FI112915B - Process for the preparation of dry-treated particles - Google Patents

Description

! 112915

This invention relates to a process for the preparation of dry-treated particles comprising an active ingredient in admixture with a biocompatible polymer.

As used herein, the term "active ingredient" is used to mean any therapeutically active substance or mixture that could be advantageously administered to a human or other animal for the purpose of diagnosing, curing, alleviating, treating or preventing a disease. The term "polymer" is used to encompass homopolymers and / or copolymers. Finally, " dry-treated particles " can be understood as particles prepared by a process wherein any constituent of said particles may not need to be dissolved in any solvent that should be removed prior to recovery of said particles.

Particles or microparticles containing one or more active ingredients, methods for their preparation and their use in pharmaceutical compositions are well known. When the preparation of such microparticles involves the suspension or dissolution of the polymer in a solvent, the microcapsules so obtained generally contain (at least) residues of the solvents used in their treatment; this may be • ': barrier to some therapeutic uses. When the preparation of such microparticles involves extrusion and / or grinding, this implies the formation of particles having irregular external surfaces; the presence of the active ingredient on the outer surfaces and the irregularity of said surfaces do not allow precise control of the release effect in the case of microparticles designed to release an effective amount of the active ingredient over a predetermined period of time.

'·; However, some methods are known for producing particles without the use of solvent and molding techniques: For example, in International PCT Application WO92 / 21326, the process comprises modifying a mixture of a drug and a biocompatible polymer by heating a liquid intermediate: the liquid phase is poured into a temporary matrix consisting of crystals, the liquid phase is transformed into a solid phase by cooling, then the matrix is removed from the solid phase by washing, thus the solid phase is in a form comprising depressions of the structure of the temporary matrix crystals. spherical, so that they do not give the mi-5 any close control of the required characteristics.

Another method described as hot-melt encapsulation (see, for example, E. Mathiowitz and R. Langer, Journal of Controlled Release, 5: 13-22 (1987)) has been studied and described; the method comprising admixing the drug and the molten polymer, then suspending said mixture in an immiscible solvent of the selected polymer and drug. After stabilizing the resulting emulsion, it is cooled to solidification of the core material. According to this method, the polymer used is only a polymer having a low melting point, i.e., 70-80 ° C, or lower if a polymer with a higher melting point is involved, said polymer must be combined with a plasticizer to lower the melting point to can be performed. Thus, it is impossible to obtain particles comprising only the drug and only the high melting point polymer, and changing such a process at a high treatment temperature, for example to use said process with a pure high melting point polymer, results in adhesion of the ingredients and possible degradation of the drug. Furthermore, the microspheres thus obtained have a granulated outer surface, and the low melting point of the polymer used may be the storage of said microspheres; and barrier to storage.

'·': In the 25 GB patent 2246514 the method allows, by suitable gel treatment, far- ;;; converting the particles prepared by techniques well known in the art of mass production, extrusion and grinding, into a substantially spherical shape while removing the active ingredient in the outer coating. The thus obtained: 'particles which have been treated dry and without using any solvents are called' 1; · '30 into microballs; these substantially spherical particles having the active ingredient removed from the overlay coating allow the effective release of the active ingredient "·" · for a predetermined period of time; · During the son, with good control of the release and release effect. Although the above process is very satisfactory, as far as the products are much better compared to the starting material, said starting material has the disadvantage of lower purity with respect to an active ingredient - such as a peptide - which is generally sensitive to extrusion and grinding; such steps are generally detrimental to purity, which is currently reduced by 1-5%. Given the high cost of the peptide material and the potential disadvantages associated with the presence of drug degradation products, this is an important consideration.

Further, when such microspheres are obtained from extruded and milled particles, the amount of said microspheres in the core is generally less than 10 to 10%: the process can be used to obtain microspheres greater than 10% in the core, but the active ingredient is substantially lost during processing. to obtain microspheres containing more than 15% of the core due to the easy friability of the rods. Therefore, in some situations, it may be desirable to obtain particles having a core content greater than 15% to 15%.

According to the invention, a new process for the preparation of particles is proposed which avoids the disadvantages of the techniques described in the previous processes.

20

Compared to the aforementioned GB patent, the process according to the invention is carried out without using the prepared particles but starting with only '· microspheres ingredients and carrier phase, and with techniques only heating / cooling and · mixing; Conventional techniques such as dry mixing, extrusion and milling are no longer necessary. The process of the invention may be carried out to provide microspheres containing 1, 5, 10, 15% or more in the core.

By the process of the invention, the particles are also substantially in the shape of a bead and lack an active ingredient from the surface: they can also be called microspheres; in addition, the particles of the invention have been treated dry and mi- ':' without the use of solvents.

4, 112915

The invention provides a process for preparing substantially spherical dry-processed particles consisting of an active ingredient incorporated into a high melting point polymer comprising the steps of: - adding, with stirring, said biocompatible polymer and said active ingredient in either solid or liquid form; within the amount of the biocompatible polymer, within an immiscible, homogeneous liquid carrier phase having a viscosity of between 3000 and 15000 mPa.s (25 ° C), said active ingredient and the biocompatible polymer being insoluble in said homogeneous carrier liquid phase, mixing until microspheres of a biocompatible polymer are formed and the active ingredient is completely immersed in the microspheres until the required size of the microspheres is reached, at which the processing temperature is higher than the glass point of the compatible polymer, and - finally recovering the microspheres thus obtained.

According to the invention, the process for preparing the dry-treated particles may comprise the following series of steps: - adding, with stirring, a phase containing the biocompatible polymer having a high melting point to an immiscible, homogeneous liquid carrier having a viscosity of 3000-15000 mPa.s; (At 25 ° C) and said biocompatible polymer is also insoluble in said carrier; - subjecting the mixture thus obtained to a temperature above the glass point of the biocompatible polymer, by suitable heating or cooling,:: - then stirring is maintained until microspheres of the biocompatible polymer are present within the required size range, the active ingredient insoluble in the homogeneous carrier liquid phase, either in solid or liquid form, and in appropriate proportions to the amount of the biocompatible polymer, 112915 - finally, after adding a suitable detergent that is neither a solvent for the biocompatible polymer nor the active ingredient, recovering microspheres by filtration and screening, and - subjecting the particles to a possible sterilization step.

5

Alternatively, according to the invention, the process for preparing the dry-treated particles may comprise the following series of steps: - adding, with stirring, a phase containing the active ingredient which is thermally stable at the treatment temperature to an immiscible, homogeneous liquid carrier having a viscosity of 3000-15000 -s (at 25 ° C), and said active ingredient is insoluble in the carrier phase, - stirring the resultant mixture using a suitable heating or cooling method at a higher temperature of the glass of the high melting point biocompatible polymer, - then adding stirring the glass point of the biocompatible polymer at a temperature higher than the biocompatible polymer in appropriate proportions to the amount of the biocompatible polymer, said polymer also being in a homogeneous liquid carrier phase insoluble, 20 - maintaining the mix to allow the formation of microspheres of the biocompatible polymer and the active ingredient to proceed to the micropal-Los of the biocompatible polymer until complete absorption, then mixing is stopped and the mixture is cooled, - finally, a suitable biocompatible and the active ingredient, then recover the resulting microspheres by filtration and screening, and optionally subject the particles to a sterilization step.

In a further embodiment, the method of the invention may comprise the following; 30 stages of step: - adding, with stirring, a phase containing a high melting point, biocompatible polymer, an active ingredient at processing temperature;. Thermally stable, in appropriate proportions to the amount of biocompatible polymer; , within a homogeneous liquid carrier phase having a viscosity of 3000-15000 mPa * s (at 25 ° C) of said carrier phase, said active ingredient and active ingredient being insoluble in said carrier phase, subjecting the mixture thus obtained to suitable heating - or cooling method 5 using a glass point of the biocompatible polymer to a higher temperature, - maintaining agitation to allow the formation of microspheres of the biocompatible polymer and the progressive passage of the active ingredient to the micropal-Los until its complete absorption, then mixing lo decanting and cooling the mixture, 10 - finally, after addition of a suitable detergent, which is neither a solvent of the biocompatible polymer nor of the active ingredient, the microspheres thus obtained are recovered by filtration and screening, and - possibly subjected to a sterilization step.

Apparently, the processing temperature should be clearly lower than the temperatures at which the ingredients may decompose.

The invention thus provides dry-treated particles which are substantially spherical and consist of a mixture of the active ingredient with a high melting point, biocompatible polymer, the outer coating of which is substantially free of the active ingredient. Such particles can be used in pharmaceutical compositions. The dry-treated particles obtained according to the invention may be administered orally or by injection. For injection, the particle size should be less than 200 µm. For oral administration, said particles preferably have a size of 0.8 to 5 mm.

Your carrier may contain at least one homo- or copolymer and may comprise up to 100% of its composition. Your carrier may be a silicone oil, an injectable oil; 'Such as sesame oil, peanut oil or castor oil, which may be in a suitable thickening agent; · 'Thickened, such as stearate.

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

5

However, when a silicone oil is used as the carrier phase, the hydrophobic or hydrophilic nature of the active ingredient is of no importance due to the insolubility of most of the active ingredient in such phase.

The biocompatible polymer used in accordance with the invention may be a polysaccharide, a cellulose polymer (e.g., hydroxymethylcellulose, hydroxypropylmethylcellulose), polyvinylpyrrolidone or a polypeptide. Alternatively, the biocompatible polymer used may be a biocompatible and biodegradable polymer such as a homopolymer or copolymer of? -Caprolactone, denatured protein, poly-15 orthoesters or polyalkyl cyanoacrylate. Alternatively, the biocompatible polymer used may be a biocompatible and bioabsorbable polymer such as a homopolymer or copolymer of lactic acid or glycolic acid. Further, the biocompatible polymer used is a high melting point biocompatible polymer: said polymer may advantageously be a biocompatible polymer having a melting point above 150 ° C.

Preferably, the biocompatible polymer used to prepare microspheres designed to release an effective amount of the active ingredient over a predetermined period of time is a biodegradable polymer having a glass point (i.e., 25 Tg) between 25 and 200 ° C, and preferably between 35 and 150 ° C. In a preferred embodiment, the biocompatible polymer may be a bioabsorbable polymer.

According to the invention, the active ingredient may be in solid or liquid form at room temperature. Thus, the liquid form can be understood as the liquid form which '; '30 is immiscible with the carrier phase.

': ": During the process, the most important parameters related to the size of the microspheres are the mixing conditions, the temperature and the viscosity of the carrier phase.

8 112915

The mixing can be maintained during the temperature increase, or it can be started when the temperature has reached a temperature higher than the glass point of the biocompatible polymer.

The mixing can be accomplished using various means such as a polytron or an ultrasonic generator; the ultrasonic generator involves mixing with heating.

The particle size of the biocompatible polymer used as the starting material is not critical and the particle size may be indifferent from about 300 µm to about 5 mm: the size will in any case be reduced to the required size by suitable mixing and / or heating. For example, particles having a size of 5 mm can be obtained by low mixing in a high viscosity carrier phase, while particles having a size of 300 µm can be obtained by vigorous mixing in a lower viscosity carrier phase.

15

The homogeneous carrier phase may have a viscosity of 3000-15000 mPa.s (25 ° C). Preferably, the viscosity is 5000-12000 mPa-s (at 25 ° C), and more preferably about 10,000 mPa-s (at 25 ° C).

Depending on the stability of the components and the various parameters involved, a rapid process for incorporation of the active ingredient into the polymer matrix can be performed at a temperature above 100 ° C, and sterilization can take place at the same time. Apparently, the polymer matrix may be previously sterilized: when the matrix is heated to biohydrogen; If sterilization is performed at temperatures higher than glass points, sterilization may be performed simultaneously. When the gel is hydrophilic, the pressure is increased to avoid the vapor phase: for example, the polymer within the carrier phase can be autoclaved at about 120 ° C for about 20 minutes and then cooled to a suitable treatment temperature. In any case, the particles obtained according to the invention may be sterilized: if necessary by any known technique, such as, for example, X-ray sterilization.

The following examples illustrate the invention.

9, 112915

EXAMPLE 1 This example demonstrates that the particles of the invention do not contain the active ingredient in a homogeneous outer coating.

5

Carrierase: silicone oil (y = 10,000 mPa.s at 25 ° C)

Biocompatible polymer: polylactide dicoglycolide, called PLGA, 50/50 (mass average molecular weight range = 40000-50000)

Fabricated Active Ingredient: Blue Hydrophilic Dye, i.e. Blue Patente V-10 Particle Size: 10 µm PLGA 50/50 was added to a reactor containing 100 ml silicone oil. The PLGA mixture was dispersed for 5 min at room temperature with stirring. Stirring was stopped and the mixture was heated to 110 ° C. Stirring was resumed and blue dye was added. The stirring was maintained at 125 ° C for 30 min to incorporate the artificial active ingredient in dry microspheres; stirring was stopped and the mixture was allowed to cool overnight in a freezer at 20 ° C. The mixture was washed with myristic acid isopropyl ester, filtered and dried to recover blue particles. No leaching was observed during washing with silicone oil or detergent.

The particles thus obtained were dispersed in 200 ml of water, but no water color was observed. epithelial. The particles were dispersed in dichloromethane and then diluted with water: · the water turned blue.

; ': 25 Example 2:': Carrierase: silicone oil (y = 10,000 mPa.s at 25 ° C)

Biocompatible polymer: PLGA 50/50, ground to 200 pn

Active Ingredient: D-Trp6LHRH Pamoate - Particle Size: 5-10 µm: ***: 30 µL, 5g PLGA 50/50 was added with stirring to a reactor containing 500ml of silicone oil.

.. ,,; The PLGA 50/50 particles were dispersed in oil and the mixture was heated to 80-100 ° C.

Then 0.175 g of peptide particles were added with stirring. A peptide particle can be detected; '. progressive penetration of the keloids into and / or onto the polymer particles. The mixture 10 112915 was stirred for 20 min at the same temperature and then heated to 125 ° C. Stirring was then stopped and the mixture was cooled to 25 ° C, diluted with 9 volumes of myristic acid isopropyl ester as detergent, and filtered at 3 µm to give 4.5 g of particles.

5

Example 3

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

Biocompatible polymer: PLGA 50/50, milled to 200 µm Active ingredient: D-Trp6LHRH acetate - particle size: 5-10 µm 5 g of PLGA 50/50 was added to a reactor containing 500 ml of silicone oil with stirring. The PLGA 50/50 particles were dispersed in oil and the mixture was heated to 80-100 ° C. Then, 0.170 g of peptide particles were added with stirring. Progressive passage of peptide particle-crystals into and / or on the surface of the polymer particles can be observed. The mixture was stirred for 20 min at the same temperature and then heated to 125 ° C. Stirring was then stopped and the mixture was cooled to 25 ° C, diluted with 9 volumes of myristic acid isopropyl ester as detergent and filtered at 3 µm to give 4.8 g of particles.

20

Example 4 '* Carrier phase: silicone oil (γ = 10,000 mPa.s at 25 ° C)

Biocompatible polymer: PLGA 50/50, milled to 200 µm! '*; Active Ingredient: Somatulin Pamoate Particle Size: 5-10 µm 5 g PLGA 50/50 was added with stirring to a reactor containing 500 ml of silicone oil. The PLGA 50/50 particles were dispersed in oil and the mixture was heated to 100-120 ° C.

Then, 0.980 g of peptide particles were added with stirring. Progressive passage of the peptide particles to and / or onto the polymer particles can be observed. The mixture was stirred for 30 min at the same temperature and then heated to 130 ° C.

; <| Stirring was then stopped and the mixture was cooled to 25 ° C, diluted with 9 volumes. myristic acid isopropyl ester as a detergent and filtered with 3 µm of. 5.1 g of particles were obtained.

u 112915

Example 5

Carrier phase: polyvinylpyrrolidone K60 in water (45% w / v) (γ = 10,000 mPa · s at 25 ° C) 5 Biocompatible polymer: PLGA 50/50, milled to 200 µm

Active ingredient: steroids (progesterone) - particle size: 5-10 µm 8 g PLGA 50/50 was added with stirring to a reactor containing 500 ml of PVP gel. PLGA 50/50 particles were dispersed in the gel and the mixture was heated to 95 ° C. Then 2.44 g of progegsterone particles were added with stirring. Progressive uptake of steroid particles into and / or on the polymer particles can be observed. The mixture was stirred for 30 min at the same temperature. Stirring was then stopped and the mixture was cooled to 25 ° C, diluted with 10 volumes of water as a detergent and filtered at 8 µm to give 9.96 g of particles.

15

Example 6

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

Biocompatible polymer: ε-caprolactone polymer, milled to 200 µm Active ingredient: D-Trp6LHRH pamoate, particle size: 5-10 µm / 1 g of polymer was added to the reactor containing 500 ml of silicone oil. Poly-: '. the meri particles were dispersed in oil and the mixture was heated to 80 ° C. Then: · 37 mg of peptide particles were added with stirring. Progressive peptide particles can be observed; 25 to and / or onto the polymer particles. The mixture was stirred for 10 min. 'At 110 ° C. Stirring was then stopped and the mixture was cooled to 25 ° C, diluted with 9 volumes of myristic acid isopropyl ester as detergent and filtered at 3 µm to give 0.952 g of particles.

:: 30 Example 7 ;: Carrierase: aluminum stearate in sesame oil (4% w / v) (y = 12,500 mPa.s · 25 ° C); '. Biocompatible polymer: PLGA 50/50, milled to 200 µm 12112915

Active ingredient: triptorelin pamoate, particle size: 5-10 µm 10 g PLGA 50/50 was added with stirring to a reactor containing 500 ml Al stearate in sesame oil. The PLGA 50/50 particles were dispersed in the gel and the mixture was heated to 5 120 ° C. Then, 0.638 g of peptide particles with 100 mg of sorbitan fatty acid esters were added with stirring.

Progressive uptake of peptide particles into and / or onto the polymer particles can be observed. The mixture was stirred for 20 min at 120 ° C. Stirring was then stopped and the mixture was cooled to 25 ° C, diluted with 20 volumes of ethanol as a detergent and filtered with 8 g to give 9.2 g of particles.

Example 8 Carrierase: aluminum stearate in sesame oil (4% w / v) (y = 12500 mPa.s at 25 ° C)

Biocompatible polymer: poly-ε-caprolactone, milled to 200 µm Active ingredient: triptorelin pamoate, particle size: 5-10 µm 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: was heated to 120 ° C. Then, 0.638 g of peptide particles with 100 mg of span 80 were added with stirring. Progressive uptake of peptide particles into and / or onto the polymer particles can be observed. The mixture was stirred for 30 min; : 25 at 120 ° C. Stirring was then stopped and the mixture was cooled to 25 ° C, diluted with 20 volumes of ethanol as a detergent and filtered with 8 l to give: 8.7 g of particles.

'; Example 9; '·, Carrier base: silicone oil (y = 10,000 mPa.s at 25 ° C)

Biocompatible Polymer: PLGA 75/25, powdered 200 ppm Active Ingredient: Tilquinol (Antibacterial) - Particle Size: 5-10 µm 13,12915 8 g of PLGA 75/25 and 1.23 g of tilin quinol particles were added to a reactor containing 500 ml of silicone oil. The mixture was heated to 80-100 ° C. Progressive formation of microspheres and passage of account quinol particles into said microspheres can be observed. The mixture was stirred for 30 min at the same temperature. Stirring was then stopped and the mixture was cooled to 25 ° C, diluted with 9 volumes of myristic acid isopropyl ester as detergent and filtered at 8 µm to give 8.25 g of particles.

Example 10 10

Carrierase: aluminum stearate in sesame oil (4% w / v) (γ = 12500 mPa-s at 25 ° C)

Biocompatible polymer: PLGA 75/25, milled to 200 µm Active ingredient: tiliquinol (antibacterial), particle size: 5-10 µm 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. 10 g of PLGA 75/25 was then added with stirring. Progressive formation of microspheres and passage of account quinol particles into said microspheres can be observed. The mixture was stirred for 25 min at the same temperature. Stirring was then stopped and the mixture was cooled to 25 ° C, diluted with 20 volumes of ethanol. slurry and filtered with 1 mm to give 11.3 g of particles.

Claims (13)

A process for producing substantially spherical dry-treated particles consisting of an active component incorporated in a high melting polymer, characterized in that - adding, above mixing, the above-mentioned biocompatible polymer and the above-mentioned active component, either in solid or liquid form, and in suitable conditions relative to the amount of said biocompatible polymer, into an immiscible homogeneous carrier phase in liquid form, said viscosity of said carrier phase being 3000-15000 mPa.s (25 ° C), wherein the above active component and the biocompatible polymer is insoluble in the above homogeneous carrier phase; for the biocompatible polymer, and - s eventually, the obtained microspheres are recovered. 2. A process according to claim 1, characterized in that - during mixing, a phase containing high melting point biocompatible polymer is added into an immiscible homogeneous liquid carrier phase, the viscosity of said carrier phase being 3000-15000 mPa (25 ° C: ssa), and as the aforementioned biocompatible polymer is insoluble in said carrier phase, the so obtained mixture is brought into admixture, using a suitable heating or cooling method, to a temperature above the biocompatible polymer glazing point. , - the mixture is maintained until microspheres within the required size range of the biocompatible polymer rise, - then added under mixing at a temperature above the vitrification point of the biocompatible polymer, the active component which is insoluble in the homogeneous carrier phase, antigen in solid or liquid. and in suitable conditions relative to the amount of the biocompatible The polymer is maintained to allow a progressive incorporation of the active component of the biocompatible polymer to its full absorption, then the mixture is discontinued, and the mixture is cooled, - finally where a suitable detergent is added which is not a solvent. for the biocompatible polymer or active component, the so-obtained microspheres are collected by filtration and sieving, and - particles are possibly subjected to a sterilization stage. 3. A process according to claim 1, characterized in that 10. a phase containing an active component which is heat stable at treatment temperature is added into an immiscible homogeneous liquid carrier phase, the viscosity of said carrier phase being 3000-15000. mPa-s (25 ° C: ssa), and said active component is insoluble in the carrier phase, the mixture thus obtained is subjected during mixing to a suitable heating or cooling method, a temperature higher than the glazing point of the biocompatible polymer. with the high melting point, - then added under mixing at a temperature higher than the biocompatible polymer's glazing point in suitable conditions relative to the amount of biocompatible polymer, which polymer is also insoluble in the homogeneous liquid-formed carrier phase, - the mixture is maintained to form microspheres of biocompatible polymer and enable a prog recessively incorporating the active component into the biocompatible polymer microspheres to its complete absorption, then mixing is terminated and mixing is cooled, finally adding suitable detergent, which is a solvent for the biocompatible polymer or active component, the so-called microspheres. is filtered and sieved, and the particles are possibly subjected to a sterilization stage. 30 4. A process according to claim 1, characterized in that - adding a phase containing a high melting point biocompatible polymer, an active component which is heat stable at treatment temperature, in suitable conditions relative to the amount of biocompatible polymer, into the immiscible , homogeneous liquid-shaped carrier phase, said carrier phase viscosity is 3000-15000 mPa-s (25 ° C: ssa), and which biocompatible polymer and active component are insoluble in said carrier phase, the so obtained mixture is brought into admixture using of suitable heating or cooling methods to a temperature above the biocompatible polymerization point, - final When suitable detergent is added which does not constitute a solvent for the biocompatible polymer or the active component, the so-obtained microspheres are recovered by filtration and sieving, and particles are optionally subjected to a sterilization stage. 5. A process according to any one of claims 1-4, characterized in that the viscosity of the carrier phase is 5000-12000 mPa-s (25 ° C; ssa). Process according to claim 5, characterized in that the viscosity of the carrier phase is about 10000 mPa-s (25 ° C: ssa). 20 7. A process according to any one of claims 1-4, characterized in that the carrier phase is a hydrophobic gel. A method according to claim 7, characterized in that the hydrophobic gel: is thickened oil. 25 A method according to any one of claims 1-4, characterized in, the carrier phase is a hydrophilic gel. Process according to claim 9, characterized in that the hydrophilic gel: 30 is water-based. ''. 11. A process according to claim 1, characterized in that the carrier phase is silicone oil. 21 112915 12. A process according to claim 1, characterized in that the biocompatible polymer is a biodegradable polymer with a glazing point between 25 and 200 ° C. 5 13. A process according to claim 1, characterized in that the biocompatible polymer is biodegradable polymer, the melting point of which is above 150 ° C.