SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (72) Inventors: PATEL, Mitesh Natavarlal; Gufic Bios

Transcription

1 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/ Al 13 April 2017 ( ) P O P C T (51) International Patent Classification: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 31/00 ( ) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/IN20 16/ OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 7 October 2016 ( ) TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 3858/MUM/ October 2015 ( ) IN TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicant: GUFIC BIOSCIENCES LIMITED [IN/IN]; DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, N.H.No.8, Near Grid, Kabilpore, Navsari, Gujarat LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (IN). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (72) Inventors: PATEL, Mitesh Natavarlal; Gufic Bios GW, KM, ML, MR, NE, SN, TD, TG). ciences Limited, N.H.No.8, Near Grid, Kabilpore, Navsari, Declarations under Rule 4.17 : Gujarat (IN). DAVE, Mafatlal Tribhovandas; as to applicant's entitlement to apply for and be granted a Gufic Biosciences Limited, N.H.No.8, Near Grid, Kabil patent (Rule 4.1 7(H)) pore, Navsari, Gujarat (IN). CHOKSI, Pranavkumar Jayesh; Gufic Biosciences Limited, N.H.No.8, Near as to the applicant's entitlement to claim the priority of the Grid, Kabilpore, Navsari, Gujarat (IN). earlier application (Rule 4.1 7(in)) (74) Agent: NAIR, Gopakumar G.; Gopakumar Nair Associ of inventorship (Rule 4.17(iv)) ates, 3rd Floor, 'Shivmangal', Near Big Bazaar, Akurli Published: Road, Kandivali (East), Maharashtra, Mumbai (IN). with international search report (Art. 21(3)) (81) Designated States (unless otherwise indicated, for every before the expiration of the time limit for amending the kind of national protection available): AE, AG, AL, AM, claims and to be republished in the event of receipt of AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, amendments (Rule 48.2(h)) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, o (54) Title: FREEZE DRIED PARENTERAL FORMULATION OF MICAFUNGIN SODIUM AND TO PROCESS THEREOF o (57) Abstract: The present invention discloses stable freeze dried pharmaceutical formulations of Micafungin which comprises Micafungin sodium; a suitable stabilizing agent and alkalizing agent, for parenteral administration, wherein, the formulation is devoid of polysaccharide, disaccharide or mammalian derived stabilizing agent Lactose. The pharmaceutical formulation provides sufficient stabilization of Micafungin sodium thus improving the shelf life of the product during storage.

2 ' FREEZ E DRIE D PAR ENT ERAL FOR M ULATION O F MICA FUNGIN SODIUM AND T O PROC ESS T H EREO F Field of invention: The present invention relates to freeze dried, pharmaceutical formulation of Micafungin sodium along with a suitable stabilizing agent and alkalizing agent for parenteral administration wherein said formulation is free from polysaccharide, disaccharide or mammalian derived stabilizing agent Lactose. The pharmaceutical formulation provides sufficient stabilization of Micafungin sodium thus improving the shelf life during storage. The invention further relates to a process of preparation thereof. Background of the invention: Fungal infections are an important problem, particularly in immune compromised patients, resulting from A IDS infections, aggressive cancer treatment the growing use of organ transplants, and othernosocomial situations. Advanced medical therapies have created a critical need for new safe fungi cidalagents that can be used to treat disseminated infections. Systemic mycoses are not easily diagnosed; andthe patient has usually been infected for quite some time before symptoms appear. Thus, empiric therapyneeds to begin immediately, but currently available treatments have posed problems with toxicity or resistance. The clinically available drugs were limited to amphotericin B, azoles, and flucytosine, although voriconazole and caspofungin have sincebeen marketed. However, these drugs have problems regarding antifungal spectra of activity, toxicity or resistance. Furthermore, the emergence of multi-azole-resistant strains of Candida is leading to manyserious fungal infections. Much interest has been focused on developing safer and more effective antifungalagents.(pure Appl. Chem., Vol. 79, No. 4, pp , 2007.)

3 Recently, a new class of antifungals, the echinocandins, has been developed.! hese agents interfere with cell wall biosynthesis by non-competitive inhibition of 1, 3- d-glucan Synthase, an enzyme present in fungi but absent in mammalian cells (Walsh et al., 2000; Ernst, 2001). They are used to treat a variety of fungal infections, including invasive infections due to either Candida or Aspergillus. These antifungals have shown clinical efficacy and a more favourable adverseevent (A E) profile compared with those of conventional antifungal agents. Micafungin sodiumis a semi synthetic lipopeptide (echinocandin) synthesized by a chemical modification of a fermentation product of Coleophomaempetri F Micafungin inhibits the synthesis of 1,3- beta- D-glucan, an integral component of the fungal cell wall. Chemically, Micafungin sodium is Pneumocandin A0,1-[(4R,5R)-4,5-dihydroxy-N2-[4-[5-[4'(pentyloxy)phenyl]-3- isoxazolyl]benzoyl]-l-ornithine]-4-[(4s)-4-hydroxy-4-[4- hydroxy- 3- (sulfooxy) phenyl] - L-threonine]-, monosodium sal t( Formulal). Micafungin sodium is a light-sensitive, hygroscopic white powder that is freely soluble in water, isotonic sodium chloride solution, Ν,Ν-dimethylformamide and dimethyl sulfoxide, slightly soluble in methyl alcohol, and practically insoluble in acetonitrile, ethyl alcohol (95%), acetone, diethyl ether and n-hexane). The chemical structure of Micafungin sodium is:

4 Micafungin sodium is marketed as lyophilized product for intravenous infusion by AstellasPharma US, Inc. under the trade name MY CAMINE. Micafungin sodium is indicatedfor the treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis, Abscesses, Esophageal Candidiasis and Prophylaxis of Candida Infections in Patients Undergoing Hematopoietic Stem Cell Transplantation. Currently available formulations in lyophilized vial contain lactose as stabilizing agent which does not provide desirable stability due to the sensitivity of Micafungin sodium against environmental stress. Also, the formulation containing lactose is not suitable for patients with lactose intolerance. Significant drawbacks exist, however, to the use of lactose in a pharmaceutical composition. Lactose has been attributed to transmission of certain stable viruses, prions or other infectious or pathogenic compounds, e.g., human transmissible spongiform encephalopathy (TSE). Consequently, there is increased regulatory scrutiny of pharmaceutical compositions containing lactose. Therefore, there is a need for a replacement for mammalian derived stabilizers. Indian patent number disclose a pharmaceutical composition of Micafungin in lyophilized form comprising lactose as stabilizing agent. Further, Micafungin Sodium is generally unstable to light, heat, humidity, acid, and the like, it is necessary to develop a pharmaceutical composition for stabilizing the compound and the salts thereof for parenteral administration. I n view of the instability and mammalian derived stabilizers of Micafungin sodium in preparing the lyophilized product for parenteral administration as mentioned above, the present inventors felt a need to provide a stable Micafungin sodium injectable formulation which is free from polysaccharide and disaccharide with good shelf life and free from lactose to avoid lactose intolerance.

5 While screening for suitable agents for stabilizing the formulation, the inventors have unexpectedly found that stabilized pharmaceutical formulation of Micafungin can be prepared for parenteral administration, without employing polysaccharide and disaccharide. Summary of the invention: It is an object of the present invention to provide a replacement for mammalian derived excipients lactose in pharmaceutical compositions containing Micafungin Sodium. I n accordance with above, in an aspect the present invention provides prelyophilized pharmaceutical formulation comprising Micafungin or pharmaceutically acceptable salt thereof along with a suitable stabilizing agent in an aqueous vehicle, wherein, the formulation is free from polysaccharide and disaccharide. I n a preferred aspect, pharmaceutically acceptable salt of Micafungin is Micafungin sodium. The Micafungin sodium is stabilized by adding stabilizing agents selected from the group consisting of a polyvinyl pyrrolidone (Kollidon PF 12), Dextrose, Galactose and mixture thereof in aqueous vehicle to obtain pre-lyophilized formulation. Preferably, the stabilizing agent is polyvinyl pyrrolidone (Kollidon PF 12). I n another aspect the pre-lyophilized pharmaceutical formulation of Micafungin sodium and stabilizing agent is freeze dried and provided as a drug concentrate, suitable for parenteral administration. According to the invention, the freeze dried formulation comprises an effective amount of stabi Iizer in the range of 0Omg to 000 mg.

6 The ph of the formulation is maintained in the range of 5 to 7 using alkalizing agent. I n another aspect, the present invention provides a method for stabilization of Micafungin sodium in an aqueous solution which comprises combining Micafungin sodium in an aqueous vehicle with a stabilizing agent selected from the group consisting of polyvinyl pyrrolidone (Kollidon PF 12), Dextrose, Galactose and mixture thereof; preferably polyvinyl pyrrolidone (Kollidon PF 12). Detailed description of the invention: The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be fully understood and appreciated. Micafungin Sodium is generally unstable to light, heat, humidity, acid, and the like, it is therefore necessary to develop a pharmaceutical composition for stabilizing the compound and the salts thereof for parenteral administration. Accordingly, the present invention provides stable pharmaceutically acceptable composition/formulation for parenteral administration or intravenous infusion comprising of Micafungin sodium as the active using a suitable stabilizer and maintaining appropriate ph of the formulation. I n an embodiment, the present invention provides pre-lyophilized pharmaceutical composition comprising Micafungin sodium; a pharmaceutically acceptable stabilizing agent selected from the group consisting of polyvinyl pyrrolidone (Kollidon PF 12), Dextrose, Galactose or mixture thereof in an aqueous vehicle and an alkalizing agent, wherein, ph of said composition is in the range of 5.0 to 7.0 and wherein, the pre-lyophilized composition is devoid of polysaccharide and

7 disaccharide. The aqueous vehicle according to the invention is water for injection. Micafungin sodium is present in the composition in an amount ranging from mg to 100 mg/vial; more preferably 50mg to 100 mg/vial. Micafungin sodium is stabilized using a suitable stabilizing agent where Micafungin sodium can be maintained in a dissolved state in the aqueous solution thereby preventing crystallization or crystalline growth of Micafungin sodium. The stabilizing agent is selected from the group consisting of polyvinyl pyrrolidone (Kollidon PF 12), Dextrose, Galactose or mixture thereof. I n one preferred embodiment, the stabilizing agent is polyvinyl pyrrolidone (Kollidon PF 12). I n a preferred embodiment, the pre-lyophilized pharmaceutical composition comprises Micafungin sodium in an amount ranging from mg to 100 mg/vial; an effective amount of polyvinyl pyrrolidone (Kollidon PF 12) in the range of 100mg to 1000mg as a stabilizing agent in aqueous vehicle and 0.1 N sodium hydroxide solution as alkalizing agent for ph adjustment. The pre-lyophilized composition thus provided in aqueous vehicle is filtered to remove particulate matter, filled into vials and subjected to freeze drying cycle to obtain freeze dried composition. The present inventors observed during experimentation that there is an increase in total impurities on storage of the lyophilized composition at 40 3 for 3 months. Since, Micafungin is not stable to humidity it was necessary to reduce the water content to the desirable extent to obtain the freeze dried product with reduced total impurities and increased stability. I n an embodiment, the present invention provides freeze dried composition of Micafungin sodium with water content less than 2.0%w/w, preferably in the range

8 of 1.0 to 1.5%w/w; most preferably the water content is i n an amount of about.2%w/w. I n another embodiment, the present invention provides stable, freeze dried, pharmaceutical composition for parenteral administration, which is free from polysaccharide and disaccharide, comprising; a) Micafungin sodium i n an amount of 1 to 100mg/vial; b) a pharmaceutically acceptable stabilizing agent selected from the group consisting of a polyvinyl pyrrol idone (Kollidon PF 12), Dextrose, Galactose or mixture thereof; and c) alkalizing agent, wherein, ph of said composition is in the range of 5.0 to 7.0and water content less than 2%w/w. The stabilizing agent is preferably polyvinyl pyrrol idone (Kollidon PF 12) used i n an amount of 00 to 0OOmg. I n one preferred embodiment, the stable freeze dried pharmaceutical composition for parenteral administration, comprising; i. Micafungin sodium i n an amount of 50 nrga/ial; ii. 200mg of Kollidon PF-12 i n aqueous vehicle as a stabilizing agent; iii. 0.1 N sodium hydroxide solution as alkalizing agent; wherein ph of said composition is i n the range of 5.0 to 7.0and water content less than 2%w/w. I n another preferred embodiment, the stable freeze dried pharmaceutical composition for parenteral administration comprising; i. Micafungin sodium i n an amount of 100 mg/vial; ii. 400 mg of Kollidon PF-12 i n aqueous vehicle as a stabilizing agent; iii. 0.1 N sodium hydroxide solution as alkalizing agent; wherein, ph of said

9 composition is in the range of 5.0 to 7.0and water content less than 2%w/w. According to an embodiment, the invention provides freeze drying process which involves cooling of pre-lyophilized pharmaceutical composition at suitable temperature not less than -50eC, raising temperature to OeCat suitable pressure of 150 mtorr to 100 mtorr in 30 hours, then at 75 mtorr, further raising temperature to +15eC in 20 hrs, to obtain freeze-dried composition. The secondary drying of the composition is carried at a temperature in the range of +12 to for 3 hours. The freeze dried composition of Micafungin containing Kollidon PF-12 in aqueous vehicle as a stabilizing agent with water content less than 2.0%w/w have total impurities less than the prior art formulations as illustrated in example 3 below. Such composition after freeze drying is chemically and physically stable over an extended period of time and is suitable for intended pharmaceutical use after reconstitution with suitable vehicle/diluents such as water for injection, sodium chloride injection or 5% dextrose injection. The freeze dried Micafungin sodium provided in accordance with the invention when reconstituted with 5 ml of suitable vehicle contains final drug concentrate of 0 mg/ml. I n another embodiment, the invention provides a process for preparation of freeze dried pharmaceutical composition of the invention which comprises a)providing pre-lyophilized composition consisting of Micafungin sodium dissolved in aqueous vehicle containing stabilizing agent and alkalizing agent and b) lyophilizing the composition to obtain freeze dried pharmaceutical composition with water content less than 2%. The freeze dried composition comprising

10 Micafungin sodium may be diluted with suitable diluents before administration as IV injection. The final concentration of solution may be reduced to further desired level using 5% Dextrose infusion prior to administration to a patient. The pharmaceutical compositions of the present invention are administered to a patient according to a dosing regimen. It should be understood that the specific dosing regimen for any particular patient will depend on a variety of factors, including age, body weight, general health, sex, diet, time of administration, specific disease being treated, and the severity of the condition among other factors and the judgment of the treating physician. I n conclusion, the present invention provides freeze dried pharmaceutical composition comprising Micafungin sodium which is free from polysaccharide and disaccharide without compromising the stability of drug and its solution before Lyophilisation and as freeze dried composition with less than 2%w/w water content, with reduced amount of total impurities which is stable for the entire period of the shelf life. The use of Kollidon PF-12 as stabilizing agent eliminates significant drawbacks of the use of mammalian derived stabilizer such as lactose and the parenteral formulation of the present invention is suitable for administration to lactose sensitive patients as well as to normal patients providing the desired therapeutic activity with no side effects. Other features and embodiments of the invention will become apparent by the following examples which are given for illustration of the invention rather than limiting its intended scope. Various changes and modifications to the disclosed embodi ments w i11be apparent to those ski 11ed in the art. Experimental:

11 Example: Gm Micafungin sodium (active) was added to an aqueous solution containing 4 gm of Lactose and stirred for some time. Then added 7.6 mg anhydrous citric acid and stirred for some time to get clear solution. Adjusted the Ph of the solution to about 5.5 with 0.1 N Sodium Hydroxide solution and cooled down the solution below 20eC. Filtered the solution and the resulting solution was loaded into 20 vials (10 ml vial) with each containing 2.5 ml solution. The solution in each vial was lyophilized using freeze dryer according to conventional method, thereby obtaining the lyophilized compositions each comprising 50mg of Micafungin sodium. The resulting lyophilized preparation was stored at 40eC, and the residue of Micafungin was tested after 3 months and the results are provided in below table. Example: Gm Micafungin sodium (active) was added to an aqueous solution containing 4 gm of polyvinyl pyrrol idone (Kollidon PF-12) and stirred for some time to get clear solution. Adjusted ph with 0.1 N Sodium Hydroxide solution to about 5.4.Filtered the solution and the resulting solution was loaded into 20 vials (10 ml vial) with each containing 2.5 ml solution. The solution in each vial was lyophilized using freeze dryer according to conventional method, thereby

12 obtaining the lyophilized compositions each comprising 50 mg of Micafungin sodium. The resulting lyophilized preparation was stored at 2-8eC, 25eC and 40eC, and the residue of Micafungin was tested upto 3 months and the results are provided i n below table. Since the example 1 and example 2 showed increase i n total impurities i.e. 4.93% and 3.86% respectively after 3 months at 40 3, the present inventors further carried changes i n lyophilisation to get desired water content and modification i n ph for reducing the impurities content. Accordingly the invention provides freeze drying process which involves cooling of pre-lyophilized pharmaceutical composition at suitable temperature not less than -50eC, raising temperature to OeCat suitable pressure of 150 mtorr to 100 mtorr in 30 hours, then at 75 mtorr, further raising temperature to + 5eC in 20 hrs, to obtain freeze-dried composition. This was followed by secondary drying of the freeze dried composition to a temperature i n the range of +12 to +18 for 3

13 hours. The resulting freeze dried or lyophilized preparation was stored at 40eC and 75% humidity up to 3 months. Example: 3 Tests were carried out in the similar manner as in Example 2 except that 12.5 mg, 25 mg, 50 mg, 75 mg, 100 mg of Micafungin sodium were used with 200 mg polyvinyl pyrrolidone (Kollidon PF-12).The resulting lyophilized preparation was stored at 40e C and 75% humidity, and the residue of Micafungin was tested after 3 months and the results are provided in below table. A mount of Test Items 0 hours After 3 months Micafungin at 40eC and 75% sodium added humidity (mg) ph* Residual amount (%) Total impurities (%) Water content (%) ph* Residual amount (%) Total impurities (%) Water content (%) ph* Residual amount (%) Total impurities (%) Water content (%) ph* Residual amount (%) Total impurities (%) Water content (%)

14 ph* Residual amount (%) Total impurities (%) Water content (%) *ph of reconstituted solutions of composition in 5 ml water for injection A s is obvious from Example 3, all the lyophilized compositions were stable. Example: Gm Micafungin sodium (active) was added to an aqueous solution containing 4 gm of polyvinyl pyrrol idone (Kollidon PF-12) and stirred for some time to get clear solution. Adjusted ph with 0.1 N Sodium Hydroxide solution between 5.0 to 7.0. Filtered the solution and the resulting solution was loaded into 20 vials (10 ml vial) with each containing 2.5 ml solution. The solution in each vial was lyophilized using freeze dryer according to conventional method, thereby obtaining the lyophilized compositions each comprising 50 mg of Micafungin sodium. The resulting lyophilized preparation was stored at 70eC and the residue of Micafungin was tested after9 days and the results are provided in below table. *ph of reconstituted solutions of composition in 5 ml water for injection A s is obvious from Example 4, all the compositions were stable after lyophilizing the sol uti on contai ning M icafungi n sodi um at ph 5.0 to 7.0.

15 W e claim, 1. Stable, pre-lyophilized pharmaceutical composition free from polysaccharide and disaccharide for parenteral administration, wherein said composition comprising; i. M icafungi n sodi um in an amount of 1mg to OOmg/vial; ii. A pharmaceutically acceptable stabilizing agent polyvinyl pyrrol idone (Kol Iidon PF 12) in an aqueous vehicle; and iii. 0.1 N Sodium Hydroxide solution as alkalizing agent, wherein, ph of said composition is in the range of 5.0 to The pre-lyophilized pharmaceutical composition according to claim 1 comprises an effective amount of polyvinyl pyrrolidone (Kollidon PF 12)in the range of 0Omg to 000 mg as stabi Iizi ng agent. 3. The pre-lyophilized pharmaceutical composition according to claim 2 comprises an effective amount of polyvinyl pyrrolidone (Kollidon PF 12) in the range of 0Omg to 500 mg as a stabi Iizi ng agent. 4. Stable freeze dried pharmaceutical composition for parenteral administration, comprising; i. Micafungin sodium in an amount of 1mg to 100 mg/vial; ii. 100mg to 1000mg of polyvinyl pyrrolidone (Kollidon PF-12) in aqueous vehi cle as a stabi Iizing agent; iii. 0.1 N sodium hydroxide solution as alkalizing agent, wherein, ph of said composition is in the range of 5.0 to 7.0 and water content less than 2.0%w/w. 5. The freeze dried pharmaceutical composition for parenteral administration according to claim 4, comprising; i. Micafungin sodium in an amount of 50 mg/vial;

16 ii. 200mg of polyvinyl pyrrolidone (Kollidon PF-12) in aqueous vehi cle as a stabi Iizing agent; iii. 0.1 N Sodium Hydroxide solution as alkalizing agent; wherein ph of said composition is in the range of 5.0 to 7.0and water content less than 2.0%w/w. 6. The freeze dried pharmaceutical composition for parenteral administration according to claim 4, wherein said composition comprising; i. Micafungin sodium in an amount of 100 mg/vial; ii. 400 mg of polyvinyl pyrrolidone (Kollidon PF-12) in aqueous vehi cle as a stabi Iizing agent; iii. 0.1 N Sodium Hydroxide solution as alkalizing agent; wherein ph of said composition is in the range of 5.0 to 7.0and water content less than 2.0%w/w. 7. A process for preparation of freeze dried pharmaceutical composition comprising a) providing pre-lyophilized composition consisting of Micafungin sodium dissolved in aqueous vehicle containing stabilizing agent and alkalizing agent and b) lyophilizing the composition to obtain freeze dried pharmaceutical composition. 8. The process according to claim 7, wherein, stabilizing agent is polyvinyl pyrrolidone (Kollidon PF 12), and the alkalizing agent is 0.1 N Sodium Hydroxide solution. 9. A method of increasing stability of Micafungin or a pharmaceutically acceptable salt in an aqueous solution, comprising a step of combining Micafungin or a pharmaceutically acceptable salt thereof with a stabilizing agent polyvinyl pyrrolidone (Kollidon PF 12) in accordance with claim. 10. The Micafungin Sodium composition according to any of the preceding claim, wherein the composition is free of the mammalian derived stabilizing agent Lactose.

17 nternat ona app cat o o. PCT/IN2016/ A CLASSIFICATION O F SUBJECT MATTER A61K31/00 Version= 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) A 6 1 K 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 base and, where practicable, search terms used) Patseer, IPO Internal Database C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No WO (Al) SUN CHANG AN (CN) ET AL (30 OCTOBER 2014) ABSTRACT, Examples 1-2, paragraphs [ ]. U S 2013/ (Al) YUNHAI HONG ET AL (12 DECEMBER 2013) Page 1, paragraphs [ ], Examples. WO A l, RAU HARALD [DE] ET AL (2 8 JULY 2011) Abstract, page 10, paragraph [0120], page 20, paragraph [0227]. Further documents are listed in the continuation of Box C. See patent family annex * Speciai categories of cited documents: later document published after the international filing date or priority "A" document defining the general state of the art which is not considered date and not in conflict with the application but cited to understand to be of particular relevance the principle or theory underlying the invention "E" earlier application or patent but published on or after the international "X" document of particular relevance; the claimed invention cannot be filing date considered novel or cannot be considered to involve an inventive "L" document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of another citation or other speciai reason (as specified) Ύ document of particular relevance; the claimed invention cannot be considered to involve an inventive step when the document is "O" document referring to an oral disclosure, use, exhibition or other combined with one or more other such documents, such combination means being obvious to a person skilled in the art "P" document p lished prior to t international filing date but later than the priority date claimed & document member of the same pate family Date of the actual completion of the international search Date of mailing of the international search report Name and mailing address of!he ISA/ Authorized officer Indian Patent Office Dasari Ayodhya Plot No. 32, Sector 14,Dwarka, ew Delhi Facsimile No. Telephone No Form PCT/ISA/210 (second sheet) (January 2015)

18 Information on patent family members International application No. PCT/IN2016/ Citation Pub. Date Family Pub. Date WO A l TW A CN A U S 2013/ A l WO A l JP A CN A WO A l U S A l EP A l Form PCT7ISA/210 (patent family annex) (January 2015)