NL9400795A - Process for the preparation of dry-processed particles, dry-processed particles obtained by this process and pharmaceutical preparations containing such particles. - Google Patents

Description

METHOD FOR PREPARING DRY PROCESSED PARTICLES, DRY PROCESSED PARTICLES OBTAINED THAT PROCESS AND PHARMACEUTICAL PREPARATIONS CONTAINING SUCH PARTICULATES

The present invention relates to a process for preparing dry-processed particles containing an active ingredient mixed with a biocompatible polymer. The invention also relates to dry-processed particles obtained by this method and to pharmaceutical preparations containing such particles.

In this application, the term "active ingredient" means any therapeutically active substance or therapeutically active mixture that can be advantageously administered to humans or animals for diagnosis, cure, relief, treatment or prevention of diseases. By the term "polymer" is meant homopolymers, copolymers or a combination thereof. Finally, by "dry-processed particles" is meant particles prepared by a process in which none of the components of the particles are to be dissolved in a solvent, which must be removed to recover the particles.

Particles or microparticles containing one or more active ingredients, methods for their preparation and use in pharmaceutical preparations are known. When the preparation of such microparticles comprises suspending or dissolving a polymer in a solvent, the obtained microcapsules usually contain (at least) traces of the solvents used in their preparation; this may hinder certain therapeutic applications. If the preparation of such microparticles involves extrusion and / or grinding, this results in particles having an irregular external surface; the presence of the active ingredient on the outer surface of the particles and the irregularity of this surface prevent the precise control of the bursting effect in case the microparticles are intended to release an effective amount of an active ingredient for a predetermined period of time to give.

Some methods of manufacturing particles that do not use a solvent and extrusion and / or grinding techniques are known. For example, patent application WO92 / 21326 relates to a process comprising the conversion of a mixture of a drug and biocompatible polymers into an intermediate liquid phase by heating, the liquid phase being poured onto a temporary matrix consisting of crystals, the liquid phase is converted to a solid phase by cooling and then the solid phase matrix is removed by washing. Thus, the solid phase occurs in a form where impressions of the structure of the crystals of the temporary matrix are present. Consequently, the particles thus obtained have an irregular external surface and are thus not spherical, so that the properties required for precise control of the release are not obtained.

Hot melt encapsulation is another method that has been investigated and described (see, e.g., E. Mathiowitz and R. Langer, Journal of Controlled Release, 5 (1987) 13-22; the method involves mixing a drug and a molten polymer, followed by suspending this mixture in a solvent that is immiscible with the selected polymer and the drug After stabilization of the obtained emulsion, it is cooled until the core material solidifies, however, according to this method, only a polymer with a low melting point, i.e., 70-80 ° C or less, when using a polymer with a higher melting point, this polymer must be used or combined with a plasticizer to lower the melting point to a temperature at which the process can be carried out, so it is impossible obtain particles containing only the drug and a high melting point polymer and carry out such a process at a high temperature hours, for example, to use it for a pure polymer with a high melting point, leads to the constituents sticking and possible degradation of the drug. In addition, the microspheres thus obtained have a granular external surface, and the low melting point of the polymer used can prevent the storage and preservation of the microspheres.

With the method described in British Patent 2246514 it is possible by means of an appropriate treatment in a gel to make particles which have been manufactured by conventional methods known in the pharmaceutical industry, extruding and grinding, substantially spherical, wherein in the external coating no active ingredient is present. The particles thus obtained, which are dry-processed without the use of a solvent, are called microspheres; these substantially spherical particles with no active ingredient in the outer coating provide a delayed release of an effective amount of an active ingredient for a predetermined period of time, whereby the release and burst effect can be well controlled. Although this method is quite satisfactory, since the products have greatly improved over the starting material, the starting material has the disadvantage that it is less pure with respect to the active ingredient - such as a peptide - which is usually sensitive to extrusion and grinding. Such steps usually have an adverse effect on purity, usually decreasing by 1 to 5%. Considering the high cost of the peptide and the potential drawbacks of the presence of degradation products in the drug, this is an important point.

In addition, if such microspheres are obtained from particles produced by extrusion and milling, the core loading of such microspheres is usually less than 10%; the method can be used to obtain microspheres with a core load greater than 10%, but there is a substantial loss of active ingredient during processing, and the method cannot be used to obtain microspheres with a core load of more than 15% due to the crumbling of the rods. In some cases, it may be desirable to obtain particles with a core load greater than 15%.

The invention provides a method of preparing particles without the drawbacks of the prior art methods.

In contrast to the method of the above-mentioned British Patent, the method of the present invention does not start from manufactured particles, but as starting materials only the constituents of the microspheres and a carrier phase are used and only heating / cooling and stirring techniques are used; conventional techniques such as dry mixing, extrusion and grinding are no longer necessary. The method of the invention can be used to obtain microspheres with a core loading of 1, 5, 10, 15% or more.

Also, the particles obtained according to the present invention are almost spherical and do not contain any active ingredient in the outer coating, therefore they may also be called microspheres. In addition, the particles of the present invention are dry-processed without using solvents.

The invention provides a process for preparing dry-processed particles which are substantially spherical and which consist of an active ingredient incorporated in a high melting point biocompatible polymer comprising the following steps: mixing the biocompatible polymer with stirring and the active ingredient, either in solid or liquid form in an appropriate amount with respect to the amount of the biocompatible polymer, with an immiscible homogeneous liquid carrier phase, the carrier phase having a viscosity of 3,000 to 15,000 mPa.s (at 25 ° C) and the active ingredient and the biocompatible polymer are insoluble in the homogeneous liquid carrier phase, - continue stirring to form microspheres of the biocompatible polymer and the active ingredient is fully incorporated therein, until microspheres whose sizes are in the desired range, the processing being obtained temperature is above the glass transition temperature of the biocompatible polymer, and - finally, the microspheres thus obtained recover.

According to the invention, the process for preparing dry-processed particles may successively comprise the following steps: - stirring mixing a phase containing a high melting point biocompatible polymer with an immiscible homogeneous liquid carrier phase having a viscosity of 3,000 up to 15,000 mPa.s (at 25 ° C), and in which the biocompatible polymer is insoluble, bringing the resulting mixture to a temperature above the glass transition temperature of the biocompatible polymer with stirring using a suitable heating or cooling medium - continuing the stirring until microspheres of the biocompatible polymer, the size of which is in the required range, are formed, - then adding an active ingredient which is insoluble, while stirring at a temperature above the glass transition temperature of the biocompatible polymer. in the homogeneous liquid carrier phase, either in solid or liquid form, in the j correct amount with respect to the amount of the biocompatible polymer, - continuing to stir so that more and more of the active ingredient is incorporated into the microspheres of the biocompatible polymer until the active ingredient is completely absorbed, followed by stopping stirring and cooling the mixture, - finally after adding a suitable detergent in which neither the biocompatible polymer nor the active ingredient dissolves, by filtering and recovering the obtained microspheres and - optionally subjecting the particles to a sterilization step.

According to the invention, the process for preparing dry-processed particles may successively comprise the following steps: - mixing, while stirring, a phase containing a component which is thermostable at the temperature of the process, with an immiscible homogeneous liquid carrier phase having a viscosity has from 3,000 to 15,000 mPa.s (at 25 ° C) and in which the active ingredient is insoluble, - bringing the resulting mixture to a temperature above the glass transition temperature of a glass temperature while stirring using a suitable heating or cooling medium. biocompatible polymer which is added in the next step, - then adding a biocompatible polymer at a temperature above its glass temperature in the appropriate amount with respect to the amount of active ingredient, the polymer also being insoluble in the homogeneous liquid carrier form. se, - continuing to stir, so that the microspheres of h The biocompatible polymer is formed and more and more of the active ingredient is incorporated into the microspheres of the biocompatible polymer until the active ingredient is completely absorbed, and then the stirring is stopped and the mixture is cooled - finally after adding a suitable detergent in which neither the biocompatible polymer nor the active ingredient is soluble, then filtering and sieving the obtained microspheres and optionally subjecting the particles to a sterilization step.

In another embodiment, the method of the invention successively comprises the following steps: - stirring mixing a phase containing a high melting point biocompatible polymer with an ingredient thermostable at the temperature of the method, in the appropriate amount with relative to the amount of the biocompatible polymer, in an immiscible homogeneous liquid carrier phase, having a viscosity of 3,000 to 15,000 mPa.s (at 25 ° C) and in which the biocompatible polymer and the active ingredient are insoluble, - stirring, using a suitable heating or cooling medium, the resulting mixture at a temperature above the glass transition temperature of the biocompatible polymer, - continuing the stirring to form microspheres of the biocompatible polymer and increasingly of the active ingredient into the microspheres of the biocompatible polymer until the active ingredient is completely absorbed, then stop stirring and cool the mixture, - and finally after adding a suitable detergent in which neither the biocompatible polymer nor the active ingredient dissolves, filtering and recovering the microspheres obtained and - optionally subjecting the particles to a sterilization step.

It will be clear that the temperature of the process must be considerably below the temperature at which the components can break off.

The invention also provides dry-processed particles obtained by the method of the present invention, which particles are substantially spherical and consist of a mixture of an active ingredient and a high melting point biocompatible polymer, and wherein the outer coating of the particles is substantially does not contain any active ingredient.

Finally, the invention provides pharmaceutical preparations containing these particles. The dry-processed particles of the invention can be administered orally or by injection. When the particles are administered by injection, they are preferably less than 200 µm. When the particles are administered orally, their size is preferably in the range of 0.8 to 5 mm.

The carrier phase contains at least one homo- or copolymer in an amount up to 100%. The carrier phase can be a silicone oil, an injectable oil such as sesame oil, peanut oil or castor oil, which can be thickened by a suitable thickening agent, such as a stearate.

The carrier phase can be a hydrophobic or a hydrophilic gel. When the active ingredient is hydrophilic, the gel is preferably a hydrophobic, such as, for example, thickened oil; the microspheres can be recovered by washing the mixture with a suitable hydrophobic detergent such as isopropyl myristate. When the active ingredient is hydrophobic, the gel is preferably a hydrophilic gel, such as, for example, aqueous gel; the microspheres can be recovered by washing the mixture with a suitable hydrophilic detergent, such as, for example, water or a mixture of water and ethanol.

When silicone oil is used as the carrier phase, the hydrophobic or hydrophilic character of the active ingredient is of no importance because most of the active ingredients are insoluble in such a phase.

The biocompatible polymer used in the invention can be a polysaccharide, cellulose polymer (e.g., hydroxymethyl cellulose, hydroxypropylmethyl cellulose), polyvinylpyrrolidone or a polypeptide. The biocompatible polymer used may also be a biocompatible and biodegradable polymer, such as a homopolymer or copolymer of ε-caprolactone, a denatured protein, polyorthoesters or polyalkyl cyanoacryl (ate). The biocompatible polymer used may also be a biocompatible and bioresorbable polymer, such as a homopolymer or copolymer of lactic acid and glycolic acid. The biocompatible polymer used also has a high melting point. It is advantageous if the biocompatible polymer has a melting point above 150 ° C.

The biocompatible polymer used for the preparation of microspheres intended to deliver an effective amount of an active ingredient for a predetermined time, preferably has a glass transition temperature (Tg) between 25 and 200 ° C, more preferably between 35 and 150 ° C. In a preferred embodiment, the biocompatible polymer is a bioresorbable polymer.

According to the invention, the active ingredient can be in solid or liquid form at room temperature. By liquid form is meant a liquid form that is immiscible with the carrier phase.

During the process, the main parameters affecting the size of the microspheres are the stirring conditions, the temperature and the viscosity of the carrier phase.

Stirring may be effected during the raising of the temperature or stirring may be started if the temperature has reached a value above the glass transition temperature of the biocompatible polymer. Stirring can be done in various ways, for example with a polytron or an ultra-sound generator. The ultra-sound generator stirs and heats at the same time.

The size of the particles of the biocompatible polymer used as the starting material is not critical and the size of the particles can range from about 300 µm to 5 mm; in any case, the particles will be reduced to the required size by stirring and / or heating appropriately. For example, 5 mm particles can be obtained by slowly stirring in a highly viscous carrier phase, while 300 µm particles can be obtained by vigorous stirring in a lower viscosity carrier phase.

The viscosity of the homogeneous carrier phase can be from 3,000 to 15,000 mPa.s (at 25 ° C). Preferably, the viscosity is 5,000 to 12,000 mPa.s (at 25 ° C), more preferably about 10,000 mPa.s (at 25 ° C).

Depending on the stability of the components and the various parameters involved in the process, the incorporation of the active ingredient into the polymer matrix can be performed quickly by running the process at a temperature above 100 ° C, and thus sterilized simultaneously turn into. Of course, the polymer matrix can be pre-sterilized: if the matrix is heated to a temperature above the glass transition temperature of the biocompatible polymer, sterilization will occur simultaneously. If the gel is hydrophilic, the pressure must be increased to avoid forming a vapor phase; for example, the polymer in the carrier phase can be autoclaved at 120 ° C for about 20 minutes, and then cooled to the appropriate processing temperature. In any case, the particles obtained by the method of the invention can be sterilized, if necessary, by any known technique, for example by radiation sterilization.

The following examples illustrate the invention.

Example 1

This example shows that the particles of the invention do not contain an active ingredient in the outer homogeneous coating.

Carrier phase: silicone oil (γ = 10,000 mPa.s at 25 ° C)

Biocompatible Polymer: Poly Lactide co Glycoli-de, designated PLGA, 50/50 (weight average molecular weight = 40,000 to 50,000).

Fictional active ingredient: blue hydrophilic dye, for example Blue Patente V - particle size: 10 / Lim.

PLGA 50/50 was added to a reactor containing 100 ml of silicone oil. The PLGA mixture was dispersed with stirring at room temperature for 5 minutes. Stirring was stopped and the mixture was heated to 110 ° C. Stirring was resumed and the blue dye was added. Stirring was continued at 125 ° C for 30 minutes to incorporate the fictitious active ingredient into the dry microspheres; stirring was stopped and the mixture was allowed to cool in a freezer at 20 ° C overnight. The mixture was washed with isopropyl myristate, filtered and dried to yield blue particles. Neither the silicone oil nor the detergent was colored during washing.

The particles thus obtained were dispersed in 200 ml of water, but the water was found not to be colored. The particles were dispersed in dichloromethane and the dispersion was then diluted with water; the water turned blue.

Example 2

Carrier phase: silicone oil (γ = 10,000 mPa.s at 25 ° C)

Bio-compatible polymer: PLGA 50/50, milled to 200 μιη

Active ingredient: D-Trp6LHRH pamoate - particle size: 5 to 10 µl 5 g PLGA 50/50 was added with stirring to a reactor containing 500 ml silicone oil. The PLGA 50/50 particles were dispersed in the oil and the mixture heated to 80-100 ° C. Then 0.175 g of peptide particles were added with stirring. The inclusion of more and more peptide particles in the polymer particles and / or on the surface of the polymer particles can be observed. The mixture was stirred at the same temperature for 20 minutes and then heated to 125 ° C. Stirring was then stopped and the mixture was cooled to 25 ° C, diluted with 9 parts by volume of isopropyl myristate as detergent and filtered with a 3 Mm filter to yield 4.5 g of particles.

Example 3

Carrier phase: silicone oil (γ = 5,000 mPa.s at 25 ° C)

Bio-compatible polymer: PLGA 50/50, ground to 200 Mm

Active ingredient: D-Trp6LHRH acetate - particle size: 5 to 10 µm.

5 g of PLGA 50/50 was added with stirring to a reactor containing 500 ml of silicone oil. The PLGA 50/50 particles were dispersed in the oil and the mixture heated to 80-100 ° C. Then 0.170 g of peptide particles were added with stirring. The inclusion of more and more peptide particles in the polymer particles and / or on the surface of the polymer particles can be observed. The mixture was stirred at the same temperature for 20 minutes and then heated to 125 ° C. Stirring was then stopped and the mixture was cooled to 25 ° C, diluted with 9 parts by volume of isopropyl myristate as detergent and filtered with a 3Mm filter to yield 4.8 g of particles.

Example 4

Carrier phase: silicone oil (γ = 10,000 mPa.s at 25 ° C)

Bio-compatible polymer: PLGA 50/50, ground to 200 Mm

Active ingredient: somatulin pamoate - particle size: 5 to 10 µl 5 g PLGA 50/50 was added with stirring to a reactor containing 500 ml silicone oil. The PLGA 50/50 particles were dispersed in the oil and the mixture heated to 100-120 ° C. Then 0.980 g of peptide particles were added with stirring. The inclusion of more and more peptide particles in the polymer particles and / or on the surface of the polymer particles can be observed. The mixture was stirred at the same temperature for 30 minutes and then heated to 130 ° C. Stirring was then stopped and the mixture was cooled to 25 ° C, diluted with 9 parts by volume of isopropyl myristate as a detergent and filtered with a 3 µm filter to yield 5.1 g of particles.

Example 5

Carrier phase: polyvinylpyrrolidone K60 in water (45% w / v) (γ = 10,000 mPa.s at 25 ° C)

Bio-compatible polymer: PLGA 50/50, ground to 200 µm

Active ingredient: steroids (progesterone) particle size: 5 to 10 µm 8 g PLGA 50/50 was added with stirring to a reactor containing 500 ml PVP gel. The PLGA 50/50 particles were dispersed in the gel and the mixture was heated to 95 ° C. 2.44 g of progesterone particles were then added with stirring. The inclusion of more and more steroid particles in the polymer particles and / or on the surface of the polymer particles can be observed. The mixture was stirred at the same temperature for 30 minutes. Stirring was then stopped and the mixture was cooled to 25 ° C, diluted with 10 parts by volume of water as a detergent and filtered with an 8 µl filter to yield 9.96 g of particles.

Example 6

Carrier phase: silicone oil (γ = 10,000 mPa.s at 25 ° C)

Bio-compatible polymer: e-caprolactone polymer, ground to 200 µm

Active ingredient: D-Trp6LHRH pamoate - particle size: 5 to 10 µm 1 g of the polymer was added with stirring to a reactor containing 500 ml of silicone oil. The polymer particles were dispersed in the oil and the mixture was heated to 80 ° C. Then 37 mg of peptide particles were added with stirring. The inclusion of more and more peptide particles in the polymer particles and / or on the surface of the polymer particles can be observed. The mixture was stirred at 110 ° C for 10 minutes. Stirring was then stopped and the mixture was cooled to 25 ° C, diluted with 9 parts by volume of isopropyl myristate as detergent and filtered with a 3 µl filter to yield 0.952 g of particles.

Example 7

Carrying phase: aluminum stearate in sesame oil (4% w / v) (γ = 12 500 mPa.s at 25 ° C)

Bio-compatible polymer: PLGA 50/50, ground to 200 Mm

Active ingredient: triptorelin pamoate - particle size: 5 to 10 mm 10 g of PLGA 50/50 was added with stirring to a reactor containing 500 ml of Al stearate in sesame oil. The PLGA 50/50 particles were dispersed in the gel and the mixture heated to 120 ° C. Then 0.638 g of peptide particles with 100 mg of sorbitan fatty acid ester were added with stirring. The inclusion of more and more peptide particles in the polymer particles and / or on the surface of the polymer particles can be observed. The mixture was stirred at 120 ° C for 20 minutes. Stirring was then stopped and the mixture was cooled to 25 ° C, diluted with 20 parts by volume of ethanol as a detergent and filtered with an 8 Ml-fliter to yield 9.2 g of particles.

Example 8

Carrier phase: aluminum stearate in sesame oil (4% w / v) (γ = 12 500 mPa.s at 25 ° C)

Bio-compatible polymer: poly-e-caprolactone, ground to 200 mm

Active ingredient: triptorelin pamoate - particle size: 5 to 10 µg 10 g of poly-ε-caprolactone was added with stirring to a reactor containing 500 ml of Al stearate in sesame oil. The poly-ε-caprolactone particles were dispersed in the gel and the mixture heated to 120 ° C. Then 0.638 g of peptide particles with 100 mg of span 80 were added with stirring. The inclusion of more and more peptide particles in the polymer particles and / or on the surface of the polymer particles can be observed. The mixture was stirred at 120 ° C for 30 minutes. Stirring was then stopped and the mixture was cooled to 25 ° C, diluted with 20 parts by volume of ethanol as a detergent and filtered with an 8 µl filter to yield 8.7 g of particles.

Example 9

Carrier phase: silicone oil (γ = 10,000 mPa.s at 25 ° C)

Bio-compatible polymer: PLGA 75/25, ground to 200 Mm

Active ingredient: tiliquinol (bactericidal) particle size: 5 to 10 µm 8 g PLGA 75/25 and 1.23 g tiliquinol particles were added with stirring to a reactor containing 500 ml silicone oil. The mixture was heated to 80-100 ° C. The gradual formation of the microspheres and the inclusion of more and more tiliquinol particles in the microspheres can be observed. The mixture was stirred at the same temperature for 30 minutes. Stirring was then stopped and the mixture was cooled to 25 ° C, diluted with 9 parts by volume of isopropyl myristate as detergent and filtered with an 8 M 2 filter to yield 8.25 g of particles.

Example 10

Carrier phase: aluminum stearate in sesame oil (4% w / v) (γ = 12 500 mPa.s at 25 ° C)

Bio-compatible polymer: PLGA 75/25, ground to 200 Mm

Active ingredient: tiliquinol (bactericidal) particle size: 5 to 10 mm 2.16 g of tiliquinol particles were added with stirring to a reactor containing 500 ml of Al stearate in sesame oil. The tiliquinol particles were dispersed in the gel and the mixture was heated to 120 ° C. Then 10 g PLGA 75/25 was added with stirring. The gradual formation of the microspheres and the inclusion of more and more tiliquinol particles in the microspheres can be observed. The mixture was stirred at the same temperature for 25 minutes. Stirring was then stopped and the mixture was cooled to 25 ° C, diluted with 20 parts by volume of ethanol as a detergent and filtered with a 1 mm filter to yield 11.3 g of particles.

Claims (16)

Process for preparing dry-processed particles which are substantially spherical in shape and consist of an active ingredient which is incorporated in a high-melting biocompatible polymer, characterized in that: - the stirring is carried out with the biocompatible polymer and the active ingredient, or in solid or liquid form, in an appropriate amount with respect to the amount of the biocompatible polymer, mixes with an immiscible homogeneous liquid carrier phase having a viscosity of 3,000 to 15,000 mPa.s (at 25 ° C) and wherein the active ingredient and the biocompatible polymer are insoluble, then continue stirring to form microspheres of the biocompatible polymer and the active ingredient to be fully incorporated into the microspheres until microspheres the size of which is in the desired range are obtained, wherein the processing temperature is above the glass transition temperature of the biocompatible polymer, and - finally the microspheres thus obtained win. 2. Process according to claim 1, characterized in that: - while stirring, a phase containing a high-melting biocompatible polymer is mixed with an immiscible homogeneous liquid carrier phase having a viscosity of 3,000 to 15,000 mPa.s ( at 25 ° C) and in which the biocompatible polymer is insoluble, - stirring using a suitable heating or cooling medium the mixture thus obtained at a temperature above the glass temperature of the biocompatible polymer, - continuing stirring until microspheres of the biocompatible polymer having a size in the required range, then, with stirring at a temperature above the glass transition temperature of the biocompatible polymer, an active ingredient which is insoluble in the homogeneous liquid carrier phase, either in solid or liquid form, in the add appropriate amount with respect to the amount of the biocompatible polymer, - stirring continues thus that more and more of the active ingredient is incorporated into the microspheres of the biocompatible polymer until the active ingredient is fully absorbed, then stops stirring and cools the mixture, finally after adding a suitable detergent in which neither the biocompatible polymer nor the active ingredient is soluble, the microspheres obtained are collected by filtration and sieving, and - if necessary, the particles are subjected to a sterilization step. Process according to Claim 1, characterized in that: - while stirring, a phase containing a component which is thermostably active at the temperature of the process is mixed with an immiscible homogeneous liquid carrier phase having a viscosity of 3,000 to 15 000 mPa.s (at 25 ° C), in which the active ingredient is insoluble, - stirring using a suitable heating or cooling medium the temperature of the obtained mixture above the glass transition temperature of a high melting point biocompatible polymer is added in the next step, - then, while stirring at a temperature above its glass temperature, adds a biocompatible polymer in the appropriate amount with respect to the amount of the active ingredient, the polymer also being insoluble in the homogeneous liquid carrier phase, - the stirring continues to form microspheres of the biocompatible polymer and increasingly of the active agent The ingredient is incorporated into the microspheres of the biocompatible polymer until the active ingredient is completely absorbed, then the stirring is stopped and the mixture cools, - finally after the addition of a suitable detergent in which neither the biocompatible polymer nor the active ingredient dissolves, the microspheres obtained by filtration and sieving, and - optionally subjecting the particles to a sterilization step. Process according to claim 1, characterized in that: - with stirring a phase comprising a biocompatible polymer with a high melting point and a component which is thermostable at the temperature of the process in the correct amount with respect to the amount of the biocompatible polymer mixes with an immiscible homogeneous liquid carrier phase which has a viscosity of 3,000 to 15,000 mPa.s (at 25 ° C), and in which the biocompatible polymer and the active ingredient are insoluble, - with stirring using a suitable heating or cooling medium, the resulting mixture brings to a temperature above the glass temperature of the biocompatible polymer, - stirring continues to form microspheres of the biocompatible polymer and increasingly of the active ingredient into the microspheres of the biocompatible polymer until the active ingredient is completely absorbed, then stirring stops and the mixture cools - finally after adding a suitable detergent in which neither the biocompatible polymer nor the active ingredient dissolves, the microspheres obtained by filtration and recovery, and - optionally subjecting the particles to a sterilization step. Process according to any one of claims 1 to 4, characterized in that the carrier phase has a viscosity of 5,000 to 12,000 mPa.s (at 25 ° C). Process according to claim 5, characterized in that the carrier phase has a viscosity of about 10,000 mPa.s (at 25 ° C). A method according to any one of claims 1 to 4, characterized in that the carrier phase is a hydrophobic gel. A method according to claim 7, characterized in that the hydrophobic gel is a thickened oil. A method according to any one of claims 1 to 4, characterized in that the carrier phase is a hydrophilic gel. A method according to claim 9, characterized in that the hydrophilic gel is an aqueous gel. A method according to any one of claims 1 to 4, characterized in that the carrier phase is silicone oil. A method according to any one of claims 1 to 11, characterized in that the biocompatible polymer is a biodegradable polymer with a glass transition temperature between 25 and 200 ° C. A method according to any one of claims 1 to 12, characterized in that the biocompatible polymer is a biodegradable polymer with a melting point above 150 ° C. Dry-processed particles obtained by a method according to any one of claims 1 to 13, characterized in that the particles are substantially spherical and consist of a mixture of an active ingredient with a high melting point biocompatible polymer, and that the external coating of these particles contains practically no active ingredient. Particles according to claim 14, characterized in that the particles are intended to deliver an effective amount of an active ingredient over a predetermined period. Pharmaceutical composition, characterized in that it contains particles according to claim 14 or 15, mixed with a therapeutically acceptable diluent or carrier suitable for the chosen mode of administration.