AU2007263004A1

AU2007263004A1 - Sustained release formulations of aromatase inhibitors

Info

Publication number: AU2007263004A1
Application number: AU2007263004A
Authority: AU
Inventors: Oliver Lambert; Marc Riemenschnitter; Vitomire Vucenovic
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2006-06-22
Filing date: 2007-06-20
Publication date: 2007-12-27
Also published as: JP2009541264A; CA2654113A1; RU2009101810A; KR20090026345A; EP2037884A2; WO2007147861A3; CN101511341A; MX2008015917A; WO2007147861A2

Description

WO 2007/147861 PCT/EP2007/056166 Sustained Release Formulations of Aromatase Inhibitors Field of the Invention This invention relates to sustained release (depot) formulations of drugs such as aromatase inhibitors, e.g. letrozole, in a biodegradable and biocompatible polymeric carrier, e.g. a matrix or a coating, e.g. in the form of a implant, semisolid formulation or preferably a microparticle (also known as a microcapsule or a microsphere) or a nanoparticle (also known as a nanosphere). Summary of the Invention This invention relates to sustained release formulations, e.g. microparticle and/or nanoparticle formulations, of a drug, especially of an aromatase inhibitor such as letrozole, providing a satisfactory drug plasma level and in a encapsulating polymer matrix. The polymer matrix may be a synthetic or natural polymer. The invention also discloses the use of said sustained release formulation in treating cancer diseases, e.g. breast cancer. The sustained release formulations may be in the form of e.g. microparticles, nanoparticles, implants or semisolid formulations leading to a sustained release between one and six months, preferably between one and three months. Detailed Description of the Invention It has been found that administration of sustained release formulation comprising an aromatase inhibitor, e.g. embedded in a biocompatible pharmacologically acceptable polymer, gives release of all or of substantially all of the active agent over an extended period of time, e.g. several weeks up to 6 months, preferably over at least 2 to 3 months. Accordingly, the present invention provides a sustained release formulation of letrozole or a pharmaceutically acceptable salt therof e.g. embedded in a biocompatible pharma cologically acceptable polymer matrix. The compound of the invention may be present in an amount of from about 1 to about 50%, more usually about 15 to about 40%, even more preferably about 25% to about 35%, e.g. about 30% by weight of the sustained release formulation.

WO 2007/147861 PCT/EP2007/056166 -2 The polymer matrix of the sustained release formulation may be a synthetic or natural polymer. The polymer may be either a biodegradable or non-biodegradable or a combination of biodegradable and non-biodegradable polymers, preferably biodegradable. By "polymer" is meant an homopolymer or a copolymer. The polymer matrix is designed to degrade sufficiently to be transported from the site of administration within one to 6 months after release of all or substantially all the active agent. Suitable polymers include: (a) linear or branched polyesters which are linear chains radiating from a polyol moiety, e.g. glucose, (b) polyesters such as D-, L- or racemic polylactic acid, polyglycolic acid, polyhydroxy butyric acid, polycaprolactone, polyalkylene oxalate, polyalkylene glycol esters of acids of the Kreb's cycle, e.g. citric acid cycle, and the like and combinations thereof, (c) polymers of organic ethers, anhydrides, amides, and orthoesters, (d) copolymers of organic esters, ethers, anhydrides, amides, and orthoesters by them selves or in combination with other monomers, or (e) polyvinylalcohol. The polymers may be cross-linked or non-cross-linked, usually not more than 5%, typically less than 1%. The preferred polymers of this invention are linear polyesters. The linear polyesters may be prepared from the a-hydroxy carboxylic acids, e.g. lactic acid and glycolic acid, by condensation of the lactone dimers, see e.g. US 3,773,919, the contents of which are incorporated herein by reference. The preferred polyester chains in the linear polymers are copolymers of the a-carboxylic acid moieties, lactic acid and glycolic acid, or of the lactone dimers. The molar ratios of lactide: glycolide of polylactide-co-glycolides preferably used according to the invention is preferably from about 100:0 to 40:60, e.g. 90:10 to 40:60, e.g. 85:15 to 65:35. Linear polyesters, e.g. linear polylactide-co-glycolides (PLG/PLGA), preferably used according to the invention have a weight average molecular weight (Mw) between about 10,000 and about 500,000 Da, e.g. about 50,000 Da, and a polydispersity M,/Mn e.g.

WO 2007/147861 PCT/EP2007/056166 -3 between 1.2 and 2. Suitable examples include e.g. those commonly known and commercially available as Resomers@ from Boehringer Ingelheim. Branched polyesters, e.g. branched polylactide-co-glycolides, preferably used according to the invention may be prepared using polyhydroxy compounds e.g. polyol e.g. glucose or mannitol as the initiator. These esters of a polyol are known and described e.g. in GB 2,145,422 B, the contents of which are incorporated herein by reference. The polyol contains at least 3 hydroxy groups and has a molecular weight of up to 20,000 Da, with at least 1, preferably at least 2, e.g. as a mean 3 of the hydroxy groups of the polyol being in the form of ester groups, which contain poly-lactide or co-poly-lactide chains. Typically 0.2% glucose is used to initiate polymerization. The branched polyesters (Glu-PLG/Glu-PLGA) have a central glucose moiety halving rays of linear polylactide chains, e.g. they have a star shaped structure. The branched polyesters having a central glucose moiety having rays of linear polylactide-co-glycolide chains (Glu-PLG/Glu-PLGA) may be prepared by reacting a polyol with a lactide and preferably also a glycolide at an elevated temperature in the presence of a catalyst, which makes a ring opening polymerization feasible. The branched polyesters having a central glucose moiety having rays of linear polylactide-co-glycolide chains (Glu-PLG/Glu-PLGA) preferably have an weight average molecular weight Mw in the range of from about 10,000 to 200,000, preferably 25,000 to 100,000, especially 35,000 to 60,000, e.g. about 50,000 Da, and a polydispersity e.g. of from 1.7 to 3.0, e.g. 2.0 to 2.5. The intrinsic viscosities of star polymers of M, 35,000 and Mw 60,000 are 0.36 respectively 0.51 dl/g in chloroform. A star polymer having a Mw 52,000 has a viscosity of 0.475 dl/g in chloroform. The desired rate of degradation of polymers and the desired release profile for compounds of the invention may be varied depending on the kind of monomer, whether a homo- or a copolymer or whether a mixture of polymers is employed. A mixture of polymers may comprise at least two different kinds of polymers, e.g. as listed under (a) to (e) above, or two polymers of the same polymer class with different properties. For example, a mixture of polymers may comprise a polymer having a medium weight average molecular weight, e.g. from about 30,000 to about 60,000 Da, e.g. of about 50,000 Da, and of a polymer having a low weight average molecular weight, e.g. of about 2.000 to about 20,000 Da, e.g. of about 10,000 Da.

WO 2007/147861 PCT/EP2007/056166 -4 The polymer matrix may be present in a total amount of about 40 to 99% by weight of the sustained release formulation. The terms microsphere, microcapsule, microparticle, nanoparticles and nanospheres are considered to be interchangeable with respect to the invention, and denote the encapsulation of the drugs by the polymer, preferably with the drug distributed throughout the polymer, which is then a matrix for the drug. In that case the terms microsphere or more generally microparticle are used. The microparticles of this invention may further comprise an agent that may influence the porosity of the microparticles. Non limiting examples of such an agent include: a) Polyvinyl pyrrolidone, preferably with a molecular weight of between about 2,000 and about 20,000 Da. Suitable examples include those commonly known as Povidone K12 F with an average molecular weight of about 2,500 Da, Povidone K15 with an average molecular weight of about 8,000 Da, or Povidone K17 with an average molecular weight of about 10,000 Da. Preferably, the polyvinyl pyrrolidone is present in an amount of from about 0.1 to about 50%, e.g. about 10%, by weight of the microparticles. b) Carboxymethyl cellulose sodium (CMC-Na), preferably having a low molecular weight. The viscosity may be, e.g. up to 20 cP for a 2% aqueous solution or a viscosity of from 8 to 25 mPa s. Conveniently the degree of substitution is from about 0.5 to about 1.45, preferably about 0.7. Typically the sodium content is about 5% to about 12%. Preferably, the CMC-Na is present in an amount of from about 0.1 to about 20%, e.g. about 5%, by weight of the microparticles. c) Dextrin, e.g. with an average molecular weight ranging from 1,000 to 50,000 Da, preferably 5,000 Da. Preferably the dextrin has a fine particle size distribution, e.g. x90 less than 20 microns. Preferably, the dextrin is present in an amount of from about 0.1 to about 10%, e.g. about 5%, by weight of the microparticles. d) Polyethyleneglycol, e.g. with weight average molecular weight ranging from about 1,000 to about 10,000 Da, preferably from about 1,000 to about 3,350 Da. Suitable examples include those commonly known and commercially available under the trade name Carbowax@ from Dow&Union Carbide, with e.g. Mw of 3,350 Da. Polyethyleneglycol with an weight average molecular weight of 3,350 Da has a viscosity of 76 to 110 cSt at 98.9 +/- 0.3 0 C. Polyethyleneglycol with Mw ranging from 1000 to 3500 DA has viscosities ranging from 16 to 123 cSt 98.9 +/- 0.3 0

C.

WO 2007/147861 PCT/EP2007/056166 -5 The microparticles of this invention may further comprise a surfactant. Suitable surfactants include non-ionic surfactants such as a) Poloxamers, also known as polyoxyethylene polyoxypropylene block copolymers, e.g. having a molecular weight from about 2000 to about 8000 Da. The degree of polymerization of the ethylene moiety is typically 80 to about 110 units. The degree of polymerization of the propylene moiety is typically 20 to about 60 units. Examples of such compounds suitable for use in accordance with the present invention are those known and commercially available, e.g. under the trade name Pluronic@ F68 available from BASF Germany. A further product of this class is Poloxamer 188. b) Polyoxyethylene-sorbitan-fatty acid esters e.g. mono- and tri-lauryl, palmityl, stearyl and oleyl esters e.g. of the type known and commercially available under the trade name TWEEN@, e.g. Tween 20 [polyoxyethylene(20)sorbitanmonolaurate], 21 [polyoxyethylene(4)sorbitanmonolaurate], Tween 40 [polyoxyethylene(20)sorbitan monopalmitate], Tween 60 [polyoxyethylene(20)sorbitanmonostearate], Tween 80 [polyoxyethylene(20)sorbitanmonooleate], Tween 65 [polyoxyethylene(20) sorbitantristearate], Tween 85 [polyoxyethylene(20)sorbitantrioleate], Tween 21 [poly oxyethylene(4)sorbitanmonolaurate], Tween 61 [polyoxyethylene(4)sorbitanmonostea rate], and Tween 81 {polyoxyethylene(5)sorbitanmonooleate]. Preferred are Tween 20 and Tween 80. c) Sorbitan fatty acid esters e.g. of the type known and commercially available under the trade name SPAN, for example including sorbitan monolauryl, monopalmityl, mono stearyl, tristearyl, monooleyl and trioleyl esters. d) Lecithins, e.g. soy bean phospholipid, e.g. as known and commercially available under the trade name Lipoid@ S75 from Lipoid; or egg phospholipid, e.g. as known and commercially available under the trade names Phospholipon@ 90 from Nattermann, Epikuron 100H or Epikuron 145V, Epikuron 170 or Epikuron 200 from Degussa, Bioactives. Preferably, poloxamers, Tween 20 and/or Tween 80 are used. e) Reaction products of a natural or hydrogenated castor oil and ethylene oxide. The natural or hydrogenated castor oil may be reacted with ethylene oxide in a molar ratio of WO 2007/147861 PCT/EP2007/056166 from about 1:35 to about 1:60, with optional removal of the polyethyleneglycol component from the products. Various such surfactants are commercially available. The polyethyleneglycol-hydrogenated castor oils available under the trademark CREMOPHOR are especially suitable. Particularly suitable are CREMOPHOR RH 40, which has a saponification number of about 50 to 60, an acid number less than about 1, a water content ( Fischer) less than about 2%, an nD of about 1.453 to 1.457 and an HLB of about 14 to 16; and CREMOPHOR RH 60, which has a saponification number of about 40 to 50, an acid number less than about 1, an iodine number of less than about 1, a water content (Fischer) of about 4.5 to 5.5%, an no 2 5 of about 1.453 to 1.457 and an HLB of about 15 to 17. An especially preferred product of this class is CREMOPHOR RH40. Also suitable are polyethyleneglycol castor oils such as that available under the trade name CREMOPHOR EL, which has a molecular weight (by steam osmometry) of about 1630, a saponification number of about 65 to 70, an acid number of about 2, an iodine number of about 28 to 32 and an nD25 of about 1.471. Similar or identical products which may also be used are available under the trademarks NIKKOL (e.g. NIKKOL HCO-40 and HCO-60), MAPEG (e.g. MAPEG CO-40h), INCROCAS (e.g. INCROCAS 40), and TAGAT (for example polyoxyethylene-glycerol fatty acid esters e.g. TAGAT RH 40; and TAGAT TO, a polyoxyethylene-glycerol trioleate having a HLB value of 11.3; TAGAT TO is preferred). These surfactants are further described in Fiedler loc. cit.. f) Polyoxyethylene fatty acid esters, for example polyoxyethylene stearic acid esters of the type known and commercially available under the trademark MYRJ (Fiedler, loc. cit., 2, p.1042-1043). An especially preferred product of this class is MYRJ 52 having a D 2 5 of about 1.1., a melting point of about 40 to 440C, an HLB value of about 16.9., an acid value of about 0 to 1 and a saponification no. of about 25 to 35. g) Diocusate salts, e.g. dioctylsulfosuccinate or di-{2-ethylhexyl]-succinate (Fiedler, c cit., 1, p. 487). h) Propylene glycol mono- and di-fatty acid esters such as propylene glycol dicaprylate (also known and commercially available under the trademark MIGLYOL 840), propylene glycol dilaurate, propylene glycol hydroxystearate, propylene glycol isostearate, WO 2007/147861 PCT/EP2007/056166 -7 propylene glycol laurate, propylene glycol ricinoleate, propylene glycol stearate and so forth (Fiedler, loc. cit., 2, p. 1285). i) Polyoxyethylene alkyl ethers such as those commercially available under the trademark BRIJ, e.g., Brij 92V and Brij 35. j) Tocopherol esters, e.g., tocopheryl acetate and tocopheryl acid succinate. A combination of surfactants may also be used. In case the polymer or polymers used to embed the compound of the invention is an ester, the microparticles of this invention preferably further comprise a basic compound such as a basic salt, e.g. basic zinc carbonate, magnesium hydroxide, magnesium carbonate, or protamine, e.g. human protamine or salmon protamine, or natural or synthetic polymers bearing amine-residues such as polylysine or dimethylaminoethylmethacrylate. Reference is made to the extensive literature on the subject for these and other excipients and procedures mentioned herein, see in particular Handbook of Pharmaceutical Excipients, Second Edition, edited by Ainley Wade and Paul J. Weller, American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London; and Lexikon der Hilfsstoffe fOr Pharmazie, Kosmetik and angrenzende Gebiete edited by H.P. Fiedler, 4th Edition, Editio Cantor, Aulendorf and earlier editions which are incorporated herein by reference. Procedures which may be used to prepare the microparticles of the invention may be conventional or known in the art or based on such procedures e.g. those described in L. Lachman et al. The Theory and Practice of Industrial Pharmacy, 3rd Ed, 1986, H. Sucker et al, Pharmazeutische Technologie, Thieme, 1991, Hager's Handbuch der pharmazeutischen Praxis, 4th Ed. (Springer Verlag, 1971), Remington's Pharmaceutical Sciences, 13th Ed., (Mack Publ., Co., 1970) or later editions and in E. Mathiowitz's Encyclopedia of Controlled Drug Delivery (John Wiley & Sons, Inc, 1999). Typically, the microparticles of the invention are produced by the following process.

WO 2007/147861 PCT/EP2007/056166 -8 The present invention in another aspect provides a process for the preparation of microparticles of the invention comprising (i) preparation of an internal organic phase comprising (ia) dissolving the polymer or polymers in a suitable organic solvent or solvent mixture, and optionally - dissolving/dispersing a porosity-influencing agent in the solution obtained in step (ia), or - adding a basic salt to the solution obtained in step (ia), - adding a surfactant to the solution obtained by step (ia); (ib) suspending the compound of the invention in the polymer solution obtained in step (ia), or dissolving the compound of the invention in a solvent miscible with the solvent used in step (ia) and mixing said solution with the polymer solution, or directly dissolving the compound of the invention in the polymer solution, or dissolving the compound of the invention in form of a water soluble salt in an aqueous phase and emulsifying said aqueous solution with the polymer solution (ia); (ii) preparation of an external aqueous phase comprising (iia) preparing a buffer, e.g. acetate or phosphate buffer, and (iib) dissolving a stabilizer in the solution obtained in step (iia); (iii) mixing the internal organic phase with the external aqueous phase e.g. with a device creating high shear forces, e.g. with a turbine or static mixer, to form an emulsion; and (iv) hardening the microparticles by solvent evaporation or solvent extraction, e.g. cross flow filtration, washing the microparticles, e.g. with water, collecting and drying the microparticles, e.g. freeze-drying or drying under vacuum. Suitable organic solvents for the polymers include e.g. ethyl acetate, acetone, THF, acetonitrile, or halogenated hydrocarbons, e.g. methylene chloride, chloroform or hexafluoro isopropanol. Suitable examples of a stabilizer for step (iib) include a) Polyvinyl alcohol (PVA), preferably having a weight average molecular weight from about 10,000 to about 150,000 Da, e.g. about 30,000 Da. Conveniently the polyvinyl alcohol has low viscosity having a dynamic viscosity of from about 3 to about 9 mPa s when measured as a 4% aqueous solution at 20oC or by DIN 53015. Suitably the WO 2007/147861 PCT/EP2007/056166 -9 polyvinyl alcohol may be obtained from hydrolyzing polyvinyl acetate. Preferably, the content of the polyvinyl acetate is from about 10 to about 90% of the polyvinyl alcohol. Conveniently the degree of hydrolysis is about 85 to about 89%. Typically the residual acetyl content is about 10 to 12 %. Preferred brands include Mowiol@ 4-88, 8-88 and 18 88 available from Clariant AG Switzerland. Preferably the polyvinyl alcohol is present in an amount of from about 0.1 to about 5%, e.g. about 0.5%, by weight of the volume of the external aqueous phase; b) Hydroxyethyl cellulose (HEC) and/or hydroxypropyl cellulose (HPC), e.g. formed by reaction of cellulose with ethylene oxide and propylene oxide respectively. HEC and HPC are available in a wide range of viscosity types; preferably the viscosity is medium. Preferred brands include Natrosol@ from Hercules Inc., e.g. Natrosol@ 250MR, and Klucel@ from Hercules Inc. Preferably, HEC and/or HPC is present in a total amount of from about 0.01 to about 5%, e.g. about 0.5%, by weight of the external aqueous phase; c) Polyvinyl pyrolidone, suitably with a molecular weight of between about 2,000 and 20,000 Da. Suitable examples include those commonly known as Povidone K12 F with an average molecular weight of about 2,500 Da, Povidone K15 with an average molecular weight of about 8,000 Da, or Povidone K17 with an average molecular weight of about 10,000 Da. Preferably, the polyvinyl pyrolidone is present in an amount of from about 0.1 to about 50%, e.g. 10% by weight of the volume of the external aqueous phase; d) Gelatin, preferably porcine or fish gelatin. Conveniently, the gelatin has a viscosity of about 25 to about 35 cps for a 10% solution at 20oC. Typically pH of a 10% solution is from about 6 to about 7. A suitable brand has a high molecular weight, e.g. Norland high molecular weight fish gelatin obtainable from Norland Products Inc, Cranbury New Jersey USA. Preferably, the gelatin is present in an amount of from about 0.01 to about 5%, e.g. about 0.5%, by weight of the volume of the external aqueous phase. Preferably, polyvinyl alcohol is used. Preferably, no gelatin is used. Preferably, the microparticles are gelatin-free. The microparticles may have a diameter from a few submicrons to a few millimeters, e.g. from about 0.01 microns to about 2 mm, e.g. from about 0.1 microns to about 500 microns. For pharmaceutical micro-particles, diameters of at most about 250 microns, e.g. 1 to 250 microns, e.g. 10 to 200 microns, preferably 10 to 130 microns, more preferably 10 to WO 2007/147861 PCT/EP2007/056166 - 10 90 microns, are strived for, e.g. in order to facilitate passage through an injection needle. Impants ma be e.g. from about 1to 10 cubic nun. Content uniformity of the microparticles and of a unit dose is excellent. Unit doses may be produced which vary from about 75% to about 125%, e.g. about 85 to about 115%, e.g. from about 90 to about 110%, or from about 95 to about 105%, of the theoretical dose. The microparticles in dry state may e.g. be mixed, e.g. coated, with an anti agglomerating agent, or e.g. covered by a layer of an anti-agglomerating agent e.g. in a prefilled syringe or vial. Suitable anti-agglomerating agents include e.g. mannitol, glucose, dextrose, sucrose, sodium chloride, or water soluble polymers such as polyvinylpyrrolidone or polyethylene glycol, e.g. with the properties described above. Preferably, an anti-agglomerating agent is present in an amount of about 0.1 to about 10%, e.g. about 4% by weight of the microparticles. Prior to administration, the microparticles are suspended in a vehicle suitable for injection. Preferably, said vehicle is water based. However, when using water as a vehicle, the microparticles of the invention may not suspend and may float on the top of the aqueous phase. In order to improve the capacity of the microparticles of the invention to be suspended in an aqueous medium, the vehicle preferably comprises a wetting agent. The wetting agent is chosen to allow a quick and suitable suspendibility of the microparticles in the vehicle. Preferably, the microparticles are quickly wettened by the vehicle and quickly form a suspension therein. Accordingly, the present invention further provides a pharmaceutical composition comprising microparticles of the invention and a water-based vehicle comprising a wetting agent. Suitable wetting agents for suspending the microparticles of the invention in a water based vehicle include non-ionic surfactants such as poloxamers, or polyoxyethylene sorbitan-fatty acid esters, the caracterstics of which have been described above. A mixture of wetting agents may be used. Preferably, the wetting agent comprises Pluronic F68, Tween 20 and/or Tween 80.

WO 2007/147861 PCT/EP2007/056166 - 11 The wetting agent or agents may be present in about 0.01 to about 1% by weight of the composition to be administered, preferably from 0.01 to 0.5% and may be present in about 0.01 to 5 mg/ml of the vehicle, e.g. about 2 mg/ml. Preferably, the vehicle further comprises a tonicity agent such as mannitol, sodium chloride, glucose, dextrose, sucrose, or glycerins. Preferably, the tonicity agent is mannitol. The amount of tonicity agent is chosen to adjust the isotonicity of the composition to be administered. In case a tonicity agent is contained in the microparticles, e.g. to reduce agglomeration as mentioned above, the amount of tonicity agent is to be understood as the sum of both. For example, mannitol preferably may be from about 1% to about 5% by weight of the composition to be administered, preferably about 4.5%. Preferably, the vehicle further comprises a viscosity increasing agent. Suitable viscosity increasing agents include carboxymethyl cellulose sodium (CMC-Na), sorbitol, polyvinyl pyrrolidone, or aluminium monostearate. CMC-Na has a low viscosity. Embodiments may be as described above. Typically, CMC Na has a low molecular weight. The viscosity may be of from about 1 to about 30 mPa s, e.g. from about 10 to about 15 mPa s when measured as a 1% (w/v) aqueous solution at 25 0 C in a Brookfield LVT viscometer with a spindle 1 at 60 rpm, or a viscosity of 1 to 15 mPa*s for a solution of NaCMC 7LF (low molecular weight) as a 0.1 to 1% solution in water. Polyvinylpyrrolidone having properties as described above may be used. A viscosity increasing agent, e.g. CMC-Na, may be present in an amount of from about 0.1 to about 1%, e.g. about 0.7% or about 1.75% of the vehicle, e.g. in a concentration of about 1 to about 30 mg/ml in the vehicle, e.g. about 7 mg/ml or about 17.5 mg/ml. In a further aspect, the present invention provides a kit comprising microparticles of the invention and a vehicle of the invention. For example, the kit may comprise microparticles comprising the exact amount of compound of the invention to be administered, e.g. as described below, and about 1 to about 5 ml, e.g. about 2 ml of the vehicle of the invention. In one embodiment, the dry microparticles, optionally in admixture with an anti agglomerating agent, may be filled into a container, e.g. a vial or a syringe, and sterilized e.g. using y-irradition. Prior to administration, the microparticles may be suspended in the container by adding a suitable vehicle, e.g. the vehicle described above. For example, the microparticles, optionally in admixture with an anti-agglomerating agent, a viscosity WO 2007/147861 PCT/EP2007/056166 - 12 increasing agent and/or a tonicity agent, and the vehicle for suspension may be housed separately in a double chamber syringe. In another embodiment, under sterile conditions dry sterilized microparticles, optionally in admixture with an anti-agglomerating agent, may be suspended in a suitable vehicle, e.g. the vehicle described above, and filled into a container, e.g. a vial or a syringe. The solvent of the vehicle, e.g. the water, may then be removed, e.g. by freeze-drying or evaporation under vacuum, leading to a mixture of the microparticles and the solid components of the vehicle in the container. Prior to administration, the microparticles and solid components of the vehicle may be suspended in the container by adding a suitable vehicle, eg, water, e.g. water for infusion, or preferably a low molarity phosphate buffer solution. For example, the mixture of the microparticles, optionally the anti-agglomerating agent, and solid components of the vehicle and the vehicle for suspension, e.g. water, may be housed separately in a double chamber syringe. A method of administering an aromatase inhibitor to a subject which comprises administering parenterally to a subject in need of such treatment a depot formulation as defined above, especially for the treatment of cancer, preferably breast cancer. The drugs for use in the processes of the invention are preferably aromatase inhibitors. Examples of aromatase inhibitors include those selected from exemestane, formestane, aminoglutethimide, vorozole, fadrozole, anastrozole, letrozole, roglethimide, pyridoglutethimide, trilostane, testolactone, atamestane, 1-methyl-1,4-androstadiene 3,17-dione and pharmaceutically acceptable salts of these compounds. The most preferred aromatase inhibitor for use in the processes and formulations of this invention may is letrozole which is disclosed in U.S. Patent No. 4,978,672 which issues December 18, 1990. The formulations of the present invention are especially useful for letrozole a compound which is practically insoluble in water. The aromatase inhibitors are indicated for use in the treatment of tumors, especially breast cancer, wherein long term application of the drug is envisaged. The activity and characteristics of the microparticles and the compositions of the invention may be indicated in standard clinical or animal tests. The compounds of the invention are released from the microparticles of the invention and from the compositions of the invention over a period of several weeks up to 6 months, preferably over at least 2 to 3 months WO 2007/147861 PCT/EP2007/056166 -13 Appropriate dosage of the composition of the invention will of course vary, e.g. depending on the condition to be treated (for example the disease type or the nature of resistance), the drug used, the effect desired and the mode of administration. The terms microsphere, microcapsule, microparticle, nanoparticle, and nanosphere are considered to be interchangeable with respect to the invention, and denote the encapsulation of the drugs by the polymer, preferably with the drug distributed throughout the polymer, which is then a matrix for the drug. In that case preferably the terms microsphere or nanosphere or more generally microparticle or nanoparticle are used. The sustained release formulations can also be made by other methods known per se, e.g. if the drug is stable enough for the production of an implant, by heating microparticles or nanoparticles containing an aromatase inhibitor, e.g. letrozole in a polylactide-co glycolide, especially such as described above or a mixture thereof obtained by mixing an aromatase inhibitor and the polymer, at a temperature of e.g. from 70* to 100* C and extruding and cooling the compact mass, after which the extrudate is cut and optionally washed and dried. Conveniently the formulations according to the invention are produced under aseptic conditions. The formulations according to the invention may be utilized in depot form, e.g. injectable microspheres, implants or semisolid formulations. They may be administered in conventional manner, e.g. subcutaneous or intramuscular injection, e.g. for indications known for the drug contained therein. The sustained release formulations containing letrozole may be administered for all the known indications of letrozole, e.g. as an aromatase inhibitor as disclosed in US 4,978,672, and most especially for breast cancer. Conveniently the sustained release formulation comprises an aromatase inhibitor, e.g. letrozole in a biodegradable biocompatible polymeric carrier which, when administered to a rat subcutaneously at a dosage of 10 mg letrozole per kg of animal body weight, exhibits a concentration of a letrozole in the blood plasma of at least 0.3 ng/ml and preferably less than 20 ng/ml during a 30 day term, or conveniently a 60 day's term.

WO 2007/147861 PCT/EP2007/056166 - 14 Alternatively conveniently the sustained release formulation comprises an aromatase inhibitor, e.g. letrozole in a biodegradable biocompatible polymeric carrier, which, when administered to a rabbit intramuscularly at a dosage of 5 mg per kg of body weight, exhibits a concentration of an aromatase inhibitor of at least 0.3 ng/ml during a 50 day's term and conveniently a concentration of at most 20 ng/ml. The following examples illustrate the invention: M, of polymers is the mean molecular weight as determined by GLPC using polystyrene as standard. EXAMPLE 1 One g of poly (D,L,-lactide-co-glycolide) (50:50) molar, Polydispersity ca. 1.7, is dissolved in 10 ml of methylene chloride with magnetic stirring followed by the addition of 75 mg of letrozole. The drug substance (DS) is solved. The solution is sprayed by means of a high speed turbine (Niro Atomizer) and the small droplets dried in a stream of warm air generating microparticles or nanoparticles. The microparticles or nanoparticles are collected by a cyclone and dryed overnight at room temperature in a vacuum oven. The microparticles or nanoparticles are washed with 1/15 molar acetate buffer pH 4.0 during 5 minutes and dried again at room temperature in a vacuum oven. After 72 hours the microparticles or nanoparticles are sieved (0.125 mm mesh size) to obtain the final product. EXAMPLE 2 An appropriate amount of the PLGA polymers is dissolved in an appropriate amount of dichloromethane to give an appropriate polymer concentration. An appropriate amount of drug substance is weight into a glass beaker and the polymer solution is poured over the drug substance. For microparticles or nanoparticles with a drug load of 40% and a polymer concentration of 7.0% the numbers are as the following: 3 g of the PLGA polymers are dissolved into 40 g dichloromethane to give a 7.0 % (w) polymer solution. 2.0 g of letrozol is weight into a glass beaker and the polymer solution is poured over the drug substance and stirred until dissolved. 10.00 g of Polyvinylalcohol PVA 18-88, 3.62 g KH 2

PO

4 and 15.14 g Na 2

HPO

4 are dissolved in 2.00 L deionized water to form a 0.5% PVA 18-88 solution buffered to pH 7.4.

WO 2007/147861 PCT/EP2007/056166 - 15 The polymer/drug solution is mixed with the 0.5 % PVA18-88 solution by pumping both phases in a static mixer (SMXS DN 6, 20 elements). The homogenized O/W emulsion is collected into a 2 L glass beaker which is prefilled with 1 L of the buffered PVA solution. The O/W emulsion is then concentrated with a Cross-Flow filtration unit equipped with a Membrane pump and a ceramic membrane (0,8 pm). Subsequently the microparticles or nanoparticles are diafiltrated with water and a concentrated vehicle for freeze-drying is added. Microparticles or nanoparticles are suspended in the vehicle solution and then filled into vials and freeze-dried. As a result, microparticles or nanoparticles are formed out of this process. Prepared in that way, the microparticles or nanoparticles are sterilized by gamma-irradiation with a dose of 30 kGy. EXAMPLE 3 An appropriate amount of the PLGA polymers is dissolved in an appropriate amount of dichloromethane to give an appropriate polymer concentration. An appropriate amount of drug substance is weight into a glass beaker and the polymer solution is poured over the drug substance. For microparticles or nanoparticles with a drug load of 30% and a polymer concentration of 10% the numbers are as the following: 5.6 g of the PLGA polymers are dissolved into 50.4 g dichloromethane to give a 10.0 % (w) polymer solution. 2.4 g of letrozole is weight into a glass beaker and the polymer solution is poured over the drug substance and stirred until dissolved. 10.00 g of Polyvinylalcohol PVA 18-88, 3.62 g KH 2

PO

4 and 15.14 g Na 2 HP0 4 are dissolved in 2.00 L deionized water to form a 0.5% PVA 18-88 solution buffered to pH 7.4. The polymer/drug solution is mixed with the 0.5 % PVA18-88 solution by pumping both phases in a static mixer (SMXS DN 6, 20 elements). The homogenized O/W emulsion is collected into a 2 L glass beaker which is prefilled with 1 L of the buffered PVA solution. The O/W emulsion is then heated under stirring in order to facilitate solvent evaporation and subsequently cooled down to room temperature. Subsequently the microparticles or nanoparticles are collected on a filter and washed with water. Microparticles or nanoparticles are dried and then filled into vials.

WO 2007/147861 PCT/EP2007/056166 - 16 As a result, microparticles or nanoparticles are formed out of this process. Prepared in that way, the microparticles or nanoparticles are sterilized by gamma-irradiation with a dose of 30 kGy. EXAMPLE 4 An appropriate amount of the PLGA polymers is dissolved in an appropriate amount of dichloromethane to give an appropriate polymer concentration. An appropriate amount of drug substance is weight into a glass beaker and the polymer solution is poured over the drug substance. For microparticles or nanoparticles with a drug load of 30% and a polymer concentration of 15% the numbers are as the following: 8.4 g of the PLGA polymers are dissolved into 47.6 g dichloromethane to give a 15.0 % (w) polymer solution. 2.4 g of letrozol is weight into a glass beaker and the polymer solution is poured over the drug substance and stirred until dissolved. 10.00 g of Polyvinylalcohol PVA 18-88, 3.62 g KH 2

PO

4 and 15.14 g Na 2 HP0 4 are dissolved in 2.00 L deionized water to form a 0.5% PVA 18-88 solution buffered to pH 7.4. The polymer/drug solution is mixed with the 0.5 % PVA18-88 solution by pumping both phases in a static mixer (SMXS DN 6, 20 elements). The homogenized O/W emulsion is collected into a 2 L glass beaker which is prefilled with 1L of the buffered PVA solution. The O/W emulsion is then heated under stirring in order to facilitate solvent evaporation and subsequently cooled down to room temperature. Subsequently the microparticles or nanoparticles are collected on a filter and washed with water. Microparticles or nanoparticles are dried and then filled into vials. As a result, microparticles or nanoparticles are formed out of this process. Prepared in that way, the microparticles or nanoparticles are sterilized by gamma-irradiation with a dose of 30 kGy. EXAMPLE 5 Composition of the formulations prepared by EXAMPLE 2 is described below: Normal batch size at labscale: 5 g Drug substance loading: 40% w/w drug product WO 2007/147861 PCT/EP2007/056166 - 17 Polymer concentration: 10% w/v methylene chloride Excipient Amount mg/g Femara (CGS 20267) 400 Poly(lactide-co-glycolide) 600 Excipient for freeze-drying (in 1 ml): Mannitol 38 mg Sodium-carboxymethylcellu lose 14 mg Pluronic F68 2 mg Processing material removed after manufacturing Amount in g

CH

2

CI

2 ( D: 1.325) 7.95 Polyvinylalkohol 18-88 5 Na 2

HPO

4 7.57

KH

2

PO

4 1.81 WFI Ad 1007 EXAMPLE 4: Vehicle compositions A to G CMC-Na, Mannitol and Pluronic F68 in an amount as given in Table 3 are dissolved in about 15 ml hot deionized water of a temperature of about 90*C under strong stirring with a magnetic stirrer. The resulting clear solution is cooled to 200C and filled up with deionized water to 20.0 ml. Table 3 (Amounts given in g) A B C D E F G CMC-Na 0 0 0.05 0.14 0.28 0.35 0.40 Mannitol 0 1.04 0.99 0.90 0.76 0.74 0.68 Pluronic F68 0.04 0.04 0.04 0.04 0.04 0.04 0.04 WO 2007/147861 PCT/EP2007/056166 -18 EXAMPLE 5: 867 mg of microparticles of example 1,-4 are suspended in 2.0 ml of a vehicle of composition D in 6R vials. The suspensions are homogenized by shaking for about 30 seconds. The reconstituted suspension may be injected without blocking using a 20 Gauge needle. EXAMPLE 6: 867 mg of microparticles of example 1-4 are reconstituted in 1 ml of the vehicle composition E, homogenized with a propeller mixer at 400 rpm for 1 to 12 hours and then freeze-dried in a Telstar lyophilisator. Reconstitution of the microparticle lyophilisates with 1 ml pure water (WBU) resulted in fast and good wetting of the microparticles that may be injected without blocking using a 20 Gauge needle.

Claims

1. A microparticle comprising an aromatase inhibitor in a polymeric matrix , wherein said aromatase inhibitor is distributed throughout said polymeric matrix.

2. A microparticle according to claim 1 wherein the aromatase inhibitor is in a polymeric matrix of poly(D,L-lactide co-glycolide)glucose.

3. A sustained release formulation comprising a microparticle of claim 1.

4. A sustained release formulation comprising a microparticle of claim 2.

5. A microparticle according to claim 2 wherein the surface is free of aromatase inhibitor.

6. A microparticle having a diameter of between 1 and 250 microns comprising letrozole in a free base, acid addition salt or complex form, in a biodegradeable, biocompatible polymeric matrix of a 40/60 to 60/40 polylactide-co-glycolide ester of a polyol, said polyol being selected from the group consisting of 1) a (C3-) carbon chain containing alcohol having 3 to 6 hydroxyl groups, 2) a mono-saccharide and 3) a di-saccharide, and said esterified polyol having at least 3 polylactide-co-glycolide chains.,.

7. A microparticle according to claim 6 wherein said letrozole is present in a drug load of 15% to 40% and said letrozole is distributed throughout said polymeric matrix.

8. A pharmaceutical sustained release formulation comprising as active ingredient an aromatase inhibitor or a pharmaceutically acceptable salt thereof and one ore more different polylactide-co-glycolide polymers (PLGAs)

9. The pharmaceutical composition according to claim 8 wherein the PLGAs are present as polymer blend.

10. The pharmaceutical composition according to claims 8 or 9 wherein at least one PLGA is linear. WO 2007/147861 PCT/EP2007/056166 - 20

11. The pharmaceutical composition to any of the claims 8-10 wherein the release of the active ingredient is between two weeks and six months.

12. The pharmaceutical composition according to claims 8-11 in form of microparticles, a semisolid or an implant.

13. The pharmaceutical composition according to claim 12 in form of microparticles.

14. The pharmaceutical composition according to claim 13 wherein the microparticles have a diameter between 1 micron and 250 microns.

15. The pharmaceutical composition according to 14 wherein the microparticles are covered or coated with an anti-agglomerating agent.

16. The pharmaceutical composition according to claim 15 wherein the anti-agglomerating agent is present in an amount of 3% to 5% by weight of the microparticles.

17. The pharmaceutical composition according to any of claims 8 to 16 sterilized by gamma irradiation.

18. Use of a pharmaceutical composition according to any of claims 8 to 16 for long-term maintenance therapy in cancer, especially breast-cancer

19. A method of administering letrozole or a pharmaceutically-acceptable salt thereof for long-term maintenance therapy in cancer patients, especially breast cancer, said method comprising administering to a patient in need of letrozole or a pharmaceutically-acceptable salt thereof a pharmaceutical composition according to any of claims 8 to 17.

20. A process of manufacturing microparticles according to claim 13 comprising (i) preparation of an internal organic phase comprising (ia) dissolving the polymer or polymers in a suitable organic solvent or solvent mixture; WO 2007/147861 PCT/EP2007/056166 - 21 (ib) dissolving/suspending/emulsification of the drug substance in the polymer solution obtained in step (ia); (ii) preparation of an external aqueous phase containing stabilizers; (iii) mixing the intemal organic phase with the external aqueous phase to form an emulsion; and (iv) hardening the microparticles by solvent extraction and washing and concentrating the microparticles using cross-flow ultrafiltration; (v) suspending microparticle concentrate in vehicle solution and subsequent freeze-drying of microparticles.

21. An administration kit comprising the pharmaceutical composition according to any of claims 8 to 17 in a vial, together with a water-based vehicle in an ampoule, vial or prefilled syringe or as microparticles and vehicle separated in a double chamber syringe.

22. A nanoparticle comprising an aromatase inhibitor in a polymeric matrix, wherein said aromatase inhibitor is distributed throughout said polymeric matrix.

23. A nanoparticle according to claim 1 wherein the aromatase inhibitor is in a polymeric matrix of poly(D,L-lactide co-glycolide)glucose.

24. A sustained release formulation comprising a nanoparticle of claim 1.

25. A sustained release formulation comprising a nanoparticle of claim 23.

26. A nanoparticle according to claim 23 wherein the surface is free of aromatase inhibitor.

27. A nanoparticle having a diameter of less than 1 microns comprising letrozole in a free base, acid addition salt or complex form, in a biodegradeable, biocompatible polymeric matrix of a 40/60 to 60/40 polylactide-co-glycolide ester of a polyol, said polyol being selected from the group consisting of 1) a (C.) carbon chain containing alcohol having 3 to WO 2007/147861 PCT/EP2007/056166 - 22 6 hydroxyl groups, 2) a mono-saccharide and 3) a di-saccharide, and said esterified polyol having at least 3 polylactide-co-glycolide chains, wherein said letrozole has a drug load of 15% to 40% and said letrozole is distributed throughout said polymeric matrix.