(12) United States Patent
`Frontanes et al.
`
`US006399101B1
`US 6,399,101 B1
`Jun. 4, 2002
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`(54) STABLE THYROID HORMONE
`PREPARATIONS AND METHOD OF
`MAKING SAME
`
`_
`_
`-
`(75) Inventors. Ramon A. Frontane's, Caguas, Marla
`S. Bruno, Guaynabo, Hector L.
`_
`_
`_
`G_arc1a> C1dra> an of PR (Us) pahala
`Slmamora, Cardova, TN (Us); Marla
`A. Perez, Aguas Buenas, PR (US)
`
`(73) Assignee: Mova Pharmaceutical C0rp., Caguas,
`PR (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U'S'C' 154(k)) byo days‘
`
`7/1996 AbramoWitZ et al.
`5,536,507 A
`8/1996 Fekete et 91
`5,543,155 A
`5,585,115 A 12/1996 Sherwood et al.
`5,635,209 A
`6/1997 Groenewoud et al.
`5,681,583 A 10/1997 Conte et al.
`5,725,883 A
`3/1998 staniforth et a1‘
`5 725 884 A
`3
`,
`,
`/1998 Sherwood et al.
`5,741,524 A
`4/1998 Staniforth et al.
`5,747,068 A
`5/1998 Mendizabal
`5,753,254 A
`5/1998 Khan et 81.
`5,780,057 A
`7/1998 Conte et al.
`5,800,834 A
`9/1998 Spireas et 81.
`5,858,412 A
`1/1999 Staniforth et al.
`5,866,166 A
`2/1999 Staniforth et al.
`5,895,663 A
`4/1999 IYWiI} 9t a1~
`2
`i?mfortthlet al'
`a
`a
`1 18. e a .
`6,190,696 B1 * 2/2001 Groenewoud ............. .. 424/464
`
`(21) Appl. N0.: 09/538,461
`
`(22) Filed:
`
`Mar. 30, 2000
`
`FOREIGN PATENT DOCUMENTS
`
`WO
`
`99/15155
`
`4/1999
`
`(51) Im. c1.7 ............................ .. A61K 9/20; A61P 5/14
`(52) U.S. Cl. ..................... .. 424/488; 424/464; 424/465;
`_
`514/960
`(58) Field of Search ............................... .. 424/488, 464,
`424/465; 514/960
`
`OTHER PUBLICATIONS
`Allen, J' D‘, et a1‘, “Improving DC With SMCC”, Manufac_
`turing Chemist, 19—23, Dec. 1996.
`Brownley, Jr” C_ A” et a1” “Browning of spray_processed
`Lactose”, J. OfPharm. of Sci., 53 (4); 452—454, 1964.
`
`(56)
`
`References Cited
`
`(List continued on next page.)
`
`US, PATENT DOCUMENTS
`
`Eu 6; a1‘
`2
`'
`3/1990 BOp
`4,910,023 A
`otZolakis et al.
`,
`,
`4/1991 Radebaugh et al.
`5,004,613 A
`7/1991 Huang et al.
`5,032,405 A
`5,073,380 A 12/1991 Babll et al-
`5,200,193 A
`4/1993 Radebaugh et 91-
`2
`‘7V
`$056M et all‘
`5’225’2O4 A
`7;1993 C265‘); 3 a '
`5’33O’766 A
`7/1994 Morena et' a1
`5,378,474 A
`1/1995 Morella et al.
`5,462,747 A 10/1995 Radebaugh et al.
`5,490,990 A
`2/1996 Grabowski et a1.
`
`Primary Examiner—EdWard J. Webman
`Assistant Examiner—Helen Nguyen
`(74) Attorney, Agent, or Firm—Burns, Doane, SWecker &
`Mathis’ L'L'P'
`(57)
`
`ABSTRACT
`
`Provided is a pharmaceutical preparation of thyroid hor
`mone and a process of making a tablet formulation of the
`pharmaceutical preparation using direct compression. In a
`preferred embodiment, the pharmaceutical preparation com
`prises levothyroxine sodium and silici?ed microcrystalline
`6611111059
`
`15 Claims, 16 Drawing Sheets
`
`Active
`
`Colors
`
`Active
`Blend
`
`l
`
`Color
`Blend
`
`l Excipients
`
`—>
`
`<—
`
`PreBlend
`
`l Lubricant <—
`
`Final Blend
`
`——>
`Compression
`
`Tablet
`
`Mylan Ex 1043, Page 1
`
`

`

`US 6,399,101 B1
`Page 2
`
`OTHER PUBLICATIONS
`
`Castello, R. A., et al., “Discoloration of Tablets Containing
`Amines and Lactose”, J. of Pharm. Sci., 51 (2): 106—108,
`1962.
`Debord, B., et al., “Study of Different Crystalline Forms of
`Mannitol: Comparative Behaviour Under Compression”,
`Drug Devel. and Ind. Pharm, 13 (9—11): 1533—1546, 1987.
`Duvall, R. N., et al., “Comparison of Reactivity of Amphet
`amine, Methamphetamine, and Dimethylamphetamine With
`Lactose and Related Compounds”, J. ofPharm Sci., 54 (4):
`607—611, 1965.
`Edge, S., et al., “The Location of silicon dioxide in silici?ed
`Microcrystalline Cellulose”, Pharm. Pharmacol. Commun.,
`3: 371—376, 1999.
`Gupta, V. D., et al., “Effect of EXcipients on the Stability of
`LevothyroXine Sodium Tablets”, J. of Clinical Pharm. T her,
`15: 331—336, 1990.
`Kanig, J. L., “Properties of Fused Mannitol in Compressed
`Tablets”, J. ofPharm. Sci., 53 (2): 188—192, 1964.
`Riba, X. S., et al., “Silici?ed Microcrystalline Cellulose: A
`Comparative Evaluation of This NeW high Functionality
`Direct Compression EXcipient”, Pharm. Res., 4 (11): S—11,
`#1038, 1997.
`
`Richheimer, S. L., et al., “Determination of Liothyronine
`and LevothyroXine in Thyroid Preparations by Liquid Chro
`matography”, J. ofPharm. Sci., 2 (75): 215—217, 1986.
`Sheskey, P. J ., et al., “Investigation Into The Mechanical
`Behavior of Selected Pharmaceutical Polymer EXcipients as
`Binding Agents in Roller Compaction”, Pharm. Res., 14
`(11): S—417, #2624, 1997.
`SherWood, B. E., et al., “ANeW Class of High—Functionality
`EXcipients: Silici?ed Microcrystalline Cellulose”, Pharm.
`Tech, 22 (10): 78—88, 1998.
`Tobyn, M. J ., et al., “Physicochemical Comparison BetWeen
`Microcrystalline Cellulose and Silici?ed Microcrystalline
`Cellulose”, Inter: J. ofPharm, 169: 183—194, 1998.
`Ward, D. R., et al., “Dissolution and Compatibility Consid
`erations for the Use of Mannitol in Solid Dosage Forms”, J.
`ofPharm. Sci., 58 (12): 1464—1467, 1969.
`Won, C. M., “Kinetics of Degradation of LevothyroXine in
`Aqueous Solution and in Solid State”, Pharm Res., 9 (1):
`131—137, 1992.
`Wirth, D. D., et al., “Maillard Reaction of Lactose and
`FluoXetine Hydrochloride, a Secondary Amine”,J. ofPham.
`Sci., 87 (1); 31—39, 1998.
`
`* cited by examiner
`
`Mylan Ex 1043, Page 2
`
`

`

`U.S. Patent
`
`Jun. 4, 2002
`
`Sheet 1 0f 16
`
`US 6,399,101 B1
`
`Mylan Ex 1043, Page 3
`
`

`

`U S Patent
`
`Jun. 4, 2002
`
`Sheet 2 0f 16
`
`US 6,399,101 B1
`
`Mylan Ex 1043, Page 4
`
`

`

`U.S. Patent
`
`Jun. 4, 2002
`
`Sheet 3 0f 16
`
`US 6,399,101 B1
`
`Mylan Ex 1043, Page 5
`
`

`

`U S Patent
`
`Jun. 4, 2002
`
`Sheet 4 0f 16
`
`US 6,399,101 B1
`
`Mylan Ex 1043, Page 6
`
`

`

`U S Patent
`
`Jun. 4, 2002
`
`Sheet 5 0f 16
`
`US 6,399,101 B1
`
`W,
`
`Mylan Ex 1043, Page 7
`
`

`

`U S Patent
`
`Jun. 4, 2002
`
`Sheet 6 6f 16
`
`US 6,399,101 B1
`
`Mylan Ex 1043, Page 8
`
`

`

`U S Patent
`
`Jun. 4, 2002
`
`Sheet 7 0f 16
`
`US 6,399,101 B1
`
`Mylan Ex 1043, Page 9
`
`

`

`U.S. Patent
`
`Jun. 4, 2002
`
`Sheet 8 0f 16
`
`US 6,399,101 B1
`
`Mylan Ex 1043, Page 10
`
`

`

`U S Patent
`
`Jun. 4, 2002
`
`Sheet 9 0f 16
`
`US 6,399,101 B1
`
`Mylan Ex 1043, Page 11
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`

`

`U.S. Patent
`
`Jun. 4, 2002
`
`Sheet 10 0f 16
`
`US 6,399,101 B1
`
`Mylan Ex 1043, Page 12
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`

`

`U.S. Patent
`
`Jun. 4, 2002
`
`Sheet 11 0f 16
`
`US 6,399,101 B1
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`Mylan Ex 1043, Page 13
`
`

`

`U S Patent
`
`Jun. 4, 2002
`
`Sheet 12 0f 16
`
`US 6,399,101 B1
`
`Mylan Ex 1043, Page 14
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`

`

`U.S. Patent
`
`Jun. 4, 2002
`
`Sheet 13 0f 16
`
`US 6,399,101 B1
`
`Mylan Ex 1043, Page 15
`
`

`

`U S Patent
`
`Jun. 4, 2002
`
`Sheet 14 0f 16
`
`US 6,399,101 B1
`
`Mylan Ex 1043, Page 16
`
`

`

`U.S. Patent
`
`Jun. 4, 2002
`
`Sheet 15 0f 16
`
`US 6,399,101 B1
`
`Active
`
`l<——
`l
`
`Active
`Blend
`
`Colors
`
`l<——
`l Excipients
`
`Color
`Blend
`
`_.__>
`
`<—
`
`PreBiend
`
`l Lubricant <—
`
`Final Blend
`
`————->
`A
`Compression
`
`FIG. 8
`
`Mylan Ex 1043, Page 17
`
`

`

`U.S. Patent
`
`Jun. 4, 2002
`
`Sheet 16 0f 16
`
`US 6,399,101 B1
`
`Levothyroxine Sodium Tablets Dissolution
`Profile
`0.05M, pH 7.4 Phosphate Buffer
`
`120
`100
`80_ W
`60
`40
`20
`
`% Dissolved
`
`O
`
`l
`
`l
`
`I
`
`I
`
`I
`
`I
`
`I
`
`10
`
`15
`
`60
`4O
`3O
`2O
`Time (Minutes)
`
`120
`
`FIG. 9
`
`Mylan Ex 1043, Page 18
`
`

`

`US 6,399,101 B1
`
`1
`STABLE THYROID HORMONE
`PREPARATIONS AND METHOD OF
`MAKING SAME
`
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`The present invention is directed to therapeutic agents for
`the treatment of hormone disorders and the method for
`preparing those agents. More speci?cally, the present inven
`tion relates to stable pharmaceutical preparations containing
`thyroxine drugs, especially levothyroxine sodium, Which is
`the sodium salt of the levo isomer of thyroxine. L-thyroxine
`is the principal hormone secreted by the normal thyroid
`gland. The thyroid gland is stimulated to secrete thyroid
`hormones by the action of thyroid stimulating hormone
`(TSH), Which is produced in the anterior pituitary gland.
`TSH secretion is then controlled by thyrotropin-releasing
`hormone (TRH), produced in the hypothalamus. Thyroid
`hormones circulating in the blood act as feedback inhibitors
`of both TSH and TRH secretion.
`Thyroxine may be obtained from the thyroid gland of
`domesticated animals, or alternatively, the hormone can be
`prepared synthetically. Levothyroxine and other thyroid
`hormones are knoWn to serve as speci?c replacement
`therapy When the thyroid function has been reduced or is
`completely absent for a variety of disease states, including,
`for instance, myxedema, cretinism and obesity. Levothyrox
`ine is also indicated as a pituitary TSH suppressant in the
`treatment or prevention of euthyroid goiters.
`2. Brief Description of Related Art
`Pharmaceutical preparations containing levothyroxine
`hormone are knoWn to exhibit de?ciencies With regard to
`uniformity, stability and shelf life. More speci?cally,
`levothyroxine sodium hormone is hygroscopic and degrades
`rapidly under conditions of high humidity or in the presence
`of other moisture sources or light and under conditions of
`high temperature. Moreover, levothyroxine is knoWn to
`degrade in the presence of certain pharmaceutical excipients
`such as carbohydrates, including lactose, sucrose, dextrose
`and starch, as Well as certain dyes.
`Commercial preparations currently marketed include
`Levothroid®, Levoxyl®, Synthroid® and Levo-T®. These
`products, Which include lactose as the major component of
`the excipient matrix, exhibit poor characteristics With regard
`to stability and uniformity. As noted in the Handbook of
`Pharmaceutical Excipients, Second Edition, p. 257, a
`Maillard-type condensation reaction is likely to occur
`betWeen lactose and compounds With a primary amine group
`to form broWn-colored products. Accordingly, it has been
`found that lactose reacts With levothyroxine resulting in
`degradation of the drug. It is believed that the amino group
`of the L-tyrosine portion of the levothyroxine molecule
`reacts With the glycosidic hydroxyl group of the glucose unit
`of the lactose excipient, undergoing the Maillard reaction.
`This degradation of levothyroxine results in decreased sta
`bility for the drug formulation. There is, then, a need in the
`art for a levothyroxine formulation Which does not utiliZe
`lactose or other excipients Which can react With the levothy
`roxine and lead to degradation of the drug.
`A feW attempts have been made to prepare thyroxine
`formulations Without the excipients of the commercial prod
`ucts described above. US. Pat. No. 5,225,204, issued to
`Chen et al, describes a dosage formulation complex of
`hydrated levothyroxine sodium Which includes Poloxamer
`or polyvinylpyrrolidone and is granulated With a polar
`organic solvent before being uniformly adsorbed on a cel
`
`15
`
`25
`
`35
`
`45
`
`55
`
`65
`
`2
`lulose compound. Other embodiments of the ’204 patent
`describe a levothyroxine sodium formulation prepared With
`the use of an organic solvent or in a dry state by mixing
`levothyroxine sodium With a cellulose complexing agent and
`subsequently combining this mixture With a cellulose car
`rier. No data on the stability of these formulations Was
`provided.
`US. Pat. No. 5,955,105, issued to Knoll Pharmaceutical
`Company, describes thyroid hormone preparations stabi
`liZed by an inorganic salt, a carbohydrate having a molecular
`Weight of greater than 500, or glycine. Suitable carbohydrate
`binders include microcrystalline cellulose, maltodextrin,
`starch and hydroxypropyl cellulose having a molecular
`Weight betWeen 80,000 and 1,150,000. Preferred embodi
`ments of the invention Were prepared in the substantial
`absence of lactose, glucose, sucrose, polyvinylpyrrolidone,
`and/or a Poloxamer. According to the ’105 patent, the
`levothyroxine formulations of US. Pat. No. 5,225,204 did
`not provide suitable stability. Example 1 involved the use of
`PVP and example 2 involved dry mixing levothyroxine
`sodium With hydroxypropyl cellulose With subsequent com
`bination of this mixture With a microcrystalline cellulose
`carrier. These examples of the ’204 patent Were repeated by
`the applicants of the ’105 patent and the formulations Were
`subjected to stability tests. The results of these tests are
`provided in the ’105 patent.
`US. Pat. No. 5,635,209, issued to Vintage
`Pharmaceuticals, Inc., is directed to a stabiliZed composition
`of levothyroxine sodium medication containing potassium
`iodide and a microcrystalline cellulose. This formulation
`may also include a disintegrant, a lubricant and a dye. The
`composition of the ’209 patent is undesirable since it
`includes the extra ingredient potassium iodide, Which dis
`torts the results of a determination of the stability of the
`levothyroxine sodium.
`US. Pat. No. 5,753,254, issued to Knoll
`Aktiengesellschaft, relates to a solid fast dispersing dosage
`form Wherein the therapeutic agents containing thyroid
`hormones have a formulation including the hormone, a
`disintegrating agent, a ?avoring agent and a lubricating
`agent. The disintegrating agent may be starch, agar,
`bentonite, cellulose, microcrystalline cellulose,
`methylcellulose, carmellose, croscarmellose sodium, alginic
`acid, guar gum, silicon dioxide and sodium lauryl sulphate.
`The ?avoring agent may be a sWeetening agent, a pepper
`mint oil and/or fruit ?avor, a ?avor enhancing agent or an
`ingredient Which induces the formation of saliva, such as an
`organic acid like citric and malic acid. The lubricating agent
`may be magnesium stearate, calcium stearate, stearic acid
`and mixtures thereof. Optional ingredients may also be
`present. This formulation is intended to be fast dissolving
`and stability issues are not discussed.
`Each of these patents attempts to remedy the de?ciencies
`of the commercial levothyroxine products by using various
`excipients besides the standard lactose. Microcrystalline
`cellulose (MCC) is Widely used as a ?ller and binder for
`pharmaceutical formulations prepared by both Wet granula
`tion and direct compression processes. HoWever, as set forth
`in the ’105 patent, the combination of levothyroxine and
`microcrystalline cellulose as disclosed in the ’204 patent did
`not provide adequate stability. Moreover, microcrystalline
`cellulose used in direct compression tableting has a number
`of limitations, such as loW bulk density, high lubricant
`sensitivity, poor ?oW characteristics and the in?uence of
`moisture on the compression characteristics.
`Thus, there is still a need in the art for a stable, uniform
`formulation of levothyroxine Which can be readily formed
`
`Mylan Ex 1043, Page 19
`
`

`

`US 6,399,101 B1
`
`3
`into dosage forms and Which is substantially free of the
`disadvantages, defects and limitations of the formulations
`disclosed in the art.
`An object of the present invention is to provide a stable
`thyroid hormone preparation Which can be readily formed
`into a dosage formulation. A further object of this invention
`is to provide a stabiliZed preparation of a thyroid hormone
`Which resists degradation by light, heat, humidity or asso
`ciation With commonly used eXcipients. Another object of
`the present invention is to provide a novel pharmaceutical
`preparation and a manufacturing process therefor to improve
`the product performance of levothyroXine sodium tablets in
`terms of uniformity, stability and shelf life.
`A further object of the invention is to provide a pharma
`ceutical preparation in Which an eXcipient provides a matriX
`to capture and protect levothyroXine sodium in order to
`stabiliZe the preparation. Another object of the present
`invention is to provide a process for the manufacture of
`stabiliZed levothyroXine tablets using direct compression.
`
`SUMMARY OF THE INVENTION
`
`In accordance With the foregoing objectives, there is
`provided by the present invention a stabiliZed pharmaceu
`tical preparation comprising a therapeutically effective
`amount of a thyroid hormone and silici?ed microcrystalline
`cellulose.
`In a more preferred embodiment, the thyroid hormone is
`levothyroXine sodium. The thyroid hormone preparations of
`the present invention provide a stabiliZing matriX consisting
`essentially of silici?ed microcrystalline cellulose Which cap
`tures and protects a therapeutically effective amount of
`levothyroXine sodium particles Within the stabiliZing matriX.
`In a further embodiment, the present invention is directed
`to a direct compression method for the manufacture of a
`pharmaceutical tablet preparation comprising the steps of:
`(a) forming an active blend by blending in intimate admiX
`ture silici?ed microcrystalline cellulose and a therapeutic
`agent comprising one or more thyroid hormone or hor
`mones; (b) forming a color blend by blending in intimate
`admixture one or more pharmaceutically acceptable dyes
`and silici?ed microcrystalline cellulose; (c) combining the
`active blend, the color blend and a disintegrant in a preblend;
`(d) adding a lubricant to the preblend to form ?nal blend;
`and (e) compressing the ?nal blend to form a pharmaceutical
`tablet preparation.
`
`25
`
`35
`
`45
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIGS. 1A thru 1D are scanning electron microscopy
`(SEM) micrographs shoWing the smooth crystalline struc
`ture of levothyroXine particles.
`FIGS. 2A thru 2D are SEM micrographs shoWing the
`structure of a direct miXture of amorphous and crystalline
`grade lactose.
`FIGS. 3A thru 3D are SEM micrographs shoWing the
`structure of silici?ed microcrystalline cellulose
`(Prosolv®50).
`FIGS. 4A thru 4D are SEM micrographs shoWing the
`structure of silici?ed microcrystalline cellulose
`(Prosolv®90).
`FIGS. 5A thru 5D are SEM micrographs shoWing the
`structure of a commercial levothyroXine formulation con
`taining lactose Wherein the levothyroXine is deposited on the
`surface of the lactose.
`FIGS. 6A thru 6D are SEM micrographs shoWing the
`structure of a levothyroXine preparation containing silici?ed
`
`55
`
`65
`
`4
`microcrystalline cellulose (Prosolv®50) Wherein the
`levothyroXine is captured Within the matriX of SMCC,
`according to the present invention.
`FIGS. 7A thru 7D are SEM micrographs shoWing the
`structure of a levothyroXine preparation containing silici?ed
`microcrystalline cellulose (Prosolv®90) Wherein the
`levothyroXine is captured Within the matriX of SMCC,
`according to the present invention.
`FIG. 8 is a How diagram illustrating an embodiment of a
`direct compression process according to the present inven
`tion for the production of the thyroid hormone preparation of
`the present invention.
`FIG. 9 is a graph shoWing the dissolution pro?le of the
`levothyroXine sodium preparation according to the present
`invention described in Example 1.
`
`15
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`It has been surprisingly discovered that the de?ciencies of
`the prior described pharmaceutical formulations of thyroid
`hormone can be overcome by the use of silici?ed microc
`rystalline cellulose as the main eXcipient in a tablet formu
`lation With the thyroid hormone. Silici?ed microcrystalline
`cellulose (SMCC) is a combination of microcrystalline
`cellulose and colloidal silicon dioXide. Silici?cation of the
`microcrystalline cellulose is achieved by the process
`described in US. Pat. No. 5,585,115, issued to EdWard H.
`Mendell Co., Inc.
`The combination of silici?ed microcrystalline cellulose
`and thyroid hormone provides a stable, uniform pharmaceu
`tical preparation With eXcellent shelf-life characteristics.
`While not Wishing to be bound by any theory, it is believed
`that the silici?ed microcrystalline cellulose provides a sta
`biliZing matriX for the thyroid hormone or levothyroXine
`sodium particles. This stabiliZing matriX captures and pro
`tects the levothyroXine particles, thus providing the stabili
`Zation needed to eliminate the problems previously found
`With levothyroXine pharmaceutical formulations. Moreover,
`the silici?ed microcrystalline cellulose provides eXcellent
`?oW characteristics, thus providing better process conditions
`and greater uniformity in the ?nal formulation.
`Accordingly, the novel preparations of the present inven
`tion are directed to stabiliZed pharmaceutical preparations
`comprising a therapeutically effective amount of levothy
`roXine sodium and silici?ed microcrystalline cellulose.
`Preferably, the stabiliZed pharmaceutical preparations Will
`comprise a stabiliZing matriX consisting essentially of silici
`?ed microcrystalline cellulose and a therapeutically effec
`tive amount of levothyroXine sodium particles, Which
`levothyroXine sodium particles are captured and protected
`Within the stabiliZing matriX.
`Thyroid hormones Which may be used in the pharmaceu
`tical preparations of the present invention include the fol
`loWing: L-3,5,3‘,5‘-tetraiodothyronine (levothyroXine or
`LT4); L-3,5,3‘-triiodothyronine (liothyronine or LT3); L-3,
`3‘,5‘-triiodothyronine (LrT3); L-3,5-diiodothyronine (LT2);
`or miXtures thereof. As used herein, the term thyroid hor
`mone should be understood to include all pharmaceutically
`acceptable salts thereof, preferably sodium salts.
`The thyroid hormone preferably Will be levothyroXine
`sodium and Will be present in an amount suf?cient to provide
`the desired therapeutic effect. The term “therapeutically
`effective amount” means the amount needed for the desired
`therapeutic effect and includes any additional amount or
`overage of active ingredient deemed necessary in the for
`mulation to provide the desired amount upon administration.
`
`Mylan Ex 1043, Page 20
`
`

`

`US 6,399,101 B1
`
`5
`
`1s
`
`2!
`
`5
`The amounts required for a specific therapeutic purpose
`are knownto those of skill in the art and can vary widely,
`based on the desired treatment. Due to the high potency
`exhibited by most of the thyroid hormones, the amount of
`active ingredient will generally be small, usually less than
`about 1% by weight. The minimum amount of thyroid
`hormonecanvary, so long as an effective amountis provided
`to cause the desired therapeutic effect. Generally, the thyroid
`hormone will be present in an amount from about 0.025 mg
`to about 0.3 mg.
`Thesilicified microcrystalline cellulose used in the prepa-
`ration of the present invention may be any commercially
`available combination of microcrystalline cellulose granu-
`lated with colloidal silicon dioxide. The SMCC generally
`will be as described in Sherwood et al, Pharm. Tech.,
`October 1998, 78-88, and U.S. Pat. No. 5,585,115, incor-
`porated herein by reference in its entirety. SMCC can be
`obtained commercially from Mendell, a Penwest Company,
`under the name ProSolv SMCC®. Thereare different grades
`of SMCCavailable, with particle size being the dilferenti-
`aling property among the grades. For example, ProSolv
`SMCC® 90 has a medianparticle size, by sieve analysis, in
`the region of 90 wm. ProSoly SMCC® 50 has a median
`particle size, by sieve analysis, in the region of about 40-50
`um. Gencrally, the particle size of the SMCC should not be £
`larger than about 150 microns.
`Since levothyroxine sodiumparticles have a particle size
`of about 2 to about 10 microns, the choice of SMCC particle
`size is somewhat determined by the particle differential
`between the SMCCandthe levothyroxine.It is believed that
`incorporation of material with a particle distribution closer
`to the one of the active ingredient will result in improved
`uniformity. Therefore, preferably,
`the particle size of the
`SMCC will be about 50 to about 100. A combination of
`different grades of SMCC maybe utilized.
`In one embodiment, ProSoly SMCC® 90is utilized was
`the SMCC. In another embodiment, ProSolv SMCC®50 is
`utilized as the SMCC. In a more preferred embodiment, a
`combination of ProSolv SMCC®S50 and ProSolv SMCC®90
`is used.
`
`30
`
`35
`
`40
`
`The amount ofsilicified microcrystalline cellulose used in
`the formulation of the present invention will be the amount
`necessary to stabilize levothyroxine sodium in a matrix
`which captures and protects the levothyroxine sodium par-
`ticles. Generally, the SMCC will be present in an amount of
`about 50% to about 99%. Preferably, the amount of SMCC
`will be about 90% to about 99%.
`
`45
`
`FIGS. 1A thru 1D show the smooth crystalline structure
`of levothyroxine particles. This structure is important in the 5;
`choice of an appropriate excipient for a stable levothyroxine
`pharmaceutical formulation.
`FIGS. 2A thru 2D illustrate the structure of a mixture of
`amorphousandcrystalline lactose alone and FIGS. 5A thru
`5D illustrate the structure of a drug formulation of lactose
`and levothyroxine sodium. As shown in the SEM micro-
`graphs of FIG. 5, only surface deposition of the levothy-
`roxine is observed.
`
`TIGS. 3A thru 3D and 4A thru 4D depict the textured,
`porous surfaces of ProSoly SMCC® 50 and ProSolv
`SMCC® 90. Literature describes these materials as porous
`materials, with a surtace with as much as 30% covered by
`pores of 2—3 microns mean diameter. FIGS. 6A thru 6D and
`7A thru 7D show the formulation of the invention with
`levothyroxine sodium and ProSolv SMCC® 50 andlevothy-
`roxine and ProSolv SMCC@®90,respectively. As shown,the
`SMCCfunctions as a carrier and captures the levothyroxine
`
`60
`
`65
`
`6
`particles within the porous matrix. Such physical interaction
`is believed to provide improved uniformity of the pharma-
`ceutical product during a direct compression process. This
`capture within the matrix is especially important in view of
`the gencrally low amounts of active ingredicnt present in
`thyroxine hormone formulations. ProSoly SMCC® 90. Lit-
`erature describes these materials as porous materials, with a
`surface with as much as 30% covered by pores of 2-3
`microns mean diameter. FIGS. 6 and 7 show the formulation
`of the invention with levothyroxine sodium and ProSolv
`SMCC® 50 and levothyroxine and ProSoly SMCC® 90,
`respectively. As shown, the SMCC functionsas a carrier and
`captures the levothyroxine particles within the porous
`matrix. Such physical interaction is believed to provide
`improveduniformity of the pharmaceutical product during a
`direct compression process. This capture within the matrix is
`especially important in viewof the generally low amounts of
`active ingredient present in thyroxine hormone formula-
`tions.
`
`The formulation of the present invention may include a
`numberofother ingredients for optimal characteristics of the
`pharmaceutical composition. Such other ingredients andthe
`amounts to be used are within skill of the art and are known
`in the pharmaceutical art. These may include disintegrants,
`lubricants and/or coloring agents, among others. Suitable
`disintegrants include, for example, sodium starch glycolate,
`other starches such as pregcelatinized starch, and cclluloscs.
`Suitable lubricants may be provided such as magnesium
`stearate, calcium stearate, talc and stearic acid. Anycoloring
`agent certified by the FDA may be used, such as FD&C
`Yellow #6, among others.
`The pharmaceutical preparation of the present invention
`may be prepared using a direct compression method, a dry
`granulation method or by wet granulation. Preferably, the
`thyroid hormone preparation of the prescnt invention will be
`prepared using a direct compression process. This preferred
`process consists of two main steps: blending and compres-
`sion. FIG. 8 illustrates the general process of the invention.
`The blending step is composed of an active blend, color
`blend, pre-blend, and final blend (Iubrication).
`Tn one embodiment,
`the present
`invention provides a
`method for the manufacture of a pharmaceutical
`tablet
`preparation comprising the steps of: (a) forming an active
`blend by blending in intimate admixture silicified microc-
`rystalline cellulose and a therapeutic agent comprising one
`or more thyroid hormone or hormones; (b) forming a color
`blend by blending in intimate admixture one or more phar-
`maceutically acceptable dyes andsilicified microcrystalline
`cellulose; (c) combining the active blend, the color blend
`and a disintegrant in a preblend; (d) adding a lubricantto the
`preblend to form a final blend; and (e) compressing the final
`blend to form a pharmaceutical tablet preparation.
`‘This process has been tound to be reproducible and
`strength independent. The operation of the blending equip-
`ment and settings for carrying out the process of the inven-
`tion will be understood to anyone of skill
`in the art.
`Likewise, the compression of the pharmaceutical prepara-
`tion of the present invention can be carried out by any of the
`known methods and with equipment and settings which
`would be known to one of skill in the art.
`
`
`
`A screening step may be introduced between the active
`blend and preblend portions of the blending step to prevent
`agglomeratesof active particles (+250 micronsin size) to be
`carried over to the preblend portion. For example, a screen
`#00, which contains open surface areas of 250 microns, may
`be used. Other methods and equipment utilized for screening
`
`Mylan Ex 1043, Page 21
`
`Mylan Ex 1043, Page 21
`
`

`

`US 6,399,101 B1
`
`7
`particles will be knownto those of skill in the art. The flow
`properties of the mixture are notaffected by incorporation of
`the silicified microcrystalline cellulose in the active blend
`and the screening step.
`The thyroid hormone tablets resulting from the direct
`compression process of the present invention exhibit the
`stability and uniformity required for such formulations.
`The invention will now be more fully explained by the
`following examples. However, the scope of the invention is
`not intended to be limited to these examples.
`
`EXAMPLES
`
`Example 1
`
`A preparation according to the present invention was
`prepared with the following ingredients (Lot #1355-006-
`039):
`
`Ingredients
`
`Function
`
`me/ftablet
`
`% w/w
`
`Levothyroxine, U.S.P.
`Prosoly SMCC ™ 99
`Sodium Starch Glycolalte, NF
`Magnesium Stearate, NF
`FD & C Yellow#6
`
`Active
`Diluent
`Disinltegrant
`Lubricant
`Coloring Agent
`
`0.025
`115.84
`6.15
`0.861
`0.123
`
`123 mg
`
`0.02
`94.18
`5.00
`0.70
`0.10
`
`100%
`
`1355-006-039: Initial (TO) assay 98.1%
`
`The stability results for lot 1355-006-039 at ACC/40°
`C.:75%R.H. are given below.
`1355-006-039:
`
`%o_Assay/month
`T2
`
`94.4
`
`T3
`
`93.3
`
`TL
`
`94.5
`
`to = 98.1%
`
`The results show excellent initial assay and stability. For
`this formulation, an approximately 5% initial assay drop was
`observed after three months accelerated stability. This sta-
`bility behavior represents an improvement over the lactose-
`based formula, where an 18% drop is observed under the
`same conditions. The dissolution profile met U.S.P. require-
`ments as shown in FIG. 9.
`
`Example 2
`
`8
`
`-continued
`
`0.025 mg strength
`
`Ingredients
`Prosaly SMCC ™ 90
`Sodium Starch Glycolate, NF
`Magnesium Stearate, NP
`FD & C Yellow #6
`
`Function
`Diluent
`Disintegrant
`Lubricant
`Coloring Agent
`
`mg/tablet
`104.28
`6.143
`0.857
`0.277
`
`% wiw
`84.77
`4.99
`0.70
`0.22
`
`Each of the three lots was prepared according to FIG. 8
`which is a flow chart illustrating the direct compression
`process utilized. The active blend comprises ProSolv50®
`and levothyroxine which was blendedin a blender. A portion
`of the ProSolv 90® and the color was blended in a blender
`to form the color blend. For two of the lots, the active blend
`was (hen screenedin a #60 mesh screen before passing to the
`preblend step. The rest of the ProSolv 90™ excipient was
`added to the color blend, which was then added to the
`preblend step. The preblend was mixed in a blender and
`included the active ingredient, the color blend and sodium
`starch glycolatc. The lubricant magnesium stcarate was
`addedafter the preblend step and priorto thefinal blend step.
`After the final blend, the material was then subjected to
`tablet compression via direct compression using a Courtoy
`tablet compression machine.
`‘The stability of the product is shownin the table below:
`
`30
`
`35
`
`40
`
`45
`
`Storage Condition
`Initial Ty
`RT
`
`A
`99.3%
`
`B
`101.0%
`
`c
`101.8%
`
`99.8%
`104.2%
`95.6%
`94.4%
`
`98.4%
`101.7%
`96.4%
`94.4%
`
`95.6%
`95.6%
`90.6%
`
`99.3%
`100.0%
`100.3%
`96.6%
`
`98.8%
`100.8%
`93.8%
`96.4%
`
`98.1%
`96.2%
`91.7%
`
`ND
`ND
`ND
`ND
`
`ND
`ND
`ND
`ND
`
`94.1%
`94.4%
`90.3%
`
`1 month
`2 months
`3 months
`6 months
`INT
`
`1 month
`2 months
`3 months
`6 months
`
`ACC
`
`1 month
`2 months
`3 months
`RT: 25 + 2° C., 60% R.H.
`INT: 30 + 2° C., 60% RH.
`ACC: 40 + 2° C., 75% R.A.
`ND: Not Determined
`
`While the invention has been described with preferred
`Three lots (containing 2% active overage) were manufac-
`embodiments,
`it
`is to be understood that variations and
`tured at commercial scale, containing Prosoly™ 50 (9.3%
`modifications may beresorted to as will be apparentto those
`w/w final blend) and Prosolv™ 90 (84.8% w/w final blend).
`skilled in the art. Such variations and modifications are to be
`The results of the final blend showed an average percent
`considered within the purview and the scope of the claims
`assay of 99.2% and an RSD of 0.9%. Content uniformity for
`appended hereto.
`30 tablets was found to be 102.1% with an RSD of 4.2%.
`We claim:
`The ingredients of the three lots