US 2011 0021786A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0021786 A1 Schenkel et al. (43) Pub. Date: Jan. 27, 2011 (54) PHARMACEUTICAL SOLUTIONS, PROCESS (86). PCT No.: PCT/EP09/524.54 OF PREPARATION AND THERAPEUTC USES S371 (c)(1), (2), (4) Date: Oct. 6, 2010 (75) Inventors: Eric Schenkel, Brussels (BE): Claire Poulain, Brussels (BE); (30) Foreign Application Priority Data Bertrand Dodelet, Brussels (BE): Domenico Fanara, Brussels (BE) Mar. 3, 2008 (EP) .................................. O8OO3915.9 Correspondence Address: Publication Classification MCDONNELL BOEHNEN HULBERT & BERG HOFF LLP (51) Int. Cl. 300 S. WACKER DRIVE, 32ND FLOOR C07D 207/27 (2006.01) CHICAGO, IL 60606 (US) (52) U.S. Cl. ........................................................ 548/SSO (73) Assignee: UCB PHARMA, S.A., Brussels (BE) (57) ABSTRACT (21) Appl. No.: 12/920,524 The present invention concerns a stable pharmaceutical solu tion, a process of the preparation thereof and therapeutic uses (22) PCT Filed: Mar. 2, 2009 thereof. US 2011/002 1786 A1 Jan. 27, 2011 PHARMACEUTICAL SOLUTIONS, PROCESS 0006 Seletracetam is effective in the treatment of epi OF PREPARATION AND THERAPEUTC lepsy. USES 0007. Until now, brivaracetam and seletracetam have been formulated in Solid compositions (film coated tablet, gran ules). 0008. However, an oral solution would be particularly desirable for administration in children and also in some adult 0001. The present invention concerns stable liquid formu patients. An injectable Solution could be advantageously used lations of 2-oxo-1-pyrrolodine derivatives, a process of the in case of epilepsy crisis. preparation thereof and therapeutic uses thereof. 0009 Moreover, administration of an oral dosage form is 0002 International patent application having publication the preferred route of administration for many pharmaceuti number WO 01/62726 discloses 2-oxo-1-pyrrolidine deriva cals because it provides for easy, low-cost administration. tives and methods for their preparation. It particularly dis However some patients such as children or elderly people can have problems when requested to swallow a solid formulation closes compound (2S)-2-(4R)-2-oxo-4-propyl-pyrrolidin-1- Such as a tablet or a capsule. Hence the development of a ylbutanamide known under the international non propriety liquid oral formulation is therefore desirable since it offers name of brivaracetam. improved patient compliance. 0010. However, stability storage tests have shown that aqueous solutions of 2-oxo-1-pyrrolidine derivatives were partially unstable. During these tests, degradation products in Solution are formed by basic or acid hydrolysis, in fact an epimerisation and/oramide hydrolysis occurred, but also oxi dation, with detection of hydroxyamide and hydroxyacid impurities. CA, 0011. It has now surprisingly been found that these deg radation products are not formed at pH values between 4.5 and 6.5. In fact kinetics of degradation is the slowest in normal conditions (room temperature) when the drug solu n tion has a pH value of between 4.5 and 6.5. NH2 0012. The invention relates to a stable solution of a phar Brivaracetam maceutical compound, the solution having a pH value of between 4.5 and 6.5, and the pharmaceutical compound being an 2-oxo-1-pyrrolidine derivative of formula (I), 0003 International patent application having publication number WO 2005/121082 describes a process of preparation of 2-oxo-1-pyrrolidine derivatives and particularly discloses (I) a process of preparation of (2S)-2-(4S)-4-(2,2-difluorovi RI nyl)-2-oxo-pyrrolidin-1-ylbutanamide known under the s international non propriety name of seletracetam. 1s.N O 0013 wherein, I0014) R' is Co alkyl or C. alkenyl: 10015 R is Coalkyl or Coalkenyl: 0016 X is CONRR, COOH, -COORS or CN, 0017 R is Coalkyl: 10018) R' is hydrogen or Coalkyl: I0019 R is hydrogen or Co alkyl. 0020 Preferably, the solution of the invention has a pH Seletracetam values between 5.0 and 6.0. The best results are obtained with a pH value of about 5.5. 0004 2-oxo-1-pyrrolidine derivatives are therefore par 0021. By “stable' we mean optimum of stability in normal ticularly useful in the pharmaceutical industry. condition of storage (room temperature). 0022. The term “alkyl, as used herein, is a group which 0005 Brivaracetam is effective in the treatment of epi represents Saturated, monovalent hydrocarbon radicals hav lepsy. Brivaracetam is also effective in the treatment of ing straight (unbranched), branched or cyclic moieties, or patients with refractory partial onset seizures, with or without combinations thereof. Preferred alkyl comprises 1 to 10 car secondary generalization. In the therapeutic confirmatory bons. More preferred alkyl comprises 1 to 4 carbons. Option Phase III studies the efficacy and safety of brivaracetam are ally, alkyl groups may be substituted by 1 to 5 substituents tested at doses of 5 to 100 mg per day in the adjunctive independently selected from the group consisting of halogen, treatment of adult patients (16-65 years). Brivaracetam has hydroxy, alkoxy, ester, acyl, cyano, acyloxy, acid, amide or also an indication in the treatment of Progressive Myoclonic amino group. Preferred alkyl groups are methyl, ethyl, n-pro Epilepsy and of Symptomatic Myoclonus. pyl, trifluoromethyl and trifluoroethyl. US 2011/002 1786 A1 Jan. 27, 2011 0023 The term “alkenyl as used herein represents unsub R is a C- alkyl. In another embodiment according to first stituted or substituted branched, unbranched or cyclic hydro aspect of the present invention, X is COOR, wherein R is a carbon radicals or combinations thereof having at least one Calkyl. double bond. Preferred alkenyl comprises 2 to 6 carbons. I0041. In a particular embodiment, R is methyl. More preferred alkenyl comprises 2 to 4 carbons. “Alkenyl 0042. In one embodiment according to first aspect of the moieties may be optionally substituted by 1 to 5 substituents present invention, R is hydrogen or C. alkyl. In another independently selected from the group consisting of halogen, embodiment according to first aspect of the present invention, hydroxy, alkoxy, ester, acyl, cyano, acyloxy, carboxylic acid, R" is hydrogen. amide or amino group. 0043. In one embodiment according to first aspect of the 0024. The term “halogen', as used herein, represents an present invention, R is hydrogen or C. alkyl. In another atom of fluorine, chlorine, bromine, or iodine. embodiment according to the first aspect of the present inven 0025. The term “hydroxy’, as used herein, represents a tion, R is hydrogen. group of formula—OH. 0044 Preferably R' is n-propyl or 2,2-difluororovinyl: R 0026. The term “alkoxy’, as used herein, represents a is ethyl; and X is CONH2. group of formula —OR" wherein R is C alkyl as defined 0045. In particular, the invention relates to an injectable above. solution oran oral solution. When it is an injectable solution, 0027. The term “acyl as used herein, represents a group the solution has preferably a pH value of 5.5+0.2. When it is of formula RCO , wherein R represents a C, alkyl as an oral solution, the solution has preferably a pH value of defined above. 55.0.2. 0028. The term “ester', as used herein, represents a group 0046. The amount by weight of the pharmaceutical com of formula – COOR wherein R represents a C alkyl as pound in an injectable solution is generally in the range of defined above. 0.01 mg per ml to 200 mg per ml; and preferably of 0.1 mg to 0029. The term "cyano' as used herein represents a group 50 mg per ml; and more preferably of 1 mg to 30 mg per ml. of formula—CN. 0047. The amount by weight of the pharmaceutical com 0030 The term “acyloxy” as used herein represents a pound in an oral Solution is generally in the range of 0.01 mg group of formula—O COR", wherein R is a C, alkyl as per ml to 100 mg per ml; preferably of 0.1 mg to 50 mg perml; defined above or an aryl group. and more preferably of 1 mg to 20 mg per ml. 0031. The term “aryl” as used herein, represents an 0048. Usually, the solution is aqueous or alcoholic. In a organic radical derived from an aromatic hydrocarbon by preferred embodiment of the invention, the solution is an removal of one hydrogen, for example a phenyl. aqueous solution: water is used as solvent, preferably purified 0032. The term “carboxylic acid as used herein repre water for an oral aqueous solution and water for injection and sents a group of formula—COOH. pyrogen-free for the injectable form. 0033. The term “amino group', as used herein, represents 0049. The solution can be administered directly intrave a group of formula - NH, NHR or NRR where RandR nously, intramuscular or parenterally, or designed as infusion are alkyl groups as defined above in the specification. Solutions or concentrates as Supplements to infusions. 0034. The term "amide', as used herein, refers to a group 0050. Substances for adjusting the pH value are physi of formula CO. NH CO. NHRs, or CO NR'R'', ological buffers. The pH of the compositions is maintained by wherein R and R" are alkyl groups as defined above in the a buffer system. Buffer systems comprise mixtures of appro specification. priate amounts of an acid Such as phosphoric, succinic, tar taric, lactic, or citric acid, and a base, in particular sodium 0035. The term "sulfonate group’ as used herein repre hydroxide or disodium hydrogen phosphate. Ideally, the sents a group of formula – O SO. R' wherein R is an buffer has sufficient capacity to remain in the intended pH alkyl or an aryl as defined here above in the specification. range upon dilution with a neutral, a slightly acidic or a Preferred Sulfonate groups are methanesulfonate, para-tolu slightly basic beverage.