111111111111111111111111111f!!111)111811111111111111111111111111111
`
`(12) United States Patent (cid:9)
`Jiang et al. (cid:9)
`
`(10) Patent No.: (cid:9)
`(45) Date of Patent: (cid:9)
`
`US 9,168,238 B2
`*Oct. 27, 2015
`
`(54) LEVOTHYROXINE FORMULATIONS
`
`OTHER PUBLICATIONS
`
`(71) Applicant: FRESENIUS KABI USA, LLC, Lake
`Zurich, IL (US)
`
`(72) Inventors: John Zhiqiang Jiang, Skokie, IL (US);
`Arunya Usayapant, Mundelein, IL
`(US); George Monen, Woodridge, IL
`(US)
`
`(73) Assignee: Fresenius Kabi USA, LLC, Lake
`Zurich, IL (US)
`
`( * )
`
`Notice: (cid:9)
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 14/641,426
`
`(22) Filed:
`
`Mar. 8, 2015
`
`(65)
`
`Prior Publication Data
`
`US 2015/0174246 Al (cid:9)
`
`Jun. 25, 2015
`
`Related U.S. Application Data
`
`Continuation of application No. 13/597,884, filed on
`Aug. 29, 2012, now Pat. No. 9,006,289.
`
`Provisional application No. 61/529,084, filed on Aug.
`30, 2011.
`
`Int. Cl.
`A61K 31/198
`A61K 47/26
`A61K 9/00
`A61K 9/19
`A61K 47/02
`A61K 47/10
`(52) U.S. Cl.
`CPC (cid:9)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`A61K 31/198 (2013.01); A61K 9/0019
`(2013 (cid:9) 01); A61K 9/19 (2013.01); A61K 47/02
`(2013.01); A61K 47/10 (2013.01); A61K 47/26
`(2013.01)
`
`(58) Field of Classification Search
`CPC ... A61K 31/198; A61K 47/26; A61K 9/0019;
`A61K 9/19
` A61K 31/198, 47/26, 9/0019, 9/19
`IPC (cid:9)
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`7/1993 Chen et al.
`5,225,204 A (cid:9)
`9/1999 Mitra et al.
`5,955,105 A (cid:9)
`8/2005 Hanshew, Jr. et al.
`6,936,274 B2 (cid:9)
`11/2012 Pierres et al.
`8,318,712 B2 (cid:9)
`9,006,289 B2 * 4/2015 Jiang et al. (cid:9)
`2012/0190748 Al (cid:9)
`7/2012 Treasurer
`
`FOREIGN PATENT DOCUMENTS
`
` 514/567
`
`U.S. Appl. No. 14/658,058, filed Mar. 2015, Jiang et al.*
`APP Pharmaceuticals, LLC, "Highlights of Prescribing Informa-
`tion," 2011, pp. 1-11.
`APP Pharmaceuticals, LLC, "Levothyroxine Sodium for Injection",
`2008, pp. 1-3.
`Baheti, et al, "Excipients used in lyophilization of small molecules,"
`"J. Excipients and Food Chem.," 2010, pp. 41-54, vol. 1, No. 1.
`Bedford Laboratories, "Levothyroxine Sodium for Injection," 2003,
`pp. 1-2.
`Schering Corporation, "Leventa-levothyroxine sodium solution,"
`2010, pp. 1-3.
`Vidyya Medical News Service, "Synthroid, The Most Commonly
`Prescribed Medication in the US," 2000, pp. 1-11.
`International Searching Authority, "International Search Report and
`Written Opinion for PCT/US2012/052838," Nov. 16, 2012, Pub-
`lisher: European Patent Office, Published in: EP.
`Collier, et al., "Influence of Formulation and Processing Factors on
`Stability of Levothyroxine Sodium Pentahydrate," "APPS
`PharmSiTech," May 8, 2010, pp. 818-825, vol. 11, No. 2.
`Rowe, et al., "Mannitol," "Handbook of Pharmaceutical Excipients,"
`2006, pp. 449-453.
`Beth D. Herman et al., The Effect of Bulking Agent on the Solid-State
`Stability of Freeze-Dried Methylprednisolone Sodium Succinate,
`Pharmaceutical Research, vol. 11, No. 10, pp. 1467-1473 (May 11,
`1994).
`Alexandra I. Kim et al., The physical state of mannitol after freeze-
`drying: effects of mannitol concentration, freezing rate, and a
`noncrystallizing cosolute, Journal of Pharmaceutical Sciences, vol.
`87, No. 8, pp. 931-935 (May 11, 1998).
`Searles, JA., "Freezing and Annealing Phenomena in Lyophiliza-
`tion," Freeze Diying/Lyophilization of Pharmaceutical and Biologi-
`cal Products, 3rd Edition. Ed. Louis Rey, Ed. Joan C. May. London:
`Informa Healthcare, 2010, 52-81.
`Won, CM., "Kinetics of Degradation of Levothyroxine in Aqueous
`Solution and in Solid State," Pharm. Res., 9: 131-137 (1992).
`SYNTHROID® Injection (levothyroxine sodium), Physicians' Desk
`Reference, Medical Economics, 1970 (3 pages).
`LEVOTHROID® (levothyroxine sodium) For Injection, Physicians'
`Desk Reference, Medical Economics, 1986 (3 pages).
`US Department of Health and Human Services, Food and Drug
`Administration, Center for Drug Evaluation and Research,
`Synthroid® (Levothyroxine Sodium tablets, USP) Application No.
`21-402, 2002 (17 pages).
`Gieseler et al., "Influence of Common Excipients on the Crystalline
`Modification of Freeze-Dried Mannitol," Pharmaceutical Technol-
`ogy, 3(32) (Mar. 2, 2008) (4 pages).
`Kazemifard et al., "Identification and Quantitation of Sodium-Thy-
`roxine and its Degradation Products by LC Using Electrochemical
`and MS Detection," J. Pharm. Biomed. Anal., 25(5-6): 697-711 (Jul.
`2001) (15 pages).
`Patel et al., "The Effect of Excipients on the Stability of
`Levothyroxine Sodium Pentahydrate Tablets," Int. J. Pharm., 264(1-
`2), pp. 35-43 (Oct. 2, 2003) (9 pages).
`(Continued)
`
`Primary Examiner - Kara R McMillian
`(74) Attorney, Agent, or Firm - Baker & Hostetler LLP
`
`ABSTRACT
`(57) (cid:9)
`A levothyroxine composition includes levothyroxine sodium
`and mannitol The composition is a lyophilized solid. The
`composition may include from 100 to 500 micrograms
`levothyroxine sodium and from 2 to 4 milligrams mannitol.
`
`JP (cid:9)
`
`2002284679 (cid:9)
`
`10/2002 (cid:9)
`
`30 Claims, 3 Drawing Sheets
`
`Mylan Ex 1002, Page 1
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
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`

`US 9,168,238 B2
`Page 2
`
`(56) (cid:9)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Stadalman et al., "Stability of Levothyroxine Sodium 0.4 microg/mL
`in 0.9% Sodium Chloride Injection," Prog. Transplant., 19(4), pp.
`354-357 (Dec. 2009) (4 pages).
`Strong et al., "Stability of Levothyroxine in Sodium Chloride for IV
`Administration," Can. J. Hosp. Pharm., 63(6), p. 437-443 (Nov.
`2010) (7 pages).
`United States Pharmacopeia and National Formulary (Revision Bul-
`letin) Rockville, MD: United States Pharmacopeia Convention;
`Levothyroxine pp. 1-3 (Oct. 1, 2010) (3 pages).
`US Department of Health and Human Services, Food and Drug
`Administration, Center for Drug Evaluation and Research, "Chem-
`istry Review(s)," Levothyroxine Sodium for Injection, Application
`No. 202231, Jun. 2011 (41 pages).
`US Department of Health and Human Services, Food and Drug
`Administration, Center for Drug Evaluation and Research, "Sum-
`mary Review," Levothyroxine Sodium for Injection, Application No.
`202231, Jun. 2011 (12 pages).
`US Department of Health and Human Services, Food and Drug
`Administration, Center for Drug Evaluation and Research, "Guid-
`ance for Industry: Q1A(R2) Stability Testing of New Drug Sub-
`stances and Products," Revision 2, Nov. 2003 (25 pages).
`
`US Department of Health and Human Services, Food and Drug
`Administration, Center for Drug Evaluation and Research, "Guid-
`ance for Industry: Q8(R2) Pharmaceutical Development," Revision
`2, Nov. 2009 (29 pages).
`Handbook of Pharmaceutical Manufacturing Formulations: Sterile
`Products 2nd Edition, vol. 6 (Niazi ed.), pp. 315-317 (Sep. 2009),
`ISBN: 9781420081305 (5 pages).
`Intravenous Therapy: A Comprehensive Application of Intravenous
`Therapy and Medication Administration (Nentwich ed.), pp. 357-358
`(Mar. 1990), ISBN: 0867204192 (4 pages).
`Delmar Nurse's Drug Handbook, 2009 Edition (Spratto et al. ed.), pp.
`967-969, ISBN-13: 9781428361065 (5 pages).
`LEVO-T® (levothyroxine sodium tablets, USP) Prescribing Infor-
`mation, 2002 (17 pages).
`LEVOXYL® (levothyroxine sodium tablets, USP) Prescribing Infor-
`mation, 2001 (12 pages).
`SYNTHROID® (levothyroxine sodium tablets, USP) Prescribing
`Information, 2002 (19 pages).
`THYRO-TABS® (levothyroxine sodium tablets, USP) Prescribing
`Information, 2002 (14 pages).
`UNITHROID® (levothyroxine sodium tablets, USP) Prescribing
`Information, 2000 (14 pages).
`
`* cited by examiner
`
`Mylan Ex 1002, Page 2
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`

`

`U.S. Patent (cid:9)
`
`Oct. 27, 2015 (cid:9)
`
`Sheet 1 of 3 (cid:9)
`
`US 9,168,238 B2
`
`HO
`
`NH2
`
`H2
`C —C— coo- Na+
`
`F!
`
`FIG. 1
`
`Mylan Ex 1002, Page 3
`
`

`

`lualud °Sil
`
`stoz 'a •Po
`
`c jo z PaMS
`
`Zll 8£V891% Sf1
`
`-N-100 mcg L; 10 mg M; M:L =100:1
`
`-A-200 mcg L; 10 mg M; .M:L= 501
`
`-*-500 mcg L; 10 mg M; M:L =20:1
`
`mcg L; 3 mg. M; Pvt:L= 30:1
`
`200 mcg L; 3 nig M; MI= 1.5:1
`
`-LJ-500 mcg L; 3 mg M; M:L= 6:1
`
`0.6
`
`0.55
`
`0.5
`
`0.45
`
`0.4
`
`0.35
`
`0.3
`
`0.25
`
`0.2
`
`0.15
`
`0.1
`
`0
`
`1
`
`2
`
`Time (months)
`
`FIG. 2
`
`Mylan Ex 1002, Page 4
`
`(cid:9)
`(cid:9)
`

`

`lualud °Sil
`
`stoz 'a •Po
`
`c jo c PaMS
`
`Zll 8£V891% Sf1
`
`0.4
`
`0.35
`
`-m-100 mcg L; 10 mg M; M:L= 100:1
`
`-A-200 mcg L; 10 mg M; M:L = 50:1
`
`- 500 mcg L; 10 mg M; M:L =20:1
`
`mcg L; 3 mg M; M:L= 30:1
`
`mcg L; 3 mg M; M:L=15:1
`
`0.3
`
`--€-` 500 mcg L; 3 mg M; M:L=6:1
`
`0.25.
`
`0.2
`
`0i5
`
`0.1
`
`0
`
`2
`
`3 (cid:9)
`
`.1111
`krd
`
`6
`
`Time (months)
`
`FIG. 3
`
`9
`
`12 (cid:9)
`
`18
`
`Mylan Ex 1002, Page 5
`
`(cid:9)
`(cid:9)
`

`

`1
`LEVOTHYROXINE FORMULATIONS
`
`US 9,168,238 B2
`
`2
`thyroid replacement, and/or when oral administration is not
`possible, such as for a patient in a state of myxedema coma.
`Conventional formulations of levothyroxine sodium for
`injection are preservative-free lyophilized powders contain-
`ing synthetic crystalline levothyroxine sodium and the excipi-
`ents mannitol, tribasic sodium phosphate, and sodium
`hydroxide. These conventional formulations typically con-
`tain 10 milligrams (mg) of mannitol, 700 1,1g of tribasic
`sodium phosphate, and either 200 lig or 500 1,1g of levothy-
`roxine sodium. Administration of the conventional formula-
`tion involves reconstitution of the lyophilized powder in 5
`milliliters (mL) of 0.9% sodium chloride injection (USP), to
`provide injectable solutions having levothyroxine sodium
`concentrations of 40 micrograms per milliliter (1,1g/mL) or
`100 µg/mL, respectively.
`It is desirable to provide a new formulation of levothyrox-
`ine sodium that can further improve the stability of the
`levothyroxine. Preferably a new formulation of levothyroxine
`sodium would have acceptable stability above room tempera-
`ture for an extended period of time. It is also desirable for the
`new formulation to be convenient to store, to reconstitute, and
`to administer to a patient.
`
`SUMMARY
`
`A composition is provided that includes from 100 to 500
`micrograms of levothyroxine sodium, and from 1 to 5 milli-
`grams mannitol The composition is a solid.
`A composition is provided that includes from 100 to 200
`micrograms of levothyroxine sodium, and mannitol The
`mass ratio of mannitol to levothyroxine sodium is at most
`40:1, and the composition is a solid.
`A composition is provided that includes about 500 micro-
`grams of levothyroxine sodium, and mannitol The mass ratio
`of mannitol to levothyroxine sodium is at most 10:1, and the
`composition is a solid.
`A plurality of compositions is provided, where each com-
`position includes from 100 to 500 micrograms of levothyrox-
`ine sodium and from 1 to 5 milligrams mannitol, and each
`composition is a solid. The amount of levothyroxine sodium
`in each composition spans the range of 100 to 500 micro-
`grams. The amount of mannitol is substantially the same in
`each composition. When the plurality of compositions is
`stored at 25° C., at most 0.20% of the levothyroxine sodium in
`each composition is converted to liothyronine over a period of
`12 months.
`A solid composition is provided, which is formed by a
`method that includes combining ingredients to form a liquid
`mixture, and lyophilizing the liquid mixture. The ingredients
`include a solvent, levothyroxine sodium, mannitol, and sub-
`stantially no tribasic sodium phosphate.
`A solid composition is provided, which is formed by a
`method that includes combining ingredients to form a liquid
`mixture, and lyophilizing the liquid mixture. The ingredients
`include a solvent, levothyroxine sodium, mannitol and diba-
`sic sodium phosphate. The mass ratio of mannitol to levothy-
`roxine sodium in the liquid mixture is at most 40:1.
`To provide a clear and more consistent understanding of
`the specification and claims of this application, the following
`definitions are provided.
`The term "mass ratio" of two substances means the mass of
`one substance (51) relative to the mass of the other substance
`(S2), where both masses have identical units, expressed as
`Sl:S2.
`The term "lyophilizing" means removing from a solution
`or an emulsion one or more substances having the lowest
`
`REFERENCE TO RELATED APPLICATIONS
`This application is a continuation of U.S. patent applica- 5
`tion Ser. No. 13/597,884, filed Aug. 29, 2012, which claims
`the benefit of U.S. Provisional Application No. 61/529,084,
`filed Aug. 30, 2011, which are both incorporated by reference
`in their entirety.
`
`BACKGROUND
`
`10
`
`20
`
`30
`
`A healthy thyroid produces hormones that regulate mul-
`tiple metabolic processes and that play important roles in
`growth and development, in maturation of the central nervous 15
`system and bone including augmentation of cellular respira-
`tion and thermogenesis, and in metabolism of proteins, car-
`bohydrates and lipids. The thyroid accomplishes its regula-
`tion functions by producing the hormones L-triiodothyronine
`(liothyronine; T3) and L-thyroxine (levothyroxine; T4). (cid:9)
`Thyroid hormones are believed to exert their physiologic
`actions through control of DNA transcription and protein
`synthesis. It is presently believed that the T3 and T4 hormones
`diffuse into the cell nucleus and bind to thyroid receptor
`proteins attached to DNA. This hormone nuclear receptor 25
`complex then activates gene transcription and synthesis of
`messenger RNA and cytoplasmic proteins. The physiological
`actions of thyroid hormones are believed to be produced
`predominantly by T3, approximately 80% of which is derived
`from T4 by deiodination in peripheral tissues. (cid:9)
`Both T3 and T4 are stored in the thyroid as thyroglobulin
`adducts with serum proteins. Once secreted by the thyroid, T3
`and T4 primarily exist in the circulatory system as their thy-
`roglobulin adducts, and are in equilibrium with small
`amounts (<1%) of the unbound hormones, which are the 35
`metabolically active species. T4 has higher serum levels,
`slower metabolic clearance, and a longer half-life than T3,
`which may be due to the higher affinity of serum proteins for
`T4 compared to T3.
`A patient who has had their thyroid gland removed, or 40
`whose thyroid gland functions at an undesirably low level
`(hypothyroidism), may be treated by administration of a daily
`maintenance dose of 50-100 micrograms (lig) of levothyrox-
`ine sodium. A patient in need of additional intervention may
`be treated by administration of an initial dose of 200-500 lig 45
`or 300-500 lig of levothyroxine sodium and/or with a 2"d day
`dose of 100-300 lig of levothyroxine sodium. Formal names
`for levothyroxine sodium include 4-(4-hydroxy-3,5-di-
`iodophenoxy)-3,5-diiodo-L-phenylalanine sodium, and
`L-tyro sine-0- (4 -hydroxy-3,5-diiodopheny1)-3,5-diiodo- (cid:9)
`monosodium salt. The chemical structure of levothyroxine
`sodium is shown in FIG. 1.
`Administration of levothyroxine sodium provides T4 to a
`patient. Once absorbed by the organism, the administered T4
`behaves identically to T4 that otherwise would be secreted by 55
`the thyroid gland of the patient, and binds to the same serum
`proteins, providing a supply of circulating T4-thyroglobulin
`in the patient. The administered T4 may be deiodinated in
`vivo to T3. As a result, a patient receiving appropriate doses of
`levothyroxine sodium will exhibit normal blood levels of T3, 60
`even when the patient's thyroid gland has been removed or is
`not functioning.
`Levothyroxine sodium for injection is a sterile lyophilized
`product for parenteral administration of levothyroxine
`sodium for thyroid replacement therapy. Levothyroxine 65
`sodium for injection is particularly useful when thyroid
`replacement is needed on an urgent basis, for short term
`
`50
`
`Mylan Ex 1002, Page 6
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`

`

`US 9,168,238 B2
`
`3
`boiling points by freezing the solution or emulsion and apply-
`ing a vacuum to the frozen mixture.
`The term "spans the range", with regard to a range of the
`amount of a substance in a plurality of compositions, means
`that at least one of the compositions contains the substance in
`an amount corresponding to the lowest end of the range, at
`least one of the compositions contains the substance in an
`amount corresponding to the highest end of the range, and the
`remaining compositions, if any, contain the substance in an
`amount within the range. For example, in a plurality of com-
`positions in which the amount of levothyroxine sodium spans
`the range of 100-500 lig, at least one of the compositions
`contains 100 lig levothyroxine sodium, at least one of the
`other compositions contains 500 lig levothyroxine sodium,
`and the remaining compositions, if any, contain from 100 lig
`to 500 lig levothyroxine sodium.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`The invention can be better understood with reference to
`the following drawing and description. The components in
`the figure are not necessarily to scale and are not intended to
`accurately represent molecules or their interactions, empha-
`sis instead being placed upon illustrating the principles of the
`invention.
`FIG. 1 depicts a chemical structure of levothyroxine
`sodium.
`FIG. 2 depicts graphs of the amount of liothyronine (T3)
`impurity over time at 40° C. for compositions containing 100
`("mcg"; square symbols), 200 lig (triangle symbols) or 500
`lig (circle symbols) levothyroxine sodium (1), and either 3 mg
`(open symbols) or 10 mg (open symbols) mannitol (M).
`FIG. 3 depicts graphs of the amount of T3 impurity over
`time at 25° C. for compositions containing 100 lig ("mcg";
`square symbols), 200 lig (triangle symbols) or 500 lig (circle
`symbols) levothyroxine sodium (1), and either 3 mg (open
`symbols) or 10 mg (open symbols) mannitol (M).
`
`DETAILED DESCRIPTION
`
`Lyophilized levothyroxine sodium compositions that
`include less mannitol than conventional compositions can
`protect levothyroxine from degradation at temperatures of
`25° C. and higher. These compositions also can maintain a
`consistent level of levothyroxine over a wide range of dos-
`ages. Reconstitution of the lyophilized compositions with a
`carrier liquid can yield injectable liquids having ingredients
`that are more acceptable than those in conventional compo-
`sitions.
`A levothyroxine composition may include levothyroxine
`sodium, mannitol, and optionally one or more other sub-
`stances, where the composition is a solid. Improved stability
`of levothyroxine can be achieved by lowering the mass of
`mannitol and/or the mass ratio of mannitol to levothyroxine
`sodium in the composition to a level below that of conven-
`tional levothyroxine compositions. Conventional levothyrox-
`ine compositions include 10 milligrams (mg) mannitol and
`either 200 or 500 micrograms (lug) levothyroxine sodium,
`corresponding to mass ratios of mannitol to levothyroxine
`sodium (M:L) of 50:1 and 20:1, respectively. In contrast,
`improved stability of levothyroxine can be obtained in com-
`positions having either 200 or 500 lig levothyroxine sodium
`by lowering the amount of mannitol to 1 to 5 milligrams,
`corresponding to M:L ratios of from 5:1 to 25:1 and from 2:1
`to 10:1, respectively.
`Solid levothyroxine compositions may be prepared by
`forming a liquid mixture containing a solvent, levothyroxine
`
`5 (cid:9)
`
`4
`sodium and mannitol, and lyophilizing the liquid mixture.
`Forming a liquid mixture for use in preparing the solid com-
`position may include combining ingredients including a sol-
`vent, levothyroxine sodium and mannitol. The ingredients
`also may include a phosphate buffer; however the ingredients
`preferably do not include tribasic sodium phosphate.
`A solid composition that includes levothyroxine sodium
`and mannitol may include from 25 to 1,000 lig levothyroxine
`sodium. Preferably the composition includes from 50 to 750
`levothyroxine sodium, or from 100 to 500 lig levothyrox-
`ine sodium. The amount of levothyroxine sodium in the com-
`position may be an amount sufficient for a single initial dose
`of levothyroxine sodium, an amount sufficient for a single 2"d
`15 day dose of levothyroxine sodium, or an amount sufficient for
`a daily maintenance dose of levothyroxine sodium. The
`amount of levothyroxine sodium in the composition may be a
`different therapeutic amount. For example, the amount of
`levothyroxine sodium in the composition may be an amount
`20 sufficient for half of a single initial dose, half of a single 2"d
`day dose, or half of a daily maintenance dose. Presently
`preferred amounts of levothyroxine sodium in the composi-
`tion include about 100 lig, about 200 lug, and about 500 lug.
`A solid composition that includes levothyroxine sodium
`25 and mannitol may include one or more other substances.
`Non-limiting examples of other substances include bulking
`agents, carriers, diluents, fillers, salts, buffers, stabilizers,
`solubilizers, preservatives, antioxidants, and tonicity con-
`tributors. Substances that may be useful in formulating phar-
`30 maceutically acceptable compositions, and methods of form-
`ing such compositions, are described for example in
`Remington: The Science and Practice of Pharmacy, 20th Ed.,
`ed. A. Gennaro, Lippincott Williams & Wilkins, 2000, and in
`Kibbe, "Handbook of Pharmaceutical Excipients,"3'd Edi-
`35 tion, 2000.
`A solid composition that includes levothyroxine sodium
`and mannitol may be prepared by forming a liquid mixture
`containing a solvent, levothyroxine sodium and mannitol, and
`lyophilizing the liquid mixture. Forming a liquid mixture for
`40 use in preparing the solid composition may include combin-
`ing ingredients including the solvent, levothyroxine sodium
`and mannitol. The ingredients used to form the liquid mixture
`may include a phosphate buffer; however the ingredients
`preferably do not include tribasic sodium phosphate. In one
`45 example, the ingredients used to form the liquid mixture
`include a phosphate buffer other than tribasic sodium phos-
`phate, such as dibasic sodium phosphate (Na2HPO4) or
`monobasic sodium phosphate (NaH2PO4). The amount of
`phosphate buffer in the ingredients may be an amount suffi-
`50 cient to provide a beneficial pH buffering effect in the liquid
`mixture. Preferably the ingredients used to form the liquid
`mixture include from 100 to 800 lug, from 200 to 700 lug, from
`300 to 700 lug, or from 400 to 600 lig dibasic sodium phos-
`phate. Dibasic sodium phosphate may be added as a hydrate,
`55 such as dibasic sodium phosphate heptahydrate.
`Forming the liquid mixture for use in preparing the solid
`composition may further include adding a base to the liquid
`mixture to provide a desired pH in the mixture, where the base
`is different from any buffers present in the composition, such
`60 as a phosphate buffer. The amount of the base added to the
`liquid mixture may be an amount sufficient to provide a liquid
`mixture pH in the range of 10.5 to 12.5 or from 11 to 12. The
`amount of the base may be an amount sufficient to provide a
`pH in the range of 9.5 to 11.5 or of 10 to 11 when a solid
`65 composition formed from the liquid mixture is subsequently
`reconstituted in 5 mL of 0.9% aqueous sodium chloride
`(USP). Presently preferred bases include sodium hydroxide.
`
`Mylan Ex 1002, Page 7
`
`

`

`US 9,168,238 B2
`
`5
`A solid composition that includes levothyroxine sodium
`and mannitol may include from 25 tg to less than 10 mg
`mannitol Preferably the composition includes from 0.1 to 7
`mg mannitol, from 1 to 5 mg mannitol, from 2 to 4 mg
`mannitol, or from 2.9 to 3.1 mg mannitol The amount of
`mannitol in the composition may be an amount sufficient to
`provide a beneficial bulking effect to the solid composition,
`while maintaining a M:L ratio less than 50:1, and preferably
`of 40:1 or less. For example, a solid composition that includes
`levothyroxine sodium and mannitol may have a M: L ratio less
`than 50:1, or at most 40:1. Preferably the composition has a
`M:L ratio of from 1:1 to 40:1, from 5:1 to 35:1, or from 6:1 to
`30:1. Presently preferred M:L ratios include about 6:1, about
`15:1 and about 30:1. For compositions that include less than
`500 tg levothyroxine sodium, the mass ratio of mannitol to
`levothyroxine sodium preferably is at most 40:1. For compo-
`sitions that include at least 500 tg levothyroxine sodium, the
`mass ratio of mannitol to levothyroxine sodium preferably is
`at most 10:1.
`It has been discovered that, in a solid composition that
`includes levothyroxine sodium and mannitol, the stability of
`levothyroxine may be improved by lowering the amount of
`mannitol in the composition to a level below that of conven-
`tional compositions. Conventional levothyroxine composi-
`tions include either 200 or 500 tg levothyroxine sodium, and
`include 10 mg mannitol In contrast, levothyroxine may have
`improved stability at room temperature and at elevated tem-
`peratures when present in solid compositions that include
`100, 200 or 500 tg levothyroxine sodium and include less
`than 10 mg mannitol
`The stability of levothyroxine was analyzed for solid com-
`positions that contained 100 tg levothyroxine sodium and
`from 2 mg to 10 mg mannitol. The solid compositions were
`formed by combining water, the levothyroxine sodium, the
`mannitol, and 500 tg dibasic sodium phosphate to form liquid
`mixtures, and then adding sodium hydroxide to provide a pH
`of about 11.8. Water for injection (USP) was added to each
`liquid mixture as needed to provide total volumes of 1 milli-
`liter (mL). The liquid mixtures were lyophilized to provide
`solid compositions, which were then stored in amber tinted
`vials at temperatures of 40° C. or 55° C. The stability of the
`levothyroxine in the solid compositions at different tempera-
`tures was determined by measuring the amount of liothyro-
`nine (T3) in each composition over time, as T3 is a degrada-
`tion product of levothyroxine (T4). The results of these
`measurements are listed in Table 1, below.
`
`6
`improved stability contained 4 mg, 3 mg or 2 mg mannitol,
`whereas the least stable composition contained a conven-
`tional amount of mannitol of 10 mg. The compositions having
`improved stability also had M:L ratios of at most 40:1,
`5 (cid:9) whereas the M:L ratio of the composition containing a con-
`ventional amount of mannitol was 100:1.
`As shown in Table 1, during storage at 40° C. the amount of
`T3 in the composition containing 10 mg mannitol varied from
`0.30% to 0.57% over a period of from 1 to 3 months, a range
`10 of approximately 90% [90.0%-100%x(0.57-0.30)/0.30]. In
`contrast, the amount of T3 in the compositions containing
`from 2 mg to 4 mg mannitol remained relatively stable under
`the same conditions, varying only by approximately 6%
`[5 .6%-100%x(0.19-0.18)/0.18)] . In the compositions con-
`15 taming 2 to 4 mg mannitol, at most 0.19% of the levothyrox-
`ine sodium was converted to liothyronine when stored at 40°
`C. over a period of 3 months.
`As shown in Table 1, the compositions containing less than
`10 mg mannitol maintained the stability of levothyroxine
`20 when stored at an even higher temperature of 55° C. During
`storage at 55° C. over a period of from 2 to 4 weeks, the
`amount of T3 in the compositions containing from 2 mg to 4
`mg mannitol varied only by approximately 6%
`[5 .6%-100%x(0.19-0.18)/0.18)] . In the compositions con-
`25 taming 2 to 4 mg mannitol, at most 0.19% of the levothyrox-
`ine sodium was converted to liothyronine when stored at 55°
`C. over a period of 4 weeks.
`The surprising and unexpected improvement in levothy-
`roxine stability in a solid composition upon lowering the
`30 amount of mannitol in the composition also was observed in
`solid compositions that contained more than 100 tg levothy-
`roxine sodium. The stability of levothyroxine was analyzed
`for solid compositions that contained from 100 tg to 500 tg
`levothyroxine sodium and 3 mg mannitol The solid compo-
`35 sitions were formed by combining water, the levothyroxine
`sodium, the mannitol, and 500 tg dibasic sodium phosphate
`to form liquid mixtures, and then adding sodium hydroxide to
`provide a pH of about 11.8. Water for injection (USP) was
`added to each liquid mixture as needed to provide total vol-
`40 umes of 1 mL. The liquid mixtures were lyophilized to pro-
`vide solid compositions, which were then stored in amber
`tinted vials at temperatures of 25° C. or 40° C. The stability of
`the levothyroxine in the solid compositions at different tem-
`peratures was determined by measuring the amount of T3 in
`each composition over time, as described above. The results
`of these measurements are listed in Table 2, below. Each entry
`in this table represents an average of 3 measurements.
`
`5 4
`
`TABLE 1
`
`Stability of levothyroxine in solid compositions
`containing different amounts of mannitol.
`
`Levothyroxine Sodium:
`Dibasic Sodium Phosphate:
`Mannitol:
`M:L ratio:
`
`100 jig
`500 [ig
`10 mg
`100:1
`
`100 jig (cid:9)
`500 µg (cid:9)
`4 mg (cid:9)
`40:1
`
`100 jig
`500 pg
`3mg
`30:1
`
`100 jig
`500 µg
`2 mg
`20:1
`
`TABLE 2
`
`50 (cid:9)
`
`55
`
`Stability of levothyroxine in solid compositions containing
`different amounts of levothyroxine sodium and 3 mg mannitol.
`
`Levothyroxine Sodium:
`Dibasic Sodium Phosphate:
`Mannitol:
`M:L ratio:
`
`100 jig
`500 pg
`3mg
`30:1
`
`200 jig
`500 µg
`3mg
`15:1
`
`500 jig
`500 pg
`3mg
`6:1
`
`Time
`
`Temp.
`
`% T3
`
`0
`1 month
`2 months
`3 months
`2 weeks
`4 weeks
`
`0.17
`0.34
`0.30
`0.57
`
`40° C.
`
`55° C.
`
`0.22
`0.19
`0.18
`0.18
`0.18
`0.19
`
`0.22
`0.18
`0.18
`0.18
`0.18
`0.18
`
`0.22
`0.18
`0.19
`0.18
`0.19
`0.19
`
`Time
`(mo.)
`
`0
`1
`
`60
`
`The results listed in Table 1 show that levothyroxine was
`more stable in the compositions containing less than 10 mg 65
`mannitol than in the composition containing a conventional
`amount of mannitol of 10 mg. The compositions having
`
`9
`12
`
`Temperature
`
`40° C.
`
`25° C.
`
`% T3
`
`0.12
`0.13
`0.13
`0.13
`0.14
`0.13
`0.12
`0.13
`0.12
`
`0.12
`0.13
`0.14
`0.13
`0.13
`0.13
`0.12
`0.13
`0.12
`
`0.12
`0.13
`0.13
`0.13
`0.13
`0.13
`0.12
`0.13
`0.12
`
`Mylan Ex 1002, Page 8
`
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`US 9,168,238 B2
`
`7
`The results listed in Table 2 show that levothyroxine was
`stable at room temperature and at an elevated temperature of
`40° C. when present at a variety of amounts, in solid compo-
`sitions that included only 3 mg mannitol The compositions
`containing 100 lig, 200 lig or 500 lig levothyroxine sodium
`and having improved stability contained 3 mg mannitol,
`whereas conventional levothyroxine compositions that con-
`tain 200 lig or 500 lig levothyroxine sodium include 10 mg
`mannitol The composition containing 200 µg levothyroxine
`sodium and having improved stability had a M:L ratio of only
`15:1, whereas the M:L ratio of a conventional composition
`containing 200 µg levothyroxine sodium is 50:1. The compo-
`sition containing 500 lig levothyroxine sodium and having
`improved stability had a M:L ratio of only 6:1, whereas the
`M:L ratio of a conventional composition containing 500 lig
`levothyroxine sodium is 20:1.
`As shown in Table 2, during storage at 25° C. the amount of
`T3 in the compositions containing 3 mg mannitol varied only
`by approximately 8% over a period of from 3 to 12 months
`[8.3%-100%x(0.13-0.12)10.12)]. A similar variation in the
`amount of T3 was observed when the same compositions
`were stored at an elevated temperature of 40° C. over a period
`of from 1 to 6 months [7.7%=100%x(0.14-0.13)/0.13)].
`Solid compositions that include levothyroxine sodium and
`mannitol preferably can protect levothyroxine from degrada-
`tion for a year or longer at room temperature (25° C.), and for
`6 months or longer at elevated temperatures. Referring to
`Table 2, each of the listed solid compositions maintained the
`level of T3 impurity below 0.15% for one year at 25° C. and
`for 6 months at 40° C. As shown in Table 2, in all of the
`compositions listed, at most 0.13% of the levothyroxine
`sodium was converted to liothyronine when stored at 25° C.
`over a period of 12 months. Similarly, in all of the composi-
`tions listed, at most 0.14% of the levothyroxine sodium was
`converted to liothyronine when stored at 40° C. over a period
`of 3 months or 6 months.
`Preferably, when a solid composition that includes
`levothyroxine sodium and mannitol is stored at 25° C., at
`most 0.20% of the levothyroxine sodium is converted to lio-
`thyronine (T3) over a period of 12 months. Preferably, when
`a solid composition that includes levothyroxine sodium and
`mannitol is stored at 25° C., at most 0.15% or at most 0.14%
`of the levothyroxine sodium is converted to liothyronine over
`a period of 12 months.
`Preferably, when a solid composition that inc