the ULTRA - TURRAX® type. The stirring speed may be at least 1000 rpm, preferably 2000 - 4000 rpm. The U LTRA-TU RRAX® type equipment is well known to a skilled person.

High shear mixing in step b) may be defined in that sufficient shear forces are applied to the emulsion to promote the transfer of the water-soluble plasticizer to the water phase to a degree of at least 80, 90, 95, 99 or 100 % by weight within the time of application. The time of application of the high shear mixing may be 1 - 20, 2 - 12, 3 - 10 or 3 - 8 minutes. High shear mixing in step e) may be defined in that sufficient shear forces are applied to redispers the filtrated mass in water within the time of application to give an opaque and/or foggy dispersion, where no or almost no more solid particles are detectable by the naked eye. The time of application of the high shear mixing may be

1 - 20, 2 - 12, 3 - 10 or 3 - 8 minutes.

Microfluidizer®

Microfluidizer® is a high shear mixer/Reactor (MMR) system which is considered as a continuous chemical reactor. This system produces uniform nanoparticles on a continuous (versus batch) basis with phase purity previously unachievable with conventional batch reaction technology.

It is a homogenizer that is used to create a coarse suspension, which is then pumped into the Microfluidizer® under high pressure. The Microfluidizer® equipment is well known to a skilled person.

Mean particle size

The mean particle size of the powders for instance in step (a), can be determined as follows: By air-jet screening for simple separation of the ground product into a few fractions. In the present measurement range, this method is somewhat less accurate than the alternatives. At least 70%, preferably 90% of the particles relative to the weight (weight distribution), however, should lie within the intended size range.

A highly suitable measuring method is laser diffraction for determination of particle size distribution. Commercial instruments permit measurement in air (Malvern Co. S3.01 Particle Sizer) or preferably in liquid media (LOT Co., Galai CIS 1 ).

The pre-requisite for measurement in liquids is that the polymer does not dissolve therein or the particles do not change in some other way during the measurement. An example of a suitable medium is a highly diluted (about 0.02%) aqueous polysorbate 80 solution. Particle size measurement

Light diffraction

The determination of the particle size, preferably the particle size of the dispersible powder in step i), may be performed according to the United States Pharmacopeia 36 (USP) chapter <429> and European Pharmacopeia 7.0 (EP) chapter 2.9.31 . The particle size distribution is determined utilizing a laser scattering instrument (e.g. Fa. Sympatec GmbH, type HELOS equipped with RODOS dry dispersing unit). The laser diffraction method is based on the phenomenon that particles scatter light in all directions with an intensity pattern that is dependent on particle size. A representative sample, dispersed at an adequate concentration in a suitable liquid or gas, is passed through the beam of a monochromic light source usually from a laser. The light scattered by the particles at various angles is measured by a multi-element detector, and numerical values relating to the scattering pattern are then recorded for subsequent analysis. The numerical scattering values are then transformed, using an appropriate optical model and mathematical procedure, to yield the proportion of total volume to a discrete number of size classes forming a volumetric particle size distribution (e.g. d50 or d(0.5) describes a particle diameter corresponding to 50% of cumulative undersize distribution; d90 or d(0.9) describes a particle diameter corresponding to 90% of cumulative undersize distribution).

Room temperature

Room temperature in the sense of the invention may be 20 - 25 °C, about 22 °C or 22°C.

Solubility in water

The solubility in water for an active pharmaceutical ingredient may be defined according to DAB 10 (Deutsches Arzneibuch [German Pharmacopoeia], 10th edition with 3rd revision 1994, Deutscher Apothekerverlag, Stuttgart and Govi Verlag, Frankfurt am Main, 2nd revision (1993), IV Allgemeine Vorschriften [IV General methods], p. 5 - 6, "Loslichkeit und Losungsmittel" ["Solubility and solvents"]; see also Ph. Eur. 4.07, 2004). Loading degree of Risperidone:

The microparticles were dissolved in acetonitrile followed by precipitation of the polymer with a buffer. The precipitated polymer was isolated by centrifugation and the clear supernatant was analyzed by HPLC for the drug content.

Loading degree of Paracetamol:

The microparticles were dissolved in Tetrahydrofuran (THF) overnight, the solution was turbid so using the centrifuging the solution was clear again, and it was analyzed by Ultraviolet-visible (UV/VIS) Spectroscopy.

Loading degree of BSA:

After producing the microparticles, washing it with water and filtering it, the aqueous phase was tested using the Bradford protein assay. The assay is a well-known spectroscopic analytical procedure used to measure the concentration of protein in a solution.

It is an indirect method to calculate the loaded BSA in the microparticles; by calculating it from the free BSA in the waste aqueous phase.

Examples

Materials Polymers

RESOMER® RG503 is a poly(D,L-lactide-co-glycolide) 50:50 copolymer with an inherent viscosity in the range of 0.32 - 0.44, or instance 0.43 dL/g.

RESOMER® RG 752H is a poly(D,L-lactide-co-glycolide) 75:25 copolymer with an inherent viscosity in the range of 0.14 - 0.22, or instance 0.2 dL/g. RESOMER® RG 756S is a poly(D,L-lactide-co-glycolide) 75:25 copolymer with an inherent viscosity in the range of 0.71- 1 .0.

RESOMER® 858S is a poly(D,L-lactide-co-glycolide) 85:15 copolymer with an inherent viscosity in the range of 1 .3 - 1 .7.

Stabilizer

Polyvinylalcohol (PVA), viscosity 30-50 mPa.s, molecular weight 31 ,000g/mol. Emuisifier

Tween 80 polyethylene sorbitol ester (molecular weight of 1 ,310 daltons).

Model drugs: Risperidone and Bovine serum albumin (BSA)

General method for examples 1 - 30:

Step a) middle size agglomerates of biodegradable polyester of the Resomer® type (PLGA) has been added to PEG 300, the PLGA is dispersed in the PEG 300 using a magnet stirrer for 2 min.

In case of encapsulation risperidone (examples 23 - 30) or bovine serum albumin was mixed with the dispersion.

Using the Ultraturrax® with 6000 rpm, the dispersion of Resomer® and PEG has been mixed for 2 min.

Step b) The mixture was added to 250 ml of water, which, where indicated, contained a stabilizer of (0.1 % PVA), or an emuisifier, Tween® 80, or both of PVA and Tween® together, the whole combination was mixed using the Ultraturrax® for 4 - 5 min.

Step c): The dispersion has been homogenized using the Microfluidizer®.

Microfluidizer parameter:

- 3 Loops. - Pressure: 1000 bar.

Step d): The mixture has been filtered using the vacuum pump; the filtrate got washed out from the filters using water.

Step e): The redispersed filtrate was mixed by the Ultraturrax® for 4 - 5 min.

Steps f) and q): The step of filtration and washing has been repeated for 5 times, to guarantee a complete washing for the particles.

Step h): The filtrate was washed with water 100 ml for the last time and has been placed in the freeze dryer for around 3 days.

Step i): The filtrate from step h) was collected as the final powder without the need of any milling or further comminution. The particle size was as indicated in table 1 . Except for the freeze drying the process steps were carried out at room temperature. Examples 1 - 30

Tab e 1

*)=Positive result means that a fine redispersible powder was obtained

**) = Negative result means that the emulsion could not be stirred or no particles could be formed or collected. ***)= Final stage of washing was with Microfluidizer® Table 2

Nr. Polymer Plasticizer Stabilizer emulsifier API homogenizing Loading degree

23 4g Resomer® 40g PEG 300 0.1 % PVA — 300 mg Ultra turrax® 49%

503H Risperidone

24 4g Resomer® 40g PEG 300 0.1 % PVA 0.1% 300 mg Ultraturrax® 48%

503H Tween80 Risperidone

25 4g Resomer® 40g PEG 300 — 0.1% 300 mg Ultraturrax® 29%

503H Tween80 Risperidone

26 4g Resomer® 40g PEG 300 0.1 % PVA — 300 mg Ultraturrax® 49%

503H Risperidone

27 2g Resomer® 20g PEG 300 — — 100 mg Ultraturrax® 38%

503H Risperidone

C28 2g Resomer® 20g PEG 300 — 0.1% 100 mg Microfluidizer® Below the detection 503 H Tween80 Paracetamol limits

C29 2g Resomer® 20g PEG 300 0.1 % PVA — 100 mg icrofluidizer® Below the detection 503 H Paracetamol limits

30 2g Resomer® 20g PEG 300 — 100 mg BSA Microfluidizer® 80%

503H

Claims

1 . Process for preparing a redispersible powder from a water-insoluble,

biodegradable polyester including the steps a) mixing a granulate of a water-insoluble, biodegradable polyester with a water- soluble plasticizer with a molecular weight of 100 or more, at a ratio of at least 7.5 parts per weight of the plasticizer per 1 part per weight of the water- insoluble, biodegradable polyester, to give a dispersion or solution, b) mixing the dispersion or solution from step a) with water at a ratio of at least 5 parts per weight of water per 1 part of weight of the dispersion or solution, to obtain an emulsion, c) homogenizing the emulsion from step b) by means of high shear mixing to promote the transfer of the water-soluble plasticizer to the water phase and to precipitate the water-insoluble, biodegradable polyester, d) filtrating the mixture from step c) to gain the filtrated mass, e) redispersion of the filtrated mass in water by means of high shear mixing f) filtrating the dispersion from step e) to obtain the filtrated mass, g) repeating steps e) and f) for at least one time, h) drying of the final filtrated mass, i) collection of the dried mass as the redispersible powder.

2. Process according to Claim 1 , where the redispersible powder in step i) has a particle size d(0.5) in the range of 0.1 - .5 μηη .

3. Process according to Claim 1 or 2, wherein the water-insoluble, biodegradable polyester polymer is a polylactic acid, a polyglycolic acid, a poly-caprolactone, a lactic acid-glycolic acid copolymer, a lactic acid-glycolic acid-polyethylene blockcopolymer, a lactic acid-glycolic acid-caprolactone terpolymer, a lactic acid-caprolactone copolymer, a poly dioxanone or a lactic acid-trimethylene carbonate copolymer or blends thereof.

4. Process according to any of Claims 1 to 3, wherein the water-soluble

plasticizer with a molecular weight of 100 or more is a polyethylene glycol, preferably a polyethylene glycol with a molecular weight of 200 to 2000.

5. Process according to any of Claims 1 to 4, wherein high shear mixing is

performed by an Ultraturrax® or by a Microfluidizer® equipment.

6. Process according to any of Claims 1 to 5, wherein the water phase of step b) comprises a stabilizer or an emulsifier or both.

7. Process according to Claim 6, wherein the stabilizer is a polyvinyl alcohol or a polyoxamer.

8. Process according to Claim 6, wherein the emulsifier is a polyoxyethylen- sorbitan ester.

9. Process according to Claim 6 or 8, wherein the emulsifier is

polyoxyethylen(20)-sorbitan-monooleat, polyoxylated castor oil or sodium dodecyl sulphate.

10. Process according to any of Claims 1 to 9, wherein an active pharmaceutical ingredient with a water solubility of less than 14mg/L is added in step a).

1 1 . Process according to Claim 10, wherein an active pharmaceutical ingredient is risperidone or olanzapine.

12. Process according to any of Claims 1 to 10, wherein an active pharmaceutical ingredient which is a peptide or a protein is added in step a).

13. Redispersible powder of a water-insoluble, biodegradable polyester obtained from the process according to any of the Claims 1 to 12.

14. Redispersible powder according to Claim 13 with a particle size d(0.5) in the range of 0.1 - 1 .5 μητι .