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WO 2018/069805 A2 19 April 2018 (19.04.2018) W !P O PCT

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WO 2018/069805 A2 19 April 2018 (19.04.2018) W !P O PCT (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 2018/069805 A2 19 April 2018 (19.04.2018) W !P O PCT (51) International Patent Classification: (84) Designated States (unless otherwise indicated, for every A61K 9/08 (2006.01) kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (21) International Application Number: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, PCT/IB20 17/056204 TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (22) International Filing Date: EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, 07 October 2017 (07.10.2017) MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (25) Filing Language: English KM, ML, MR, NE, SN, TD, TG). (26) Publication Langi English Published: (30) Priority Data: — without international search report and to be republished 201621034602 10 October 2016 (10.10.2016) IN upon receipt of that report (Rule 48.2(g)) (71) Applicant: FTF PHARMA PRIVATE LIMITED [IN/IN]; Plot No. 183+23 1, Above Hyundai Service Centre, Navapura Char Rasta, NH 8A, Ahmedabad-Rajkot High way, Taluka-Sanand, Ahmedabad-382 210, Ahmedabad 382 210 (IN). (72) Inventors: PATEL, Vijay; B-40, Pulin Society Part 3,Near Gayatri School, BethakNaroda, Ahmedabad-382330 Gu jarat, Ahmedabad 382330 (IN). MEHTA, Sandip; D-74, New Jash Park Society, Isanpur, Ahmedabad-382443 Gu jarat, Ahmedabad 382443 (IN). KALAVADIYA, Manoj; At: Kunad-361 250, Taluka-Jodiya, District- Jamnagar Gu jarat, Jamnagar 361 250 (IN). UMRETHIA, Manish; 194, The Meadows, Gokuldham, Near Eklavya School, Sanand- Sanathal Cross Road, Sanathal, Ahmedbad-382 210 Gu jarat, Ahmedbad 382 210 (IN). MANDAL, Jayanta Ku¬ mar; A-44, Orchid Park, Near Anjani Tower, Ramdev Na- gar, Satellite, Ahmedabad-380 015 Gujarat, Ahmedabad 380 015 (IN). (74) Agent: BABARIA, Ketana; B/137, Harisiddha Park, Near Navsarjan School, Ranip, Gujarat, Ahmedabad 382 480 (IN). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. < © 00 (54) Title: METHOD FOR PREPARATION OF LIQUID ORAL COMPOSITION OF L-THYROXIN © (57) Abstract: The present invention discloses a processes for the preparation of a stable liquid pharmaceutical composition comprising levothyroxine or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients wherein the liquid 00 composition of the present invention is used for oral administration. The present invention also discloses stable liquid compositions o comprising levothyroxine or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients prepared according to the processes of the present invention. TITLE OF INVENTION METHOD FOR PREPARATION OF LIQUID ORAL COMPOSITION OF L- THYROXIN FIELD OF THE INVENTION The present invention relates, in general, to the pharmaceutical field, and more precisely i relates to a process for preparing stable liquid pharmaceutical composition of levothyroxine (L-thyroxine) or its pharmaceutically acceptable salt thereof used for oral administration. BACKGROUND OF THE INVENTION Levothyroxine, also known as L-thyroxine, synthetic T4, or 3,5,3',5'-tetraiodo-L- thyronine, CAS number 51-48-9, is a synthetic form of thyroxine, used as a hormone substitute for patients with thyroid conditions, such as hypothyroidism, as well as conditions in which the thyroid gland becomes enlarged, causing swelling of the neck. Thyroid hormones regulate multiple metabolic processes and play an essential role in normal growth and development, and normal maturation of the central nervous system and bone. Levothyroxine sodium was initially manufactured as synthetic T4 in 1958 and it was first introduced into the market as early as before 1962 without an approved NDA, apparently in the belief that it was not a new drug. Levothyroxine sodium is very slightly soluble in water and slightly soluble in ethanol (96 percent). Levothyroxine sodium is described in the European Pharmacopoeia. The chemical designation of Levothyroxine sodium is Sodium (2S)-2-amino-3-[4-(4- hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl]propanoate. Its molecular formula is and its molecular weight is 799 (anhydrous substance). The structural formula is: Orally administered levothyroxine sodium is used as replacement therapy in conditions characterized by diminished or absent thyroid function such as cretinism, myxedema, non-toxic goiter, or hypothyroidism (Food and Drug Administration 1997; Wertheimer and Santella 2005). Levothyroxine Sodium Oral Solution is indicated for: hypothyroidism (congenital or acquired); diffuse nontoxicgoiter or Hashimoto's thyroiditis; thyroid carcinoma. The treatment of any thyroid disorder should be determined on an individual basis, taking account of clinical response, biochemical tests and regular monitoring. A pre-therapy ECG is valuable as changes induced by hypothyroidism may be confused with evidence of ischemia. If too rapid an increase of metabolism is produced (causing diarrhea, nervousness, rapid pulse, insomnia, tremors and sometimes anginal pain where there is latent myocardial ischemia), reduce the dose or withhold for 1-2 days and start again at a lower dose. United States Granted Patent No. 5,225,204, incorporated herein by reference in its entirety, discloses a stabilized and uniform pharmaceutical formulation of Levothyroxine sodium comprising a complex of Levothyroxine sodium and a water soluble polyvinylpyrrolidone adsorbed on a cellulose compound in the form of a tablet, powder or capsule.Further, United States Granted Patent No. 5,225,204 also discloses a stabilized and uniform pharmaceutical formulation of levothyroxine sodium comprising a complex of levothyroxine sodium and a block copolymer of ethylene oxide and propylene oxide adsorbed on a cellulose compound in the form of a tablet, powder or capsule. Further, United States Granted Patent No. 5,225,204 also discloses a stabilized pharmaceutical formulation of levothyroxine sodium comprising levothyroxine sodium substantially uniformly adsorbed on a cellulose compound in the form of a tablet, powder or capsule. United States Granted Patent No. 5,635,209, incorporated herein by reference in its entirety, discloses a method of making levothyroxine sodium medication by combining together: (a) levothyroxine sodium mixed with a carrier; (b) potassium iodide mixed with a carrier; (c) a disintegrant, and d. a lubricant. Further, United States Granted Patent No. 5,635,209 also discloses a method of making levothyroxine sodium medication by combining together: (a) a mixture of levothyroxine sodium mixed with microcrystalline cellulose, said mixture comprised of 1.05% levothyroxine sodium and 98.95% microcrystalline cellulose; (b) a second mixture of potassium iodide mixed with microcrystalline cellulose, said second mixture comprised of potassium iodide ranging from 0.1% to 0.7% and microcrystalline cellulose ranging from 99.9% to 99.3%; (c)croscarmellose sodium; (d) magnesium stearate, and (e) colored dye. Further, United States Granted Patent No. 5,635,209 also disclosesa medication consisting of the combination of levothyroxine sodium with potassium iodide. United States Granted Patent No. 6,491,946, incorporated herein by reference in its entirety, discloses a pharmaceutical composition comprising levothyroxine sodium, potassium iodide, microcrystalline cellulose and hydroxypropylmethylcellulose or gelatine or both hydroxypropylmethylcellulose and gelatine, which is essentially free of antioxidants. Further, United States Granted Patent No. 6,491,946 also disclosesa process for the preparation of a pharmaceutical composition comprising levothyroxine sodium, potassium iodide, microcrystalline cellulose and a binding agent, which is essentially free of antioxidants, said process comprising spraying an aqueous hydroxypropylmethylcellulose and/or gelatine solution comprising levothyroxine sodium and potassium iodide which are present in suspended form in said solution onto microcrystalline cellulose in a fluidized bed granulation, admixing a disintegrating agent and a lubricant and compressing the resultant mixture to form tablets. United States Granted Patent No. 6,555,581, incorporated herein by reference in its entirety, discloses a stable, solid, immediate release pharmaceutical composition for oral administration to treat a thyroid disorder, said composition comprising: (a) about 0.00005 wt % to about 5 wt % of a levothyroxine salt; (b) at least about 50 wt % of a β-form microcrystalline cellulose particles, said β-form microcrystalline cellulose particles having generally flat needle-shapes, a bulk density in a range of from about 0.10 g/cm3 to about 0.23 g/cm3, and a conductivity of less than about 200 µ / ; and (c) about 0.5 wt % to about 30 wt % disintegrating agent; wherein (1) at least about 90 wt % of the levothyroxine salt in the composition dissolves in an aqueous solution in less than about 5 minutes, (2) potency loss for said levothyroxine salt is no more than about 0.3% per month for a period of at least about 18 months, and (3) said composition is essentially sugar-free. United States Granted Patent No. 6,646,007, incorporated herein by reference in its entirety, discloses a process for the production of a pharmaceutical preparation, comprising spraying levothyroxine sodium and optionally liothyronine sodium, in suspended form in aqueous gelatin solution, onto a filler(s) in a fluidized bed granulation, admixing a disintegrant and lubricant and compressing the mixture to give tablets.
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