Porous microparticles

Abstract

Biodegradable microparticles having an average diameter of at least 20 and at most 100 micrometers, comprising voids evenly distributed throughout each microparticle, wherein the voids constitute at least 10 v / v% and at most 45 v / v % of the average microparticle volume, wherein the voids do not extend to the surface, and wherein the microparticles have smooth surfaces and wherein preferably at least 50% of the voids within the microparticles are larger than 3 micrometre (µm). A solvent extraction process for the preparation of porous biodegradable microparticles, comprising: (i) preparing a solution of a biodegradable polymer in a solvent, (ii) preparing a solution of NaHCO3 in water, (iii) prepare an emulsion comprising the polymer solution and the NaHCO3 solution, (iv) add the emulsion to the an aqueous solution comprising a surfactant, evaporate the solvent, and optionally (v) harvest the microparticles. Said microparticles for use in the treatment of diseases requiring dermal and tissue filling.

Description

[0001] POROUS MICROPARTICLES

[0002] Field of the invention

[0003] The invention relates to the field of microparticles, specifically to biodegradable microparticles, a process to obtain said biodegradable microparticles, a gel composition comprising said biodegradable microparticles and use of the biodegradable microparticles or the gel comprising the biodegradable microparticles for medical treatment and cosmetic applications.

[0004] Background of the invention

[0005] Biodegradable microparticles such as PCL microparticles are known in the art for use as e.g. fillers. These fillers are inserted into soft tissue for cosmetic purposes such as augmentation of the skin, but also for medical purposes such as treating a skin abnormality or disfigurement, controlling bladder function, controlling gastric reflux, for treating erectile dysfunction and for treating vocal cords.

[0006] In W02009 / 014441 , PCL microparticles having homogenous density, form and content and smooth surfaces are described. In WO2018 / 110792, porous PCL microparticles are described where the pores extend to the surface of the microparticles. It is stated in WO2018 / 110792 that the volume of these porous microparticles does not temporarily decrease shortly after injection. In KR20190085498A, porous PCL microparticles are described having a tapped density of at most 0.5g / cc, meaning that at most 69% of the volume of the microparticle is PCL since the tapped density of solid PCL microparticles is stated to be 0.72 g / cc. It is further stated in KR20190085498A that these porous microparticles prevent clogging in the needle used for injection and that the volume of the injected substance does not temporarily decrease shortly after injection. It should be noted that the pores in the microparticles of KR20190085498A are not evenly distributed throughout the particles, see e.g., the figure on page 1 of KR20190085498A.

[0007] There is a need for further improvement of microparticles used in filler compositions.

[0008] Description of the invention

[0009] The inventors have established that, surprisingly, biodegradable microparticles having similar size, but comprising substantially lower amounts of polymer, do not degrade substantially different compared to solid microparticles (microparticles having homogenous density throughout the microparticle, having no pores of voids). These novel microparticles comprise voids evenly distributed throughout the microparticle.

[0010] Accordingly, in a first aspect, there is provided for biodegradable microparticles having an average diameter of at least 20 pm and at most 100 pm, comprising voids evenly distributed throughout each microparticle, wherein the voids preferably constitute at least 10 v / v% and at most 45 v / v % of the average microparticle volume, wherein the voids do not extend to the surface, wherein the microparticles have smooth surfaces, and wherein preferably at least 50% of the voids within the microparticles are larger than 3 micrometre (pm). In an embodiment, there is provided for biodegradable microparticles having an average diameter of at least 20 pm and at most 100 pm, comprising voids evenly distributed throughout each microparticle, wherein the voids constitute at least 10 v / v% and at most 45 v / v % of the average microparticle volume, wherein the voids do not extend to the surface, wherein the microparticles have smooth surfaces, and wherein preferably at least 50% of the voids within the microparticles are larger than 3 micrometre (pm).

[0011] In another embodiment, there is provided for biodegradable microparticles having an average diameter of at least 20 pm and at most 100 pm, comprising voids evenly distributed throughout each microparticle, wherein the voids constitute at least 10 v / v% and at most 45 v / v % of the average microparticle volume, wherein the voids do not extend to the surface, wherein the microparticles have smooth surfaces, and wherein at least 50% of the voids within the microparticles are larger than 3 micrometre (pm).

[0012] In another embodiment, there is provided for biodegradable microparticles having an average diameter of at least 20 pm and at most 100 pm, comprising voids evenly distributed throughout each microparticle, wherein the voids constitute at least 10 v / v% and at most 45 v / v % of the average microparticle volume, wherein the voids do not extend to the surface, wherein the microparticles have smooth surfaces, and wherein at least 50% of the voids within the microparticles are larger than 3 micrometre (pm).

[0013] In the embodiments herein, said biodegradable microparticles are herein interchangeably referred to as the biodegradable microparticles according to the invention, the biodegradable microparticles herein, the microparticles according to the invention, the microparticles herein, or simply: the microparticles. The term “void” is to be construed as a hollow space within a microparticle that does not extend to the surface of the microparticle, in contrast to a “pore”, which does extend to the surface of the microparticle.

[0014] In the embodiments herein, the term biodegradable is synonymous to the term resorbable and typically has the meaning as known in the technical field and means that the microparticles will be degraded in vivo, i.e. within the body of a vertebrate, preferably a mammal, more preferably a human.

[0015] In the embodiments herein, the average diameter of the biodegradable microparticle may be at least 20 pm and at most 100 pm. In the embodiments herein, the average diameter of the biodegradable microparticle may be at least 25 pm and at most 100 pm. In the embodiments herein, the average diameter of the biodegradable microparticle may be at least 30 pm and at most 100 pm. In the embodiments herein, the average diameter of the biodegradable microparticle may be at least 40 pm and at most 100 pm. In the embodiments herein, the average diameter of the biodegradable microparticle may be at least 20 pm and at most 90 pm. In the embodiments herein, the average diameter of the biodegradable microparticle may be at least 20 pm and at most 80 pm. In the embodiments herein, the average diameter of the biodegradable microparticle may be at least 20 pm and at most 70 pm. In the embodiments herein, the average diameter of the biodegradable microparticle may be at least 25 pm and at most 90 pm. In the embodiments herein, the average diameter of the biodegradable microparticle may be at least 30 pm and at most 90 pm. In the embodiments herein, the average diameter of the biodegradable microparticle may be at least 35 pm and at most 80 pm. In the embodiments herein, the average diameter of the biodegradable microparticle may be at least 40 pm and at most 80 pm. In the embodiments herein, the average diameter of the biodegradable microparticle may be at least 40 pm and at most 75 pm. In the embodiments herein, at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or at least 95% of the biodegradable microparticle may have an average diameter of at least 30 pm and at most 75 pm. In the embodiments herein, at least 50% of the biodegradable microparticles has a diameter of between 25 pm and 50 pm, such as at least 50%, 51 %, 52%, 53%, 54%, 55%, 56%,

[0016] 57%, 58%, 59%, 60%, 61 %, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71 %, 72%, 73%,

[0017] 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%,

[0018] 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, at least 99% or 100%. Preferably, at least 70% ofthe biodegradable microparticles has a diameter of between 25 pm and 50 pm.

[0019] In the embodiments herein, there is preferably a multiplicity of voids present in each microparticle. Accordingly, there are preferably typically at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 20, or most preferably at least 25 voids present in each microparticle. In the embodiments herein, in the biodegradable microparticles, the voids constitute at least 10 v / v% and at most 45 v / v % of the average microparticle volume. In the embodiments herein, the voids may constitute at least 20 v / v% and at most 45 v / v % of the average microparticle volume. In the embodiments herein, the voids may constitute at least 25 v / v% and at most 45 v / v % of the average microparticle volume. In the embodiments herein, the voids may constitute preferably at least 30 v / v% and preferably at most 45 v / v % of the average microparticle volume. In the embodiments herein, the voids may constitute at least 35 v / v% and at most 45 v / v % of the average microparticle volume. In the embodiments herein, the voids may constitute 25%, 26%, 27%, 28%, 29%, 30%, 31 %, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41 %, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51 %, 52%,

[0020] 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61 %, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%,

[0021] 70%, 71 %, 72%, 73%, 74%, or 75% of the average microparticle volume. In the embodiments herein, the voids may constitute at most 25%, 26%, 27%, 28%, 29%, 30%, 31 %, 32%, 33%, 34%,

[0022] 35%, 36%, 37%, 38%, 39%, 40%, 41 %, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51 %,

[0023] 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61 %, 62%, 63%, 64%, 65%, 66%, 67%, 68%,

[0024] 69%, 70%, 71%, 72%, 73%, 74%, or at most 75% of the average microparticle volume.

[0025] In the embodiments herein, in the biodegradable microparticles, the voids are evenly distributed throughout each microparticle. This means that throughout the entire microparticle volume, the number of voids per volume unit is substantially the same.

[0026] In the embodiments herein, the voids do not extend to the surface ofthe microparticles. This means that the voids are inside the microparticles and that less than 5%, 4%, 3%, 2%, 1 %, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or most preferably less than 0.1 % of the average surface of the microparticles has no voids extending to it.

[0027] In the embodiments herein, the surface of the microparticles is smooth, as can be seen e.g. in Figure 1 . In the embodiments herein, at least 50% of the voids within the microparticles are larger than 3 micrometre (pm), as can be seen in e.g. Figure 1 B and Figure 4B. Preferably, at least 60% of the voids within the microparticles are larger than 3 micrometre (pm). More preferably at least 70% of the voids within the microparticles are larger than 3 micrometre (pm). Even more preferably at least 80% of the voids within the microparticles are larger than 3 micrometre (pm).

[0028] In the embodiments herein, the biodegradable microparticles may comprise or consist of any biodegradable polymer that is suitable for in vivo use, such as for use in medical treatment and for cosmetic applications. In the embodiments herein, the biodegradable microparticles preferably do not comprise any compound that is not suitable for in vivo use. Biodegradable polymers that are suitable for in vivo use, such as for use in medical treatment and for cosmetic applications are known to the person skilled in the art. In the embodiments herein, the biodegradable microparticles may comprise or consist of a biodegradable polymer selected from the group consisting of poly-e- caprolactone (PCL), polyglycolic acid (PGA), poly-lactic-co-glycolic acid (PLGA), PEG, PVP, PVA, poly-1 ,3-trimethylene carbonate (PTMC), and, poly (l-lactic) acid (PLA, PLLA or PDLLA), preferably, the biodegradable polymer is PCL. In the embodiments herein, if the microparticles comprise PCL, the amount of PCL in view of total synthetic polymer is preferably at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99%.

[0029] In the embodiments herein, when the biodegradable polymer is PCL, the PCL may have a number average molecular weight (Mn) of between about 1.000 g / mol and about 500.000 g / mol, such between 1.000 g / mol and 400.000 g / ml, between 1.000 g / ml and 300.000 g / mol, between 1 .000 g / mol and 200.000 g / mol, between 1 .000 g / mol and 100.000 g / mol, between 1 .000 g / mol and 50.000 g / mol, between 1.000 g / mol and 40.000 g / mol, between 1.000 g / mol and 30.000 g / mol, between 1 .000 g / mol and 20.000 g / mol, between 1 .000 g / mol and 10.000 g / mol and between 3.000 and 7.000 g / mol.

[0030] In the embodiments herein, in the biodegradable microparticles, the biodegradable polymer may be a homopolymer, a linear polymer, a branched polymer, a copolymer, a terpolymer, a blend or composite of different types of homo / co / ter-polymers, or a crosslinked polymer. Preferably, the biodegradable polymer is a homopolymer. Crosslinking may be performed using any method known to the person skilled in the art, such as, but not limited to, chemical crosslinking, thermal crosslinking and crosslinking by radiation; preferred is non-chemical crosslinking (e.g. crosslinking by radiation or by heat without addition of any chemical crosslinking agent) since the chemicals used for crosslinking may be toxic.

[0031] The biodegradable microparticles according to the invention can conveniently be used in vivo, such as in filler compositions for medical treatment and for cosmetic applications. Accordingly, in a second aspect, there is provided for an in vivo resorbable composition comprising an aqueous polysaccharide gel carrier and biodegradable microparticles according to the first aspect herein. In this second aspect, the features are preferably the features of the first aspect. In the embodiments herein, the in vivo resorbable composition of the second aspect is referred to as the composition according to the invention, or simply as: the composition.

[0032] In the embodiments herein, the aqueous polysaccharide gel carrier preferably is biodegradable and may comprise the viscoelastic property of shear thinning. The rheological term shear thinning herein has its meaning as known in the field and typically means the non-Newtonian behavior of fluids whose viscosity decreases under shear strain. Shear strain is herein defined as a strain that is parallel to an element, in contrast to a normal strain which is perpendicular to an element.

[0033] In the embodiments herein, the in vivo resorbable composition may comprise any suitable polysaccharide that enhances the viscosity of the composition, such as a polysaccharide selected from the group consisting of a cellulose-derivative polysaccharide, a starch, a chitin, a chitosan, a hyaluronic acid, a hydrophobically-modified polysaccharide, an alginate, a carrageenan, an agar, an agarose, an intramolecular complex of a polysaccharide, an oligosaccharide and a macrocyclic polysaccharide. A preferred polysaccharide is a cellulose-derivative polysaccharide such as carboxymethylcellulose, sodium carboxymethylcellulose, agar methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, microcrystalline cellulose, oxidized cellulose and a mixture thereof. A preferred cellulose-derivative polysaccharide is carboxymethylcellulose, such as sodium carboxymethylcellulose.

[0034] The person skilled in the art will comprehend that other agents may be present in the aqueous polysaccharide gel carrier, such as but not limited to (i) a density enhancing agent that may e.g. be selected from the group consisting of sorbitol, mannitol and fructose; other suitable density agents might also be used, (ii) a tonicity wetting agent such as a polysorbate (e.g. Tween 20, 40, 60, or 80); othersuitable tonicity wetting agents may also be used. The aqueous polysaccharide gel carrier according to the invention may include varying amounts of a density enhancing agent and / or a tonicity wetting enhancing agent.

[0035] The aqueous polysaccharide gel carrier according to the invention may further comprise a component selected from the group consisting of a cryoprotectant and a buffering agent. A cryo protecting agent is a chemical which inhibits or reduces the formation of damaging ice crystals in biological tissues during cooling. Suitable cryoprotecting agents include, but are not limited to sugars and carbohydrates, such as d-mannitol, lactose, sucrose, fructose, sorbitol and dextran, with d-mannitol being preferred. The concentration of a cryoprotectant in the aqueous polysaccharide gel carrier may vary depending upon the intended application and the identity of the cryoprotectant chosen. A buffering agent is a chemical compound that is or compounds that are added to a solution to allow that solution to resist changes in pH as a result of either dilution or small additions of acids or bases. Effective buffer systems employ solutions which contain large and approximately equal concentrations of a conjugate acid-base pair (or buffering agents). A buffering agent employed herein may be any such chemical compound(s) which is pharmaceutically acceptable, including but not limited to salts (conjugates acids and / or bases) of phosphates and citrates. Preferably, the resorbable polysaccharide gel carrier comprises phosphate buffered saline (PBS).

[0036] In the embodiments herein, in the in vivo resorbable composition, the gel carrier material may be present in any concentration considered suitable by the person skilled in the art. The gel carrier may be present in a concentration of about 0.2 to about 20 weight percent (w / w). In the embodiments herein, in the in vivo resorbable composition, the gel carrier material may be present in a concentration of about 1 to about 5 weight percent, such as 1 to 5 weight percent. Preferably, at least about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .2, 1 .4, 1 .6, 1 .8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.3, 3.4, 3.6, 3. 8, 4.0, 4.2, 4.4, 4.6, or 4.8 weight percent of the gel carrier material is present and at most about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11 , 10, 9, 8, 7, 6, 5, 4.8, 4.6, 4.4, 4.2, 4.0, 3.8,

[0037] 3.6, 3.4, 3.2, 3.0, 2.8, 2.6, 2.4, 2.2, 2.0, 1.8, 1.6, 1.4, 1.2, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, or 0.3 weight percent is present. More preferably, at least 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .2, 1 .4,

[0038] 1 .6, 1 .8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.3, 3.4, 3.6, 3. 8, 4.0, 4.2, 4.4, 4.6, or 4.8 weight percent of the gel carrier material is present and at most 20, 19, 18, 17, 16, 15, 14, 13, 12, 11 , 10, 9, 8, 7, 6, 5, 4.8, 4.6, 4.4, 4.2, 4.0, 3.8, 3.6, 3.4, 3.2, 3.0, 2.8, 2.6, 2.4, 2.2, 2.0, 1.8, 1.6, 1.4, 1.2, 1 .0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, or 0.3 weight percent is present. A preferred range of gel carrier material is from about 0.2 to about 8 weight percent, a more preferred range is from about 0.4 to about 7 weight percent, a more preferred range is from about 0.5 to about 6 weight percent, a more preferred range is from about 0.6 to about 5 weight percent, a more preferred range is from about 1 to about 5 weight percent. A preferred range of resorbable polysaccharide of the gel carrier is from 0.2 to 8 weight percent, a more preferred range is from 0.4 to 7 weight percent, a more preferred range is from 0.5 to 6 weight percent, a more preferred range is from 0.6 to 5 weight percent, a more preferred range is from 1 to 5 weight percent. A preferred range of gel carrier is from 0.8 to 5 weight percent, a more preferred range is from 1 to 4 weight percent, a more preferred range is from 1.8 to 4 weight percent, a more preferred range is from 2 to 4 weight percent.

[0039] In the embodiments herein, in the in vivo resorbable composition, the biodegradable microparticles may be present in a concentration of about 1 to about 40 volume percent (v / v) , such as of about 10 to about 30 volume percent (v / v) or 10 to 30 volume percent (v / v). In the embodiments herein, in the in vivo resorbable composition, the biodegradable microparticles may be present in a concentration of 1 %, 2%, 3%, 4%, 55, 6%, 7%, 8%, 9%, 10%, 11 %, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21 %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31 %, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41 %, 42%, 43%, 44%, or 45%.

[0040] In the embodiments herein, in the in vivo resorbable composition a further substance may be present, preferably an active ingredient, preferably an anesthetic. Exemplary anesthetics include, but are not limited to, lidocaine, novocaine, benzocaine, prilocaine, ripivacaine, and propofol. Other medicaments that can be employed in a composition according to the invention include: a peptide, a tissue regeneration agent, an antibiotic, a steroid, fibronectin, a cytokine, a growth factor, an analgesic, an antiseptic, alpha-, beta, or gamma-interferon, erythropoietin, a glucagon, calcitonin, heparin, interleukin-1 , interleukin-2, filgrastim, cDNA, DNA, RNA, a protein, a peptide, Human Growth Hormone (HGH), luteinizing hormone, atrial natriuretic factor, Factor VIII, Factor IX, RNA, an antibody, a chemotherapeutic, follicle-stimulating hormone and combinations thereof. The further compound may also be an excipient, such excipient is preferably of pharmaceutical grade. A preferred excipient is glycerol. Glycerol will render the composition more lubricious. Preferably, glycerol is present in a concentration of about 0.05 to about 5 weight percent (w / w). More preferably, glycerol is present in a concentration of about 0.1 to about 4 weight percent, more preferably in a concentration of about 0.2 to about 2 weight percent. Preferably, glycerol is present in a concentration of 0.05 to 5 weight percent (w / w). More preferably, glycerol is present in a concentration of 0.1 to 4 weight percent, more preferably in a concentration of 0.2 to 2 weight percent.

[0041] Preferably, all compounds of the composition according to the invention are biocompatible. Preferably, the composition according to the invention, which comprises a resorbable gel carrier (preferably an aqueous gel) and is an aqueous composition, is buffered to keep the composition at physiological pH, i.e. about pH 7.4. The person skilled in the art knows how to buffer a solution and will select the proper buffering compound. The buffering compound may be, but is not limited to, a phosphate and / or citrate.

[0042] In the embodiments herein, the in vivo resorbable composition according to the invention may be a pharmaceutical composition, meaning that all compounds and the entire combination (i.e. the composition) is of pharmaceutical grade. Alternatively, or in combination with the previous, the in vivo resorbable composition according to the invention is a cosmetic or esthetic composition. This does not exclude the composition being of pharmaceutical grade but means that it is (also) suitable for cosmetic or esthetical use. This does not exclude the composition being of pharmaceutical grade but means that it is (also) suitable for cosmetic or esthetical use.

[0043] In the embodiments herein, the in vivo resorbable composition according to the invention may be a composition for augmenting tissue, such as soft tissue, wherein the composition is an implant or filler for intradermal, deep-dermal, subdermal or subcutaneous use.

[0044] Further provided is the medical use of the in vivo resorbable composition according to the invention. Accordingly, there is provided for the in vivo resorbable composition according to the invention, for use as a medicament, preferably for treating a skin abnormality or disfigurement, for controlling bladder function, for controlling gastric reflux, for treating erectile dysfunction and / or premature ejaculation, for treating vocal cords, and / or for treatment of joint and cartilage diseases.

[0045] Further provided is the use of an in vivo resorbable composition according to the invention for the preparation of a medicament for treating a skin abnormality or disfigurement, for controlling bladder function, for controlling gastric reflux, for treating erectile dysfunction and / or premature ejaculation, for treating vocal cords, and / or for treatment of joint and cartilage diseases.

[0046] Further provided is the use of an in vivo resorbable composition according to the invention for the treatment a skin abnormality or disfigurement, for controlling bladder function, for controlling gastric reflux, for treating erectile dysfunction and / or premature ejaculation, for treating vocal cords, and / or for treatment of joint and cartilage diseases.

[0047] Further provided is a method of treating a skin abnormality or disfigurement, controlling bladder function, controlling gastric reflux, treating erectile dysfunction and / or premature ejaculation, treating vocal cords, and / or treating joint and cartilage diseases comprising administration of an in vivo resorbable composition according to the invention. Further provided is the use of an in vivo resorbable composition according to the invention in a cosmetic or esthetic application, preferably an application for augmenting tissue, more preferably an application as a dermal implant or dermal filler.

[0048] Further provided is a process for the production of the microparticles according to the invention. Accordingly, in a third aspect there is provided for a solvent extraction process for the preparation of biodegradable microparticles comprising:

[0049] (i) preparing a solution of a biodegradable polymer in a solvent,

[0050] (ii) preparing a solution of NaHCOs in water,

[0051] (iii) prepare an emulsion comprising the polymer solution and the NaHCOs solution,

[0052] (iv) add the emulsion to the an aqueous solution comprising a surfactant, evaporate the solvent, and optionally

[0053] (v) harvest the microparticles.

[0054] In the embodiments herein, said process is referred to as the process according to the invention. In this aspect, the features are preferably se features of the first and second aspect.

[0055] In the process according to the invention, the biodegradable polymer may be selected from the group consisting of PCL, PLGA, PTMC, PEG, PVP, PVA, and PLA. A preferred biodegradable polymer is PCL.

[0056] In the process according to the invention, the concentration of the biodegradable polymer in the solution in (i) may be between 5% w / w and 40% w / w, such as between 10% and 35% and between 25% w / w and 35% w / w. The solution in (i) may comprise 5%, 6%, 7%, 8%, 9%, 10%, 11 %, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21 %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31 %, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or 40% w / w ofthe biodegradable polymer. In the process according to the invention, the solution in (ii) may comprise between 0.01 % and 1 % of NaHCO3, such as between 0.1 % and 0.6% and between 0.4% and 0.6% w / w of NaHCO3. The solution in (ii) may comprise 0.01 %, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1 %, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1 % w / w of NaHCO3.

[0057] In the process according to the invention, the solvent may be an organic solvent, such as aliphatic compounds, aromatic compounds, halogen containing compounds, chloroform, compounds not containing halogens, acetone, THF, toluene ethyl acetate or ethyl lactate, etc. A preferred solvent is dichloromethane (DCM). The person skilled in the art will comprehend that a mixture of different solvents may be used.

[0058] In the process according to the invention, the surfactant may be methylcellulose and / or the concentration of the surfactant may be between 0.1 % w / w and 2.5% w / w, such as between 0.5% w / w and 1 .5% w / w. The concentration of the surfactant may be 0.1 %, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1 %, 1 .2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1 .9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4% or 2.5%. Preferred parameters for the process according to the invention are the parameters as used in the examples herein.

[0059] In a fourth aspect, there are provided, microparticles obtainable by or obtained by the process according to the third aspect herein. In this aspect, the features are preferably the features of the first, second and third aspect.

[0060] Brief description of the figures.

[0061] Figure 1 : (A) Microparticles according to the invention as obtained using the method in example 1 using 0.5% NaHCO3; (B) pore size is indicated.

[0062] Figure 2: Density (relative porosity) of the PCL microparticles according to the invention as obtained using the method in example 1.

[0063] Figure 3: Degradation of solid (dense) PCL microparticles v / s PCL microparticles according to the invention as obtained in example 1 and as determined in example 2.

[0064] Figure 4: (A) PCL microparticles according to the invention as obtained using the method in example 3 using 0.02% NaHCOs; (B) pore size is indicated.

[0065] Figure 5: Density (relative porosity) of the microparticles according to the invention as obtained using the method in example 3 using 0.02% NaHCOs.

[0066] Figure 6: LC003E PLLAcoPCL microparticles as obtained using the method in example 4.

[0067] Figure 7: DL03E PDLLA microparticles as obtained using the method in example 5.

[0068] Figure 8: PCL14coPEG microparticles as obtained using the method in example 6.

[0069] Figure 9: (A) PLLA L03 microparticles as obtained using the method in example 7; (B) Higher magnification.

[0070] Definitions

[0071] In this document and in its claims, the verb "to comprise" and its conjugations is used in its nonlimiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. In addition the verb “to consist” may be replaced by “to consist essentially of’ meaning that a product or a composition or a nucleic acid molecule or a peptide or polypeptide of a nucleic acid construct or vector or cell as defined herein may comprise additional component(s) than the ones specifically identified; said additional component(s) not altering the unique characteristic of the invention. In addition, reference to an element by the indefinite article "a" or "an" does not exclude the possibility that more than one of the elements is present, unless the context clearly requires that there be one and only one of the elements. The indefinite article "a" or "an" thus usually means "at least one". The word “about” or “approximately” when used in association with a numerical value (e.g. about 10) preferably means that the value may be the given value (of 10) more or less 10% of the value. All patent and literature references cited in the present specification are hereby incorporated by reference in their entirety.

[0072] Unless otherwise indicated each embodiment as described herein may be combined with another embodiment as described herein.

[0073] The following examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way.

[0074] Further embodiments of the invention

[0075] 1 . Biodegradable microparticles having an average diameter of at least 20 pm and at most 100 pm, comprising voids evenly distributed throughout each microparticle, wherein the voids preferably constitute at least 10 v / v% and at most 75v / v % of the average microparticle volume, wherein the voids do not extend to the surface, wherein the microparticles have smooth surfaces, wherein preferably at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 20 or at least 25 voids are typically present in each microparticle, and wherein preferably at least 50% of the voids within the microparticles are larger than 3 micrometre (pm), or, biodegradable microparticles having an average diameter of at least 20 pm and at most 100 pm, comprising voids evenly distributed throughout each microparticle, wherein the voids constitute at least 10 v / v% and at most 75v / v % of the average microparticle volume, wherein the voids do not extend to the surface, wherein the microparticles have smooth surfaces, wherein preferably at least

[0076] 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 20 or at least 25 voids are typically present in each microparticle, and wherein preferably at least 50% of the voids within the microparticles are larger than 3 micrometre (pm), or, biodegradable microparticles having an average diameter of at least 20 pm and at most 100 pm, comprising voids evenly distributed throughout each microparticle, wherein the voids preferably constitute at least 10 v / v% and at most 75v / v % of the average microparticle volume, wherein the voids do not extend to the surface, wherein the microparticles have smooth surfaces, wherein at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 20 or at least 25 voids are typically present in each microparticle, and wherein preferably at least 50% of the voids within the microparticles are larger than 3 micrometre (pm), or, biodegradable microparticles having an average diameter of at least 20 pm and at most 100 pm, comprising voids evenly distributed throughout each microparticle, wherein the voids preferably constitute at least 10 v / v% and at most 75v / v % of the average microparticle volume, wherein the voids do not extend to the surface, wherein the microparticles have smooth surfaces, wherein preferably at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 20 or at least 25 voids are typically present in each microparticle, and wherein at least 50% of the voids within the microparticles are larger than 3 micrometre (pm), or, biodegradable microparticles having an average diameter of at least 20 pm and at most 100 pm, comprising voids evenly distributed throughout each microparticle, wherein the voids preferably constitute at least 10 v / v% and at most 75v / v % of the average microparticle volume, wherein the voids do not extend to the surface, wherein the microparticles have smooth surfaces, and wherein at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 20 or at least 25 voids are typically present in each microparticle, and wherein at least 50% of the voids within the microparticles are larger than 3 micrometre (pm), or, biodegradable microparticles having an average diameter of at least 20 pm and at most 100 pm, comprising voids evenly distributed throughout each microparticle, wherein the voids constitute at least 10 v / v% and at most 75v / v % of the average microparticle volume, wherein the voids do not extend to the surface, wherein the microparticles have smooth surfaces, and wherein preferably at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 20 or at least 25 voids are typically present in each microparticle, and wherein at least 50% of the voids within the microparticles are larger than 3 micrometre (pm), or, biodegradable microparticles having an average diameter of at least 20 pm and at most 100 pm, comprising voids evenly distributed throughout each microparticle, wherein the voids constitute at least 10 v / v% and at most 75v / v % of the average microparticle volume, wherein the voids do not extend to the surface, wherein the microparticles have smooth surfaces, wherein at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 20 or at least 25 voids are typically present in each microparticle, and wherein preferably at least 50% of the voids within the microparticles are larger than 3 micrometre (pm),

[0077] 2. Biodegradable microparticles according to embodiment 1 , wherein the microparticles comprise or consist of a biodegradable polymer selected from the group consisting of PCL, PGA, PLGA, PTMC, and PLA, preferably wherein the biodegradable polymer is PCL.

[0078] 3. Biodegradable microparticles according to embodiment 1 or 2, wherein the biodegradable polymer is a homopolymer, a linear polymer, a branched polymer, a copolymer, a terpolymer, a blend or composite of different types of homo / co / ter-polymers, or a crosslinked polymer.

[0079] 4. An in vivo resorbable composition comprising an aqueous polysaccharide gel carrier and biodegradable microparticles according to any one of embodiments 1 to 3.

[0080] 5. An in vivo resorbable composition according to embodiment 4, wherein the polysaccharide is selected from the group consisting of a cellulose-derivative polysaccharide, a starch, a chitin, a chitosan, a hyaluronic acid, a hydrophobically-modified polysaccharide, an alginate, a carrageenan, an agar, an agarose, an intramolecular complex of a polysaccharide, an oligosaccharide and a macrocyclic polysaccharide.

[0081] 6. An in vivo resorbable composition according to embodiment 4 or 5, wherein the PCL microparticle are present in a concentration of about 1 to about 40 volume percent (v / v). 7. An in vivo resorbable composition according to any one of embodiments 4 to 6, wherein the gel carrier material is present in a concentration of about 0.2 to about 20 weight percent (w / w).

[0082] 8. An in vivo resorbable composition according to any one of embodiments 4 to 7, wherein a further substance is present, preferably an active ingredient, preferably an anesthetic.

[0083] 9. An in vivo resorbable composition according to any one of embodiments 4 to 8, wherein the composition is a pharmaceutical composition.

[0084] 10. An in vivo resorbable composition according to any one of embodiments 4 to 9, wherein the composition is a cosmetic or esthetic composition.

[0085] 11. An in vivo resorbable composition according to any one of embodiments 4 to 10, wherein the composition is a composition for augmenting tissue, such as soft tissue, wherein the composition is an implant or filler for intradermal, deep-dermal, subdermal or subcutaneous use.

[0086] 12. An in vivo resorbable composition according to any one of embodiments 4 to 11 , for use as a medicament, preferably for treating a skin abnormality or disfigurement, for controlling bladder function, for controlling gastric reflux, for treating erectile dysfunction and / or premature ejaculation, for treating vocal cords, and / or for treatment of joint and cartilage diseases.

[0087] 13. Use of an in vivo resorbable composition according to any one of embodiments 4 to 11 for the preparation of a medicament for treating a skin abnormality or disfigurement, for controlling bladder function, for controlling gastric reflux, for treating erectile dysfunction and / or premature ejaculation, for treating vocal cords, and / or for treatment of joint and cartilage diseases.

[0088] 14. Use of an in vivo resorbable composition according to any one of embodiments 4 to 11 for the treatment a skin abnormality or disfigurement, for controlling bladder function, for controlling gastric reflux, for treating erectile dysfunction and / or premature ejaculation, for treating vocal cords, and / or for treatment of joint and cartilage diseases.

[0089] 15. A method of treating a skin abnormality or disfigurement, controlling bladder function, controlling gastric reflux, treating erectile dysfunction and / or premature ejaculation, treating vocal cords, and / or treating joint and cartilage diseases comprising administration of an in vivo resorbable composition according to any one of embodiments 4 to 11 .

[0090] 16. Use of an in vivo resorbable composition according to any one of embodiments 4 to 11 in a cosmetic or esthetic application, preferably an application for augmenting tissue, more preferably an application as a dermal implant or dermal filler. 17. A solvent extraction process for the preparation of the biodegradable microparticles according to embodiment 1 , comprising:

[0091] (i) preparing a solution of a biodegradable polymer in a solvent,

[0092] (ii) preparing a solution of NaHCOs in water,

[0093] (iii) prepare an emulsion comprising the polymer solution and the NaHCOs solution,

[0094] (iv) add the emulsion to the an aqueous solution comprising a surfactant, evaporate the solvent, and optionally

[0095] (v) harvest the microparticles.

[0096] 18. A process according to embodiment 17, wherein the biodegradable polymer is selected from the group consisting of PCL, PLGA, PTMC, and PLA, PLLA, or PDLLA.

[0097] 19. A process according to embodiment 18 or 19, wherein the concentration of the polymer in the solution in (i) is between 5% w / w and 40% w / w, such as between 10% and 35% and between 25% w / w and 35% w / w.

[0098] 20. A process according to any one of embodiments 17 to 19, wherein the solution in (ii) comprises between 0.01 and 1 % w / w of NaHCO3.

[0099] 21. A process according to any one of embodiments 17 to 20, wherein the solvent is an organic solvent, such as dichloromethane (DCM).

[0100] 22. A process according to any one of embodiments 17 to 21 , wherein the surfactant is methylcellulose and / or wherein the concentration of the surfactant is between 0.1 % w / w and 2.5% w / w, such as between 0.5% w / w and 1 .5% w / w.

[0101] 23. Microparticles obtainable by the process according to any one of embodiments 17 to 22.

[0102] Examples

[0103] Example 1 : Preparation of PCL microparticles according to the invention

[0104] Demonstrated is the preparation of microparticles according to the invention.

[0105] Materials and Methods

[0106] • PolyCaprolactone Mw 4-6k Dalton (PC02 from Corbion)

[0107] • Methylcellulose powder A15C (Mn 63.000 g / mol)

[0108] • Deionized water (DI water)

[0109] • Dichloromethane

[0110] • NaHCO3(Baking soda)

[0111] All procedures were performed at ambient temperature, unless depicted otherwise.. Preparation of PCL microparticles according to the invention using 0.4%, 0.5% and 0.6%

[0112] NaHCCh

[0113] Step 1 .

[0114] A PCL solution in Dichloromethane (DCM); solution 01 , was prepared as following:

[0115] 36 grams of PCL with Mn 4000-6000 g / mol was placed in a 10OmL bottle together with 80 grams of DCM. The mixture was stirred with a magnetic stirrer until a clear solution was obtained.

[0116] Step 2.

[0117] A 1 % Methylcellulose (MC) surfactant solution (W1) was prepared.

[0118] The MC with an Mn of 63.000 g / mol was dissolved in DI water of 80-95°C. Subsequently, cold DI water of about 5°C was added with a concentration of 1 % MC was reached and the solution was stirred until a until a clear solution was obtained.

[0119] Step 3.

[0120] A 0.4 - 0.6% w / w solution of NaHCO3(Baking soda) (W2) was prepared.

[0121] 400-600 mg of NaHCO3was placed in a 100 mL volumetric flask together and filled up to 100 mL with DI water.

[0122] Step4.

[0123] PCL microparticles were prepared

[0124] 30 ml of the NaHCO3solution W2 was placed into a beaker. Subsequently, the PCL solution 01 was carefully placed on top of the NaHCO3solution. The W / O / W emulsion was formed by emulsifying the PCL solution and the NaHCO3solution with a high shear Ystral mixer (Ystral X 10 / 25 using a mixing shaft type 20D / F) for approximately 30-60 seconds at 26k rpm. The resulting emulsion was added to 650mL of MC solution W1 , while stirring, followed by the evaporation of DCM from the microparticles using a high shear stirrer at 1000 rpm (IKA Eurostar 20 stirrer and a 4-bladed propellor stirrer. Perpendicular to the stirrer a 250x15 mm baffle is used to stabilize the mixture). The dried microparticles were harvested via a wet-sieving process and subsequently dried under vacuum at 30-35°C.

[0125] After drying, the microparticles were examined by Scanning Electron Microscopy (SEM); see Figure 1 depicting microparticles prepared with 0.5% NaHCOs. To be able to view the inner voids, some of the microparticles were cut with a scalpel knife.

[0126] Determination of the density of the microparticles

[0127] By using the ASTM B-527 ("Standard Test Method for Determination of Tap Density of Metallic Powders and Compounds”)as guidance for determining the density of the particles, the percentage of voids can be calculated. The method is widely used for determining the density of various particles. Tapped density of a powder is the ratio of the mass of the powder to the volume occupied by the powder after it has been tapped for a defined period of time. The tapped density of a powder represents its random dense packing. Tapped density can be calculated, where / W=mass in grams, and l / f=the tapped volume in milliliters. Tapped density (g / ml=M / Vf). As reference microparticles, PCL microparticles prepared without NaHCO3, i.e., PCL microparticles without voids (solid microparticles) were used. The density for the reference microparticles was set a 100%, i.e., 0% voids. In brief, the reference microparticles were produced using a state of the art W / O evaporation method by preparing a 36%w / w PCL / DCM solution and dispersing this oil phase in the water phase (a 1 % Methylcellulose solution) with the same IKA stirrer with a 4-bladed propellor stirrer. Perpendicular to the stirrer a 250x15 mm baffle was used to stabilize the mixture. The DCM was evaporated until solid particles PCL were formed and these particles were sieved over a 50 um and 25 um sieve to collect the 25-50um microsphere fraction. These particles were concentrated and dried under vacuum at 35°C until a vacuum was reached lower than 0.1 mbar.

[0128] It was demonstrated that the microparticles according to the invention have a 40% lower density compared to the reference microparticles, corresponding to 40% voids when using 0.4, 0.5, 0.6 %w / w NaHCO3 for the W2 phase. (see Figure 2).

[0129] Example 2: Comparative degradation of solid PCL microparticles and PCL microparticles according to the invention.

[0130] The PCL microspheres obtained in example 1 were subject to accelerated degradation in the presence of KOH for 7 weeks. In brief, samples of microparticles according to the invention and reference microparticles, both as prepared in example 1 , were degraded in a 1 M KOH solution over a period of 7 weeks at 37°C. Both the solid microparticles and the microparticles according to the invention were washed with demineralised water, centrifuged and the pelleted parts were collected and dried under vacuum at 35°C until a vacuum was reached < 0.1 mbar. The dried samples were weighed on a analytical scale.

[0131] The results are depicted in Figure 3. While initial degradation (mass loss) of the microparticles according to the invention was increased compared to the solid microparticles, this effect had diminished after two weeks and the degradation remained constant (parallel lines) up and until week 6 after which degradation of both types of microparticles levelled of (horizontal lines). It is an interesting and surprising feature that the microparticles according to the invention do not degrade substantially different compared to the solid PCL microparticles.

[0132] Example 3: Preparation of PCL microparticles according to the invention with 0.02%w / w NaHCO3

[0133] Materials and Methods

[0134] PolyCaprolactone Mw 4-6k Dalton (PC02 from Corbion)

[0135] Methylcellulose powder A15C (Mn 63.000 g / mol) • Deionized water (DI water)

[0136] • Dichloromethane

[0137] • NaHCO3(Baking soda)

[0138] All procedures were performed at ambient temperature, unless depicted otherwise..

[0139] Step 1 .

[0140] A PCL solution in Dichloromethane (DCM); solution 01 , was prepared as following:

[0141] 36 grams of PCL with Mn 4000-6000 g / mol was placed in a 100mL bottle together with 80 grams of DCM. The mixture was stirred with a magnetic stirrer until a clear solution was obtained.

[0142] Step 2.

[0143] A 1 % Methylcellulose (MC) surfactant solution (W2) was prepared.

[0144] The MC with an Mn of 63.000 g / mol was dissolved in DI water of 80-95°C. Subsequently, cold DI water of about 5°C was added with a concentration of 1 % MC was reached and the solution was stirred until a until a clear solution was obtained.

[0145] Step 3.

[0146] A 0.02% w / w solution of NaHCO3(Baking soda) (W1) was prepared.

[0147] 20 mg of NaHCO3was placed in a 100 mL volumetric flask together and filled up to 100 mL with DI water.

[0148] Step 4.

[0149] PCL microparticles were prepared

[0150] 30 ml of the NaHCO3solution W1 was placed into a beaker. Subsequently, the PCL solution 01 was carefully placed on top of the NaHCO3solution. The W / O / W emulsion was formed by emulsifying the PCL solution and the NaHCO3solution with a high shear Ystral mixer (Ystral X 10 / 25 using a mixing shaft type 20D / F) for approximately 30-60 seconds at 26k rpm. The resulting emulsion was added to 650mL of MC solution (W2), while stirring, followed by the evaporation of DCM from the microparticles using a high shear stirrer at 1000 rpm (IKA Eurostar 20 stirrer and a 4-bladed propellor stirrer. Perpendicular to the stirrer a 250x15 mm baffle is used to stabilize the mixture). The dried microparticles were harvested via a wet-sieving process and subsequently dried under vacuum at 30-35°C.

[0151] After drying, the microparticles were examined by Scanning Electron Microscopy (SEM). To be able to view the voids and determine their diameter, some of the microparticles were cut with a scalpel knife. See Figure 4.

[0152] Determination of the relative porositv of the PCL microparticles

[0153] By using the ASTM B-527 ("Standard Test Method for Determination of Tap Density of Metallic Powders and Compounds”) as guidance for determining the density of the particles, the percentage of voids can be calculated. The method is widely used for determining the density of various particles.

[0154] Tapped density of a powder is the ratio of the mass of the powder to the volume occupied by the powder after it has been tapped for a defined period of time. The tapped density of a powder represents its random dense packing. Tapped density can be calculated, where / W=mass in grams, and l / f=the tapped volume in millilitres. Tapped density (g / ml=M / Vf). As reference microparticles, PCL microparticles prepared without NaHCO3, i.e., PCL microparticles without voids (solid microparticles) were used. The PCL microspheres without voids are identified as “reference” microparticles” within the Examples. The density for the reference microparticles was set a 100%, i.e., 0% voids. In brief, the reference microparticles were produced using a state of the art W / O evaporation method by preparing a 36% w / w PCL / DCM solution and dispersing this oil phase in the water phase (a 1 % Methylcellulose solution) with the same I KA stirrer with a 4-bladed propellor stirrer. Perpendicular to the stirrer a 250x15 mm baffle was used to stabilize the mixture. The DCM was evaporated until solid particles PCL were formed and these particles were sieved over a 50 um and 25 um sieve to collect the 25-50um microsphere fraction. These particles were concentrated and dried under vacuum at 35°C until a vacuum was reached lower than 0.1 mbar.

[0155] It was demonstrated that the microparticles according to the invention have approximately 40% lower density compared to the reference microparticles, corresponding to approximately 25% voids when using 0.02% w / w NaHCOs for the W1 phase. See Figure 5.

[0156] Example 4: Preparation of LC003 PLLAcoPCL microparticles

[0157] Step 1. A LC003E PLLAcoPCL (Polymer obtained from Ashland) solution in Dichloromethane (DCM); solution 01 , was prepared as follows: 36 grams of LC003E PLLAcoPCL co-polymer was placed in a 10OmL bottle together with 80 grams of DCM. The mixture was stirred with a magnetic stirrer until a clear solution was obtained.

[0158] Step 2. A 1 % Methylcellulose (MC) surfactant solution (W2) was prepared. The MC with an Mn of 63,000 g / mol was dissolved in DI water at 80-95°C. Subsequently, cold DI water of about 5°C was added until a concentration of 1 % MC was reached. The solution was stirred until a clear solution was obtained.

[0159] Step 3. A 0.02 % w / w solution of NaHCO3(Baking soda) (W1) was prepared. 20 mg of NaHCO3was placed in a 100 mL volumetric flask and filled up to 100 mL with DI water.

[0160] Step 4. LC003E PLLAcoPCL microparticles were prepared: 50 mL of the NaHCO3solution W2 was placed into a beaker. Subsequently, the LC003E PLLAcoPCL solution 01 was carefully placed on top of the NaHCO3solution. The W / O / W emulsion was formed by emulsifying the LC003E PLLAcoPCL solution and the NaHCO3solution with a high-shear Ystral mixer (Ystral X 10 / 25 using a mixing shaft type 20D / F) for approximately 30-60 seconds at 26k rpm. The resulting emulsion was added to 650mL of MC solution W2, while stirring, followed by the evaporation of DCM from the microparticles using a high-shear stirrer at 1000 rpm (IKA Eurostar 20 stirrer and a 4-bladed propeller stirrer. Perpendicular to the stirrer, a 250x15 mm baffle was used to stabilize the mixture). The dried microparticles were harvested via a wet-sieving process and subsequently photographed under light microscopy to examine the inner structure of the particles. See Figure 6.

[0161] Example 5: Preparation of DL03E PDLLA microparticles

[0162] Step 1. A DL03E PDLLA (Polymer obtained from Ashland) solution in Dichloromethane (DCM); solution 01 , was prepared as follows: 16 grams of DL03E PDLLA polymer was placed in a 100mL bottle together with 53.3 grams of DCM. The mixture was stirred with a magnetic stirrer until a clear solution was obtained.

[0163] Step 2. A 1 % Methylcellulose (MC) surfactant solution (W2) was prepared. The MC with an Mn of 63,000 g / mol was dissolved in DI water at 80-95°C. Subsequently, cold DI water of about 5°C was added until a concentration of 1 % MC was reached. The solution was stirred until a clear solution was obtained.

[0164] Step 3. A 0.02% w / w solution of NaHCO3(Baking soda) (W1) was prepared. 20 mg of NaHCO3was placed in a 100 mL volumetric flask and filled up to 100 mL with DI water.

[0165] Step 4. DL03E PDLLA microparticles were prepared: 50 mL of the NaHCO3solution W1 was placed into a beaker. Subsequently, the DL03E PDLLA solution 01 was carefully placed on top of the NaHCOg solution. The W / O / W emulsion was formed by emulsifying the DL03E PDLLA solution and the NaHCOg solution with a high-shear Ystral mixer (Ystral X 10 / 25 using a mixing shaft type 20D / F) for approximately 30-60 seconds at 26k rpm. The resulting emulsion was added to 650mL of MC solution W2, while stirring, followed by the evaporation of DCM from the microparticles using a high- shear stirrer at 1000 rpm (I KA Eurostar 20 stirrer and a 4-bladed propeller stirrer. Perpendicular to the stirrer, a 250x15 mm baffle was used to stabilize the mixture). The dried microparticles were harvested via a wet-sieving process and subsequently dried under vacuum at 30-35°C. See Figure 7.

[0166] Example 6: Preparation of PCL14coPEG microparticles

[0167] Step 1. A PCL14coPEG (Polymer obtained from Ashland) solution in Dichloromethane (DCM); solution 01 , was prepared as follows: 20 grams of PCL14coPEG co-polymerwas placed in a 100mL bottle together with 85 grams of DCM. The mixture was stirred with a magnetic stirrer until a clear solution was obtained.

[0168] Step 2. A 1 % Methylcellulose (MC) surfactant solution (W2) was prepared. The MC with an Mn of 63,000 g / mol was dissolved in DI water at 80-95°C. Subsequently, cold DI water of about 5°C was added until a concentration of 1 % MC was reached. The solution was stirred until a clear solution was obtained.

[0169] Step 3. A 0.02% w / w solution of NaHCOg (Baking soda) (W1) was prepared. 20 mg of NaHCOg was placed in a 100 mL volumetric flask and filled up to 100 mL with DI water.

[0170] Step 4. PCL14coPEG microparticles were prepared: 30 mL of the NaHCOg solution W1 was placed into a beaker. Subsequently, the PCL14coPEG solution 01 was carefully placed on top of the NaHCOg solution. The W / O / W emulsion was formed by emulsifying the PCL14coPEG solution and the NaHCO3solution with a high-shear Ystral mixer (Ystral X 10 / 25 using a mixing shaft type 20D / F) for approximately 30-60 seconds at 26k rpm. The resulting emulsion was added to 650mL of MC solution W2, while stirring, followed by the evaporation of DCM from the microparticles using a high- shear stirrer at 1000 rpm (I KA Eurostar 20 stirrer and a 4-bladed propeller stirrer. Perpendicular to the stirrer, a 250x15 mm baffle was used to stabilize the mixture). The dried microparticles were harvested via a wet-sieving process and subsequently photographed under light microscopy to examine the inner structure of the particles. See Figure 8.

[0171] Example 7: Preparation of PLLA L03 microparticles

[0172] Step 1. A PLLA L03 (Ashland polymer) solution in Dichloromethane (DCM); solution 01 , was prepared as follows: 4.5 grams of PLLA L03 polymer was placed in a 100mL bottle together with 90 grams of DCM. The mixture was stirred with a magnetic stirrer until a clear solution was obtained. Step 2. A 1 % Methylcellulose (MC) surfactant solution (W2) was prepared. The MC with an Mn of 63,000 g / mol was dissolved in DI water at 80-95°C. Subsequently, cold DI water of about 5°C was added until a concentration of 1 % MC was reached. The solution was stirred until a clear solution was obtained.

[0173] Step 3. A 0.5% w / w solution of NaHCO3(Baking soda) (W1) was prepared. 50 mg of NaHCO3was placed in a 100 mL volumetric flask and filled up to 100 mL with DI water.

[0174] Step 4. PLLA L03 microparticles were prepared: 30 mL of the NaHCO3solution (W1) was placed into a beaker. Subsequently, the PLLA L03 solution 01 was carefully placed on top of the NaHCO3solution. The W / O / W emulsion was formed by emulsifying the PLLA L03 solution and the NaHCO3solution with a high-shear Ystral mixer (Ystral X 10 / 25 using a mixing shaft type 20D / F) for approximately 30-60 seconds at 26k rpm. The resulting emulsion was added to 650mL of MC solution (W2), while stirring, followed by the evaporation of DCM from the microparticles using a high-shear stirrer at 1000 rpm (IKA Eurostar 20 stirrer and a 4-bladed propeller stirrer. Perpendicular to the stirrer, a 250x15 mm baffle was used to stabilize the mixture). The dried microparticles were harvested via a wet-sieving process and subsequently dried under vacuum at 30-35°C. See Figure 9 A and B.

Claims

Claims1. Biodegradable microparticles having an average diameter of at least 20 pm and at most 100 pm, comprising voids evenly distributed throughout each microparticle, wherein the voids preferably constitute at least 10 v / v% and at most 45v / v % of the average microparticle volume, wherein the voids do not extend to the surface, wherein the microparticles have smooth surfaces, and wherein preferably at least 50% of the voids within the microparticles are larger than 3 micrometre (pm).

2. Biodegradable microparticles according to claim 1 , wherein the microparticles comprise or consist of a biodegradable polymer selected from the group consisting of PCL, PGA, PLGA, PTMC, and PLA, PLLA or PDLLA, preferably wherein the biodegradable polymer is PCL.

3. Biodegradable microparticles according to claim 1 or 2, wherein the biodegradable polymer is a homopolymer, a linear polymer, a branched polymer, a copolymer, a terpolymer, a blend or composite of different types of homo / co / ter-polymers, or a crosslinked polymer.

4. An in vivo resorbable composition comprising an aqueous polysaccharide gel carrier and biodegradable microparticles according to any one of claims 1 to 3.

5. An in vivo resorbable composition according to claim 4, wherein the polysaccharide is selected from the group consisting of a cellulose-derivative polysaccharide, a starch, a chitin, a chitosan, a hyaluronic acid, a hydrophobically-modified polysaccharide, an alginate, a carrageenan, an agar, an agarose, an intramolecular complex of a polysaccharide, an oligosaccharide and a macrocyclic polysaccharide.

6. An in vivo resorbable composition according to claim 4 or 5, wherein the PCL microparticle are present in a concentration of about 1 to about 40 volume percent (v / v).

7. An in vivo resorbable composition according to any one of claims 4 to 6, wherein the gel carrier material is present in a concentration of about 0.2 to about 20 weight percent (w / w).

8. An in vivo resorbable composition according to any one of claims 4 to 7, wherein a further substance is present, preferably an active ingredient, preferably an anesthetic.

9. An in vivo resorbable composition according to any one of claims 4 to 8, wherein the composition is a pharmaceutical composition.

10. An in vivo resorbable composition according to any one of claims 4 to 9, wherein the composition is a cosmetic or esthetic composition.

11. An in vivo resorbable composition according to any one of claims 4 to 10, wherein the composition is a composition for augmenting tissue, such as soft tissue, wherein the composition is an implant or filler for intradermal, deep-dermal, subdermal or subcutaneous use.

12. An in vivo resorbable composition according to any one of claims 4 to 11 , for use as a medicament, preferably for treating a skin abnormality or disfigurement, for controlling bladder function, for controlling gastric reflux, for treating erectile dysfunction and / or premature ejaculation, for treating vocal cords, and / or for treatment of joint and cartilage diseases.

13. Use of an in vivo resorbable composition according to any one of embodiments 4 to 11 for the preparation of a medicament for treating a skin abnormality or disfigurement, for controlling bladder function, for controlling gastric reflux, for treating erectile dysfunction and / or premature ejaculation, for treating vocal cords, and / or for treatment of joint and cartilage diseases.

14. Use of an in vivo resorbable composition according to any one of embodiments 4 to 11 for the treatment a skin abnormality or disfigurement, for controlling bladder function, for controlling gastric reflux, for treating erectile dysfunction and / or premature ejaculation, for treating vocal cords, and / or for treatment of joint and cartilage diseases.

15. A method of treating a skin abnormality or disfigurement, controlling bladder function, controlling gastric reflux, treating erectile dysfunction and / or premature ejaculation, treating vocal cords, and / or treating joint and cartilage diseases comprising administration of an in vivo resorbable composition according to any one of embodiments 4 to 11 .

16. Use of an in vivo resorbable composition according to any one of embodiments 4 to 11 in a cosmetic or esthetic application, preferably an application for augmenting tissue, more preferably an application as a dermal implant or dermal filler.

17. A solvent extraction process for the preparation of the biodegradable microparticles according to embodiment 1 , comprising:(i) preparing a solution of a biodegradable polymer in a solvent,(ii) preparing a solution of NaHCOs in water,(iii) prepare an emulsion comprising the polymer solution and the NaHCOs solution,(iv) add the emulsion to the an aqueous solution comprising a surfactant, evaporate the solvent, and optionally(v) harvest the microparticles.

18. A process according to embodiment 17, wherein the biodegradable polymer is selected from the group consisting of PCL, PLGA, PTMC, and PLA, PLLA, or PDLLA.

19. A process according to embodiment 18 or 19, wherein the concentration of the polymer in the solution in (i) is between 5% w / w and 40% w / w, such as between 10% and 35% and between 25% w / w and 35% w / w.

20. A process according to any one of embodiments 17 to 19, wherein the solution in (ii) comprises between 0.01 and 1 % w / w of NaHCO3.

21. A process according to any one of embodiments 17 to 20, wherein the solvent is an organic solvent, such as dichloromethane (DCM).

22. A process according to any one of embodiments 17 to 21 , wherein the surfactant is methylcellulose and / or wherein the concentration of the surfactant is between 0.1 % w / w and 2.5% w / w, such as between 0.5% w / w and 1 .5% w / w.

23. Microparticles obtainable by the process according to any one of embodiments 17 to 22.

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