(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization International Bureau

(43) International Publication Date PCT (10) International Publication Number 27 March 2008 (27.03.2008) WO 2008/034819 Al

(51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K9/00 (2006.01) A61K 31/16 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 47/18 (2006.01) AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY,BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, (21) International Application Number: ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, PCT/EP2007/059827 IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY,MA, MD, ME, MG, MK, MN, MW, (22) International Filing Date: MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, 18 September 2007 (18.09.2007) PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (25) Filing Language: English ZM, ZW (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, 06121 134.8 22 September 2006 (22.09.2006) EP ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), (71) Applicant (for all designated States except US): PHAR- European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, MATEX ITALIA SRL [IT/IT]; Via Andrea Appiani, 2, FR, GB, GR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, PL, 1-20121 Milano (IT). PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (72) Inventor; and (75) Inventor/Applicant (for US only): DE TOMMASO, Vin- Declaration under Rule 4.17: cenzo [IT/IT]; Via Ramazzotti, 30, 1-20052 Monza (IT). — of inventorship (Rule 4.17(iv))

(74) Agent: SERRAVALLE, Marco; Via Don Losio, 10, Published: 1-26836 Montanaso Lombardo (LO) (IT). — with international search report

(54) Title: INJECTABLE PHARMACEUTICAL NIMESULIDE SOLUTIONS

(57) Abstract: The present invention relaters to injectable pharmaceutical nimesulide solutions comprising: water, nimesulide, an aminosugar, an organic co-solvent and a non-ionic surfactant. The solution according to the invention present nimesulide solubility higher than 40 mg/ml, preferably higher than 70 mg/ml. Injectable pharmaceutical nimesulide solutions.

[0001] The present invention relates to a nimesulide solution, suitable for injections, comprising nimesulide and an aminosugar. [0002] Nimesulide, whose chemical name is 4-nitro-2-phenoxymethanesulfonanilide, is a well known non-steroidal anti-inflamatory and antipyretic dug, useful in the presence of inflammation and pain. However, it is well known that nimesulide is sparingly soluble in water and this fact makes it more difficult oral or parenteral administration of nimesulide. Furthermore, the low solubility in water negatively influences its bioavailability. [0003] WO 91/17774 and WO 94/02177 describe inclusion compounds of nimesulide with cyclodextrins. By using such inclusion compounds, solubility of nimesulide is increased to 0.61mg/ml, which is about 20 times higher than pure crystalline nimesulide. [0004] WO 95/34553 discloses aqueous solutions of nimesulide and L-lysine. The solubility of this salt is 5.42 mg/ml, and further increases to 30.16 mg/ml in the presence of gamma-cyclodextrin at a concentration of 200 mM. [0005] WO 99/41233 discloses a preparation of nimesulide-aminosugar adducts which can be used in the preparation of injectable solutions. The adduct after preparation must be dried because nimesulide is not stable in solution at high pH values. Furthermore, the use of a solution having pH around 10 for injections, would result in considerable pain in the injection area. [0006] The composition according to the present invention allows the achievement of a nimesulide solution at concentration higher than 100 mg/ml. These formulations are obtained through the following steps:

1) Mixing a non ionic surfactant with an organic co-solvent.

2) Adding nimesulide to the mixture obtained in 1) and leaving under stirring for 15'. 3) Preparing a solution of aminosugar in water. 4) Adding the solution prepared in 3) to the suspension of nimesulide prepared in 2), while measuring the pH. [0007] At a pH between 7.5 and 9.5 nimesulide is completely dissolved. Preferably, in step 4) the pH is maintained between 6 and 9.5, most preferably between 8.0 and 9.0, by adding, if necessary, a buffer to the solution. The solution is brought to the final volume with water, is then filtered through a 0.22 µm sterilizing membrane and the solution is placed in 1 ml ampules.

[0008] The non-ionic surfactant used in step 1) can be any non-ionic surfactant suitable for pharmaceutical compositions. Examples of preferred non-ionic surfactants are glycofurol, polyethylenglycol 200, polyethylenglycol 300 and polyethylenglycol 400; the most preferred non- ionic surfactant is glycofurol. [0009] The amount of non-ionic surfactant in the final solution is preferably from 1 to 50 %w/v, preferably from 10 to 45% w/v. [00010] The organic co-solvent is a compound which is highly soluble in water and is a good solvent for nimesulide. Examples of preferred co-solvents are propylene glycol, butylene glycol, hexamethylene glycol, glycerol, N-dimethylacetamide; most preferred is propylene glycol. [0010] The amount of co-solvent in the final composition preferably varies from 5 to 70% w/v, most preferably from 15 to 60% w/v. [0011] The sum of the amount of non-ionic surfactant and organic co-solvent preferably ranges from 30% w/v to 95% w/v, preferably from 40% w/v to 90% w/v. [0012] The pH of the composition is preferably comprised between 6 and 9.5, most preferably between 8.0 and 9.0. [0013] Preferred examples of aminosugars useful in the present invention are: glucamine, glucosamine, chondrosamine and their N-alkyl derivatives such as N-methylglucamine. [0014] The aminosugar used in the present invention is essential in the solubilization of nimesulide. The molar ratio between aminosugar and nimesulide preferably varies between 0.5:1 and 10:1. If the amount of aminosugar is too low, the solubility of nimesulide will be lower than desired. However, if the amount of amino sugar is too high, the pH will increase above 9.5 and it will be necessary to add a buffer to the solution such as a citrate or a phosphate or any other pharmaceutically acceptable buffer. [0015] The nimesulide solution according to the invention can further comprise other ingredients. For example, it is possible to add cyclodextrins as known in the art. The concentration of nimesulide in the solutions according to the invention is normally higher than 40 mg/ml, preferably higher than 70 mg/ml and most preferably higher than 80 mg/ml. [0016] The solution according to the invention can also contain other ingredients. For example, it could be useful to add a local anaesthetic such as lidocaine, bupivacaine, mepivacaine, articaine, cinchocaine, etdocaine, levobupivacaine, oxetacaine, prilocaine, ropivacaine, tolycaine, trimecaine, amilocaine, proponacaine, proximetacaine, benzocaine, butacaine, butoxicaine, butylaminobenzoate, chloroprocaine, paretoxycaine, procaine, propoxicaine, tetracaine, tricaine. [0017] The following example illustrates the invention.

Example 1 Preparation of an injectable nimesulide solution [0018] 1.65 kg of glycofurol and 2.150 kg of propylene glycol are placed under stirring in a vessel. 500 g of nimesulide are added and the suspension is left under stirring for 15'. In another vessel 600 ml of distilled water are placed and 370 g of N-methylglucamine are added thereto. The N-methylglucamine solution is slowly added to the nimesulide suspension, while measuring the pH. [0019] During addition of the aminosugar, it is possible to note the solubilization of nimesulide. The solubilization is completed when reaching a pH of 8.5. After completion of the addition, the pH is comprised between 8.5 and 9.0. The solution is brought to a volume of 5 1by addition of distilled water. The solution is then filtered through a 0.22 µm sterilizing membrane and it is placed in 1 ml ampules.

Composition per 1 ml:

Nimesulide 100 mg Glycofurol 330 mg Propilene glycol 430 mg N-methylglucamine 74 mg Water up to ImI volume Claims

1. Injectable pharmaceutical nimesulide solution comprising: water, nimesulide, an aminosugar, an organic co-solvent and a non-ionic surfactant. 2. Solution according to claim 1 wherein the concentration of nimesulide in the solution is higher than 40 mg/ml, preferably higher than 70 mg/ml. 3. Solution according to claims 1-2 wherein the amino sugar is selected form glucamine, glucosamine, chondrosamine and the N-alkylderivatives thereof. 4. Solution according to claims 1-3 wherein the molar ratio between aminosugar and nimesulide varies between 1:0.5 and 10:1. 5. Solution according to claims 1-4 wherein the organic co-solvent is propylene glycol. 6. Solution according to claimsl-5 wherein the non-ionic surfactant is glycofurol. 7. Solution according to claim 1-6 wherein the amount of co-solvent in the final composition

vary from 5 to 70% w/v, preferably from 15 to 60% w/v 8. Solution according to claim 1-7 further comprising a local anaesthetic selected from: lidocaine, bupivacaine, mepivacaine, articaine, cinchocaine, etdocaine, levobupivacaine, oxetacaine, prilocaine, ropivacaine, tolycaine, trimecaine, amilocaine, proponacaine, proximetacaine, benzocaine, butacaine, butoxicaine, butylaminobenzoate, chloroprocaine, paretoxycaine, procaine, propoxicaine, tetracaine, tricaine or combinations thereof. 9. Solution according to claim 1 further comprising cyclodextrins. 10. Process for the preparation of nimesulide solutions, comprising the following steps: a. Mixing a non ionic surfactant with an organic co-solvent.

b. Adding nimesulide to the mixture obtained in a) and leaving under stirring for 15 min. c. Preparing a solution of aminosugar in water. d. Adding the solution prepared in c) to the suspension of nimesulide prepared in b), while measuring the pH. A. CLASSIFICATION OF SUBJECT MATTER INV. A61K9/00 A61K47/18 A61K31/16

According to International Patent Classification (IPC) or to both national classification and IPC

B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data bass and, where practical, search terms used) EPO-Internal , CHEM ABS Data, EMBASE, BIOSIS

C. DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

WO 99/41233 A (MICIO PHARMA CHEM. AG) 1-10 19 August 1999 (1999-08-19) claims 1-13; example 3

WO 95/34533 A (EUROPHARMACEUTICALS S .A.) 21 December 1995 (1995-12-21) cited in the application the whole document

WO 91/17774 A (BOEHRINGER INGELHEIM ITALIA S .P .A.) 28 November 1991 (1991-11-28) cited in the application the whole document

US 2005/020688 A l (K. EMBIL ET AL.) 27 January 2005 (2005-01-27) examples 1-6 V-

x Further documents are listed in the continuation of Box C. See patent family annex.

* Special categories of cited documents : "T" later document published after the international filing date 1 or priority date and not in conflict with the application but A" document defining the general state of the art which is not cited to understand the principle or theory underlying the considered to be of particular relevance invention "E" earlier document but published on or after the international "X1 document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to 1L" document which may throw doubts on priority claim (s) or involve an inventive step when the document Is taken alone which is cited to establish the publication date of another "Y" document of particular relevance; the claimed Invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the 1O" document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu¬ other means ments, such combination being obvious to a person skilled 1P" document published prior to the international filing date but in the art. later than the priority date claimed 1S" document member of the same patent family

Date of the actual completion of the international search Date of mailing of the international search report

12 November 2007 20/11/2007

Name and mailing address of the ISA/ Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NL - 2280 HV Rijswijk TeI. (+31-70) 340-2040, Tx. 3 1 651 epo nl, Fax: (+31-70) 340-3016 GLIKMAN, J

Form PCT/ISA/210 (second sheet) (April 2005) C(ContlnuaHon). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

DATABASE CA CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002441656 retrieved from STN Database accession no. 143: 292603 abstract & RU 2 260 432 A (OK. AKTS. OBSSHCHT. "NIZHEGORODSKII KHIMIKO-FARMAT. ZAV." ) 20 September 2005 (2005-09-20)

WO 2005/116086 A (THE UNIV. OF GEORGIA RESEARCH CENTER) 8 December 2005 (2005-12-08) claims 1,3,6

Form PCT/ISA/210 (continuation of second sheet) (April 2Q05) Information on patent family members PCT/EP2007/059827

Patent document Publication Patent family Publication cited in search report date member(s) date

WO 9941233 A 19-08-1999 AU 1885999 A 30-08-1999

WO 9534533 A 21-12-1995 AT 177421 T 15-03-1999 AU 693901 B2 09-07-1998 AU 2708595 A 05-01-1996 BE 1008307 A3 02-04-1996 CA 2169747 Al 21-12-1995 CZ 9600792 A3 16-10-1996 DE 69508192 Dl 15-04-1999 DE 69508192 T2 14-10-1999 DK 714386 T3 27-09-1999 EP 0714386 Al 05-06-1996 ES 2132678 T3 16-08-1999 GR 3030437 T3 30-09-1999 HU 76475 A2 29-09-1997 J P 9503002 T 25-03-1997 NZ 288150 A 24-09-1998 PL 313031 Al 27-05-1996 RU 2151764 Cl 27-06-2000 SK 35696 A3 04-12-1996 US 5756546 A 26-05-1998

WO 9117774 A 28-11-1991 AT 116135 T 15-01-1995 AU 655183 B2 08-12-1994 AU 7866591 A 10-12-1991 DE 69106361 Dl 09-02-1995 DE 69106361 T2 18-05-1995 DK 534995 T3 01-05-1995 EP 0534995 Al 07-04-1993 ES 2065687 T3 16-02-1995 FI 925224 A 18-11-1992 GR 3015468 T3 30-06-1995 HK 1006413 Al 26-02-1999 HU 65418 A2 28-06-1994 I T 1248475 B 19-01-1995 J P 3417942 B2 16-06-2003 J P 6502842 T 31-03-1994 NO 924492 A 20-01-1993

US 2005020688 Al 27-01-2005 NONE

RU 2260432 A 20-09-2005 UA 78917 C2 25-04-2007

WO 2005116086 A 08-12-2005 AU 2005248294 Al 08-12-2005 CA 2561672 Al 08-12-2005 CN 1953660 A 25-04-2007 EP 1742534 A2 17-01-2007 KR 20060132036 A 20-12-2006

A/210 (patent family annex) (April 2005)