US 2010O233O83A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0233083 A1 Dias et al. (43) Pub. Date: Sep. 16, 2010 (54) MICROPARTICLES COMPRISINGA merisable compound (having at least a functionality equal to CROSSLINKED POLYMER n); each Y independently is optionally present, and if present—each Y independently represents a moiety selected (75) Inventors: Aylvin Jorge Angelo Anthasius from the group of O, S and NRo:—each Ro is independently Dias, Maastricht (NL); Audrey chosen from the group of hydrogen and Substituted and Petit, Maastricht (NL) unsubstituted, aliphatic, cycloaliphatic and aromatic hydro carbon groups which groups optionally contain one or more Correspondence Address: moieties selected from the group of ester moieties, ether NIXON & VANDERHYE, PC moieties, thioester moieties, thioether moieties, carbamate 901 NORTH GLEBE ROAD, 11TH FLOOR moieties, thiocarbamate moieties, amide moieties and other ARLINGTON, VA 22203 (US) moieties comprising one or more heteroatoms, in particular one or more heteroatoms selected from S. O, P and N, each Ro (73) Assignee: DSM IPASSETS B.V., Heerlen in particular independently being chosen from the group of (NL) hydrogen and Substituted and unsubstituted alkyl groups, which alkyl groups optionally contain one or more heteroat (21) Appl. No.: 12/293,640 oms, in particular one or more heteroatoms selected from P. S. O and N: each Z is independently chosen from O and (22) PCT Filed: Mar. 21, 2007 S;—each R is independently chosen from the group of Sub stituted and unsubstituted, aliphatic, cycloaliphatic and aro (86). PCT No.: PCT/EP2007/002514 matic hydrocarbon groups which groups optionally contain S371 (c)(1), one or more moieties selected from the group of ester moi (2), (4) Date: Nov. 6, 2009 eties, ether moieties, thioester moieties, thioether moieties, carbamate moieties, thiocarbamate moieties, amide moieties (30) Foreign Application Priority Data and other moieties comprising one or more heteroatoms, in particular one or more heteroatoms selected from S. O. Pand Mar. 21, 2006 (EP) .................................. O6075678.0 N:—each R is independently chosen from hydrogen and Substituted and unsubstituted, aliphatic, cycloaliphatic and Publication Classification aromatic hydrocarbon groups which groups optionally con tain one or more moieties selected from the group of ester (51) Int. Cl. moieties, ether moieties, thioester moieties, thioether moi A6 IK 49/00 (2006.01) eties, carbamate moieties, thiocarbamate moieties, amide A6 IK 38/16 (2006.01) moieties and other moieties comprising one or more heteroa A6 IK 39/00 (2006.01) toms, in particular one or more heteroatoms selected from S. A 6LX 3/57 (2006.01) O, P and N, each Ro in particular independently being chosen A6IP 29/00 (2006.01) from the group of hydrogen and Substituted and unsubstituted A6IP35/00 (2006.01) alkyl groups, which alkyl groups optionally contain one or A6IP 9/06 (2006.01) more heteroatoms, in particular one or more heteroatoms A6IP 9/10 (2006.01) selected from P. S. O and N; and n is at least 2, each R is A6IP 7/02 (2006.01) chosen from hydrogen, —COOCH, -COOCHs. COSG 18/32 (2006.01) - COOCH,-COOCH.R. (52) U.S. Cl. ... 424/9.1; 514/12: 424/184.1: 514/252.17; 528/85 (I) Z Ro R2 (57) ABSTRACT | M The present invention relates to a microparticle comprising a X--Y-C-N-R-CV crosslinked polymer, which polymer is composed of a CHR crosslinkable compound represented by the formula (I) wherein X is a residue of a multifunctional radically poly 500 in articles Patent Application Publication Sep. 16, 2010 Sheet 1 of 3 US 2010/0233083 A1 O C CY Casey Spot Det WD Exp H 500 m 100 kW 4.0 SE 202 Particles C.T.", "I Patent Application Publication Sep. 16, 2010 Sheet 2 of 3 US 2010/0233083 A1 - - C2060370.s01 0.04 O. 1 0.2 0.4 1 2 4 6 10 20 40 1 OO 200 400 1 OOO 2000 Particle Diameter (um) Fig. 2 Patent Application Publication Sep. 16, 2010 Sheet 3 of 3 US 2010/0233083 A1 100 80 6 O 4 O 2 O O 1O 2O 30 40 Time (days) Fig. 3 US 2010/0233083 A1 Sep. 16, 2010 MCROPARTICLES COMPRISINGA In particular, it would be desirable to provide a microparticle CROSSLINKED POLYMER comprising a crosslinked polymer, which can be suitably processed under aggressive processing condition, with a low risk of being damaged to an unacceptable extent. Under 0001. The invention relates to microparticles comprising a aggressive processing conditions is in particular understood a crosslinked polymer, to a method of preparing Such micro condition that causes the particle to be subjected to a physical particles and to the use of the microparticles. shock, such as a (fast) change in temperature for example a 0002 Spherical microparticles (microspheres) compris change of at least 1° C. per Sec.—as happens in a freeze ing crosslinked polymers are described in WO 98/22093. drying process or a Sudden change in pressure, for example These microspheres are intended for use as a delivery system (repeated) pressurization and/or depressurization. For for a releasable compound (a drug). It is stated that the example in a pellet making machine use is made of a pressure crosslinkable polymer used to prepare the particles is not of 0.5T per cm per sec. critical. Suitable polymers mentioned in this publication are 0010. It would further be desirable to provide a micropar crosslinkable water-soluble dextrans, derivatized dextrans, ticle comprising a crosslinked polymer that canadequately be starches, starch derivatives, cellulose, polyvinylpyrrolidone, loaded with an active Substance, Such as a biologically active proteins and derivatized proteins. agent during microparticle formation and/or after the micro 0003. A disadvantage is that the pore size of the cross particle has been prepared. linked polymer must be smaller than the particle size of the 0011. Accordingly, it is an object of the present invention releasable compound. Thus, it is not possible to load the to provide a novel microparticle that can serve at least as an microspheres with the releasable compound after the micro alternative to known microparticles and in particular to pro spheres have been made. It is therefore not possible to prepare vide a microparticle that has a favourable property, Such as a master batch of the microspheres without the releasable showing good resistance against a physical shock. compound and to decide later which releasable compound to 0012 Moreover it is an object of the present invention to include in the microspheres. provide a microparticle being efficiently loadable with an 0004. It would however be desirable to be able to load active agent. microparticles afterwards, for instance because it would 0013 Another object of the present invention is to provide allow upscaling of the preparation process of the particles to a microparticle having one or more other favourable proper provide a large batch of the particles, of which if desired— ties as identified herein below. It has been found to provide a different portions can be loaded with different active agents, microparticle comprising a crosslinked polymer which poly in useful quantities for a specific purpose. Further, it would be meris composed of a crosslinkable compound represented by desirable to be able to load microparticles afterwards in case the formula an agent to be released from the microparticles may be det rimentally affected, e.g. degraded, denaturated or otherwise inactivated, during the preparation of the particles. Formula I 0005 Microparticles, comprising non-crosslinked biode Z Ro R2 gradable polyesters are described in U.S. Pat. No. 6.228,423. X-HY -U-N-K-| R / The polyesters comprise an amine group in the side chain. V These microparticles are used as a carrier for a biologically CHR active material, which is capable of eliciting an immune response. wherein 0006. Also US 2005/0013869 discloses microparticles for 0.014 X is a residue of a multifunctional radically poly a Sustained release formulation for a therapeutically active merisable compound (having at least a functionality compound. The microparticles comprise non-crosslinked equal to n); biodegradable polymers, in particular a polyester, poly(phos 0.015 each Y independently is optionally present, and— phate), poly(anhydride), poly(ortho-ester) or a mixture if present—each Y independently represents a moiety thereof. The therapeutically active compound is a carbamate, selected from the group of O, S and NRo: which is effective as an AChE inhibitor or binding agent. 0016 each Ro is independently chosen from the group 0007. The properties of known microparticles have been of hydrogen and Substituted and unsubstituted, aliphatic, reported to be detrimentally affected as a result of aggressive cycloaliphatic and aromatic hydrocarbon groups which processing for example freeze-drying. Especially in medical groups optionally contain one or more moieties selected applications and in particular in drug delivery applications, from the group of ester moieties, ether moieties, good storage stability of the drug-loaded microparticles is thioester moieties, thioether moieties, carbamate moi important. A Suitable method for providing long term product eties, thiocarbamate moieties, amide moieties and other stability of drug delivery systems is lyophilisation (freeze moieties comprising one or more heteroatoms, in par drying). ticular one or more heteroatoms selected from S, O, P 0008 To counter the above problem of detrimentally and N, each Ro in particular independently being chosen affected microparticles, cryoprotectants are used in order to from the group of hydrogen and Substituted and unsub maintain the original microparticle characteristics such as stituted alkyl groups, which alkyl groups optionally con size and shape. (See Saez et. al. European Journal of Phar tain one or more heteroatoms, in particular one or more maceutics or Biopharmaceutics 50 (2000) 379-387, Chacon heteroatoms selected from P, S, O and N: et.