(19) United States
`(12) Patent Application Publication (10) Pub. N0.: US 2012/0190748 A1
`Treasurer
`(43) Pub. Date:
`Jul. 26, 2012
`
`US 20120190748Al
`
`(54) GREATER UTILITY WITH THYROID
`HORMONE
`
`(51) Int. Cl.
`
`Publication Classi?cation
`
`
`
`(76) Inventor: (21) App1.No.:
`
`
`
`Haren Treasurer, Toronto (CA) 13/388,955
`
`(22) PCT Filed:
`
`Aug. 3, 2010
`
`
`
`311/598 A61M 5/142
`
`C07C 229/36
`
`(2006-01)
`
`(2006.01)
`
`(86) PCT No.:
`
`PCT/IB2010/002229
`
`(52) US. Cl. ........ .. 514/567; 562/444; 604/151; 604/500
`
`§ 371 (0X1),
`(2), (4) Date:
`
`Apr. 16, 2012
`
`Related U's'Apphcatlon Data
`(60) Provisional application No, 61/231,151, ?led OnAug_
`4, 2009.
`
`ABSTRACT
`(57)
`Formulations and delivery systems that include a thyroid
`hormone active agent consisting essentially of T4 should
`reduce ?uctuations in delivery of thyroid hormone.
`
`100
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`Mylan Ex 1011, Page 1
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`Patent Application Publication
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`

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`Patent Application Publication
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`Jul. 26, 2012 Sheet 6 0f 7
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`US 2012/0190748 A1
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`Patent Application Publication
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`Jul. 26, 2012 Sheet 7 0f 7
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`US 2012/0190748 A1
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`FIGURE 6
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`Mylan Ex 1011, Page 8
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`

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`US 2012/0190748 A1
`
`Jul. 26, 2012
`
`GREATER UTILITY WITH THYROID
`HORMONE
`
`CROSS-REFERENCE TO RELATED PATENT
`APPLICATIONS
`[0001] This application claims priority from US. provi
`sional application 61/231,151, ?led Aug. 4, 2009, Which is
`incorporated herein by reference in its entirety.
`
`FIELD
`
`[0002] The present application generally relates to the ?eld
`of hormonal therapy and, more particularly, to thyroid hor
`mone therapy.
`
`SUMMARY
`
`[0003] One embodiment of the invention comprehends an
`infusion system comprising (a) a container containing an
`infusate consisting essentially of thyroxine and (b) a driving
`member con?gured to drive said infusate from the container
`in a continuous manner, at a constant but user adjustable rate.
`[0004] Another embodiment provides a plurality of thyrox
`ine oral forms, Wherein each such form comprises a hormonal
`active agent that consists essentially of thyroxine and Wherein
`an incremental difference betWeen said forms in the amount
`of the
`thyroxine
`present
`is
`no greater
`than
`0.0000000125179946172623 moles.
`[0005] Pursuant to yet another embodiment of the inven
`tion, an oral dosage form is provided that comprises a con
`trolled release matrix containing a hormone active agent that
`consists essentially of thyroxine.
`
`DRAWINGS
`
`[0006] FIG. 1 schematically depicts a catheter for an infu
`sion system.
`[0007] FIG. 2 relates to the catheter implantation and pump
`positioning on a human body.
`[0008] FIG. 3 schematically illustrates an external infusion
`system and its components.
`[0009] FIG. 4A schematically depicts an implantable infu
`sion system and its components.
`[0010] FIG. 4B schematically illustrates a location of an
`implantable infusion system on a human body.
`[0011] FIG. 5 schematically illustrates a cartridge, Which
`may be used, for example, With an external or implantable
`infusion system.
`[0012] FIG. 6 schematically depicts a box of cartridges.
`
`DETAILED DESCRIPTION
`
`[0013] Unless otherWise speci?ed “a” or “an” means to one
`or more.
`[0014] The terms “thyroxine” and “T4” refer to 3,5,3',5'
`tetraiodo-L-thyronine, a salt of 3,5,3',5' tetraiodo-L-thyro
`nine, a prodrug form of 3,5,3',5' tetraiodo-L-thyronine, a salt
`of the prodrug form of 3,5,3',5' tetraiodo-L-thyronine or any
`combination thereof.
`[0015] In this description, the phrases ‘consisting essen
`tially of thyroxine’ and ‘consisting essentially of T4’ qualify
`an object, such as a formulation, a composition, a delivery
`system, a pharmaceutical product or an active agent, that
`includes one or more of the folloWing entities: 3,5,3',5' tet
`raiodo-L-thyronine, a salt of 3,5,3',5' tetraiodo-L-thyronine, a
`prodrug form of 3,5,3',5' tetraiodo-L-thyronine, or a salt of
`
`the prodrug form of 3,5,3',5' tetraiodo-L-thyronine, but that
`excludes, as best as possible, any of the folloWing entities: T3,
`also knoWn as 3,5,3‘ triiodo-L-thyronine, analogues, such as
`structural, functional, substrate, and transition state ana
`logues, of 3,5,3',5' tetraiodo-L-thyronine, and analogues,
`such as structural, functional, substrate, and transition state
`analogues, of 3,5,3‘ triiodo-L-thyronine.
`[0016] In this regard, “best as possible” means that the
`excluded entities either are absent from the object that con
`sists essentially of thyroxine or are present in the amount that
`does not detract from the bene?cial and distinctive features of
`the invention, such as achieving reduced ?uctuations in thy
`roid hormone volume of distribution and metabolism and/or
`achieving optimal distribution of thyroid hormone effect.
`[0017] Use here of each of the terms ‘T4’, “thyroxine” and
`‘3,5,3',5' tetraiodo-L-thyronine’ encompasses all isotopic
`variants of 3,5,3',5' tetraiodo-L-thyronine.
`[0018] The phrase ‘prodrug form of 3,5,3’,5' tetraiodo-L
`thyronine’ refers to a molecule in Which an atom or atoms, in
`one or more side chains of 3,5,3',5' tetraiodo-L-thyronine,
`is/are substituted or covalently bonded With another mol
`ecule/macromolecule (denoted here “the carrier molecule/
`macromolecule), Which, When administered to an organism,
`is likely to be metaboliZed (converted by physiologic pro
`cesses and interactions With exogenous or endogenous sub
`stances present Within the organism) into 3,5,3',5' tetraiodo
`L-thyronine free of its covalent bonding to the carrier
`molecule/macromolecule. Examples of appropriate prodrugs
`include but are not limited to Thyroxinyldimethylphosphi
`nate described in US. Pat. No. 6,627,660; peptide bound T4
`described in US. Pat. No. 7,163,918; T4 bound by thyroglo
`bulin/ thyroid binding globulin/ transthyretin/ albumin, and T4
`bound by polypeptide/peptide segments of thyroglobulin/
`thyroid binding globulin/transthyretin/ albumin.
`[0019] Thyroid Hormone Therapy
`[0020] The primarily active forms of thyroid hormone
`Within the body are 3,5,3',5' tetraiodo-L-thyronine (T4 or
`L-thyroxine) and 3,5,3‘ triiodo-L-thyronine (T3). T4 and T3
`are stored Within the thyroid gland4one of the largest endo
`crine organsias part of Thyroglobulin (Tg) protein mol
`ecules at amolar ratio of approximately 15:1 (18:1 by Weight)
`(Kronenberg, 2008, ch 10; for citations see REFERENCES
`section, infra).
`[0021] They are secreted from the gland at a ratio (by
`Weight) of roughly 13:1 (Kronenberg, 2008, ch. 10). The
`thyroid gland has an extremely rich vasculature, receiving 4
`to 6 ml/min/ g of blood ?oW, setting itself far above almost any
`organ in the body (the kidney only receives 3 ml/min/ g) (id.).
`As compared With other endocrine organs, the secretion of
`thyroid hormone by the thyroid gland is relatively constant.
`[0022] Quanti?cation of the exact ratio of T4 to T3 Within
`thyroglobulin and the exact ratio secreted is dif?cult due to
`the likelihood of iodine atoms to be hydrolyZed from T4 and
`T3 during analysis, and thus the exact ratio of T4 to T3 is
`unknoWn and likely to be even greater. The ratio of T4 to T3
`rises With iodine availability, and With the Widespread iodi
`nation of foodstuffs, the majority of the World’s population
`likely functions Without iodine limiting the ratio (id.).
`[0023] Both T4 and T3 are unstable molecules due to the
`likelihood of their iodine atoms to be removed by hydrolysis,
`though T3 is more unstable. Once secreted, thyroid hormone
`is tightly bound Within the blood stream by Thyroid Binding
`Globulin, Transthyretin and Albuminiminimizing hydroly
`sis. T4 is bound roughly 10 times more tightly than T3 (99.
`
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`Jul. 26, 2012
`
`96% vs 99.6%). (Kronenberg, 2008, ch. 10; Katzung, 1998,
`ch. 38). Due to protein binding, the biological half-life of T3
`is extended to approximately 1 day, and the biological half
`life of T4 is extended to approximately 6 to 7 days, giving T4
`one of the longest biological half-lives of any hormone in the
`human body (Katzung, 1998, ch. 38). The secretion of T4 and
`T3 from the thyroid gland is stimulated by Thyroid Stimulat
`ing Hormone (TSH), the secretion of Whichiby anterior
`pituitary glandiis controlled by Thyrotropin-Releasing
`Hormone (TRH). TRH is expressed in many tissues through
`out the body, hoWever the parvocellular region of the paraven
`tricular nucleus (PVN) of the hypothalamus is the source of
`the TRH that regulates TSH secretion. The PVN is in?uenced
`by various neural stimuli Which in turn are in?uenced by the
`physical and psychological condition of the body, including
`body temperature, neural chemistry (such as the presence of
`a psychotic state), circadian and other pulsatile endocrine
`rhythms Within the body, and severe physical and psychologi
`cal stresses. The secretion of TSH and TRH is also inhibited
`by higher concentrations of T4 and or T3 in a negative feed
`back manner (Katzung, 1998, ch. 38).
`[0024] At their site of action, both T3 and T4 cross the cell
`membrane. T4 is converted to produce reverse T3 (a relatively
`inactive isomer) and T3. T3 then enters the nucleus and binds
`the
`[0025] Thyroid Hormone Receptor protein (TR), causing
`dissociation of a co-repressor (CoR) protein and alloWing
`binding of co-activator (CoA) proteins, such as the Retinoid
`X Receptor protein (RXR). The T3-TR-RXR complex then
`in?uences the transcription of various genes differently than
`in their state While bound to the TR-CoR complex. The
`altered transcription alters the synthesis of various proteins
`(Kronenberg, 2008, ch. 10). The sum effect of these actions is
`unknown.
`[0026] It is knoWn that loW concentrations of T4 and T3
`produce symptoms that are termed hypothyroidism: cold
`intolerance, cool dry skin, brittle hair, decreased heart rate,
`decreased appetite/boWel movements, decreased GFR, stiff
`ness, lethargy, sloWing of cognition, hyperlipidemia,
`decreased hormone/vitamin/drug degradation and Weight
`gain; the supplementation With exogenous T4 and T3 is
`intended to reduce the severity of these symptoms (Cum
`mings, 2010, ch. 123).
`[0027] High concentrations of T4 and T3 produce symp
`toms Which is termed hyperthyroidism: heat intolerance,
`sWeating, thin hair, increased heart rate, arrythmias, increased
`appetite/boWel movements, increased GFR, Weakness,
`tremor, nervousness, hyperglycemia, increased hormone/vi
`tamin/ drug degredation and Weight loss; the discontinuation
`of supplementation, ablation of the thyroid gland, or use
`agents Which suppress T4 and T3 production is intended
`reduce the severity of these symptoms (Cummings, 2010, ch.
`123).
`[0028] The relationship betWeen T4 and T3 concentrations
`and symptoms of thyroid disease may be complicated by the
`folloWing factors:
`[0029] 1. some symptoms of hypothyroidism may occur
`With high or normal concentrations of T4 and/or T3, and that
`some symptoms of hyperthyroidism can occur With loW or
`normal concentrations of T4 and/or T3;
`[0030] 2. Weight gain may not be reliably corrected by
`normalizing T4 and/or T3 to a euthyroid levels;
`
`[0031] 3. normalization of high T4 and/or T3 concentra
`tions may not reliably result in normalization of Weight;
`rather Weight gain often ensues despite euthyroid levels;
`[0032] 4. TSH may often be elevated With loW concentra
`tions of T4 and/or T3, and the contribution of TSH’s trophic
`effect on the thyroid gland, the resulting increased endog
`enous thyroid hormone secretion, and the body’s response to
`that changing amount has alWays been neglected When con
`sidering the cause of symptoms associated With a ‘hypothy
`roid state’;
`[0033] 5. TSH may often be loW With elevated concentra
`tions of T4 and/or T3, and the contribution of thyroid gland
`atrophy in response to loW TSH levels, the resulting
`decreased endogenous thyroid hormone secretion, and the
`body’s response to that changing amount has alWays been
`neglected When considering the cause of symptoms associ
`ated With a ‘hyperthyroid state’.
`[0034] Synthetic T4 may be currently the treatment of
`choice for hypothyroidism and/or restoration of euthyroid
`TSH, T3 and T4 concentrations. T4 may be preferred over
`synthetic and other (bovine desiccated thyroid gland for
`example) preparations containing T4 and T3 in combination,
`or T3 alone, due to the shorter half life of T3 necessitating
`multiple daily doses, and greater risk of cardiotoxicity (pal
`pitations, tachycardia, congestive heart failure and myocar
`dial infarction)ioriginally thought to be due to greater activ
`ity of T3 relative to T4 (Katzung, 1998, ch. 38). Treatment
`protocols have recently been implemented With reduced inci
`dence of cardiotoxic side effects With sustained release forms
`of T3 (Restorative Medicine, 2010), demonstrating that ?uc
`tuating T3 delivery is the cause cardiotoxicity associated With
`T3 administrations, not its increased activity relative to T4.
`[0035] Based on the previous scienti?c studies (Brunova et
`al, 2003; Ross et al, 2003; Tigas et al, 2000; Dale et al, 2000;
`Pears et al, 1990; Saravanan et al, 2002; WojeWoda, 2005;
`Cohen, 2010) current means of treating hypothyroidism With
`only supplemental T4, may differ in some Way from endog
`enous thyroid hormone delivery.
`[0036] It has been proposed that treatment target euthyroid
`free T4 concentrations may be too loW and target TSH con
`centrations may be too high. While some studies demonstrate
`positive correlations betWeen TSH and body mass index
`(BMI) and/or Waist circumference (WC), and Weak to no
`inverse correlations betWeen T4, T3, free T4, and/or free T3
`concentrations and BMI or WC (Knudsen, 2005 and Micha
`laki, 2006), other studies ?nd that no signi?cant correlations
`exist (Kim, 2008 and Chomard, 1985).
`[0037] Though it has also been proposed that T4 only
`therapy may be inadequate because T3 is present in endog
`enous production and secretion of thyroid hormone, and
`therefore must be present in suitable therapy, studies demon
`strate that psychological/ general and Weight related deviation
`from the norm, is not corrected by the use of T3 only, or T3/ T4
`combination therapy (Valizadeh, 2009; Clyde, 2003; Esco
`bar-Morreale, 2005; Siegmund, 2004; Regalbuto, 2007).
`Moreover, the ratio of T4 to T3 in endogenous production is
`greatly dominated by T4, and the secreted ratio varies Widely,
`even Within the same individual, With the ratio increasing as
`does the availability of iodine.
`[0038] T4 has amongst the longest biological half life of
`any hormone in the human body (Kronenberg, 2008). Com
`pared With other hormones that are under control from secre
`tions of the hypothalamus, thyroid hormone is secreted With
`relative constancy (Kronenberg, 2008). The thyroid gland is
`
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`one of the largest glands in the human body, has amongst the
`greatest perfusion/Weight of any organ in the human body
`(allowing for homogenous distribution of thyroid hormone
`secretions throughout the body), and is the only gland
`designed to store its secretions in colloidal spheres in such
`large amount (Cummings, 2010, ch. 123). Thyroid hormone
`is primarily secreted as a prodrug (T4), Which is deiodinated
`to a more active form (T3), also alloWing for more homog
`enous distribution of thyroid hormone effect.
`[0039] Current dosing guidelines primarily employed at
`present for thyroid hormone may be based on delivering the
`highest dose possible Without suppression of TSH and/or
`consequences of a thyrotoxic state. Currently T4 is usually
`administered once daily.
`[0040] The present inventor believes that current dosing
`causes ?uctuations in thyroid hormone volume of di stribution
`and metabolism, and suboptimal distribution of thyroid hor
`mone effect throughout the body of a patient. The inventor
`believes that as the result of such disruptions TSH becomes
`suppressed (and along With it, any endogenous thyroid hor
`mone secretion/ delivery, if present) and the consequences of
`a thyrotoxic state occur. To avoid such disruptions, the present
`inventor developed thyroid hormone formulations and deliv
`ery systems that may alloW reducing and/or minimiZing these
`?uctuations, by reducing ?uctuations in delivery of thyroid
`hormone (F). The present inventor also developed dosing/
`administering protocols for thyroid hormones that may alloW
`reducing and/ or minimiZing these ?uctuations and F.
`[0041] Optimal distribution of thyroid hormone effect, in a
`mammal, may be de?ned as the distribution of thyroid hor
`mone effect Which occurs at steady state, and homeostatic
`equilibrium, When T4 is delivered continuously at a constant
`rate, homogenously across the cross sectional area of the
`junctions of the right atrium With the superior vena cava and
`inferior vena cava.
`[0042] F can be de?ned as folloWs: f(|x—xmean|)y+W(f(|y
`(x-xmean y_1|)Z), Where f is used to denote the integral during
`a speci?ed period of time, such as the time betWeen the
`beginning of one dose and the beginning of the next, or a 24
`hour period, or a one Weekperiod, or a period of several years,
`Where x is the rate, at a given point in time, of absorption/
`delivery of bioavailable thyroid hormone into the blood
`stream throughout the entire site of absorption, of the cur
`rently administered dose and previously administered dose
`(s). In this regard, xmean is the mean of x at steady state or
`during the same speci?ed period as the integral, y and Z
`quantify the relative importance of the magnitude of the value
`to Which they are applied, and W is a coe?icient quantifying
`the relative importance of the value to Which it applies. The
`present formulations and/or delivery systems may include a
`thyroid hormone active agent that consists essentially of T4;
`hence, excluding T3. The present inventor believes the pres
`ence of T3 to be undesirable because it may prevent optimally
`achieving reduced ?uctuations (as compared With T4 alone)
`in thyroid hormone volume of distribution and metabolism,
`and because it may prevent optimal distribution of thyroid
`hormone effect, due to the short half life of T3. The present
`inventor believes that using formulations and/ or delivery sys
`tems With a thyroid hormone agent consisting essentially of
`T4 should alloW for a more accurate reproduction of thyroid
`hormone endogenous production in exogenous form, com
`pared to conventional current therapy.
`[0043] The present formulations and delivery systems may
`include a thyroid hormone active agent that consists essen
`
`tially of T4, and therefore, exclude analogues, such as struc
`tural, functional, substrate, and transition state analogues of
`T3 and T4. The present inventor believes that the presence of
`such T3 and T4 analogues may be undesirable because of the
`uncertain reactivity/ effects of these analogues, and the mini
`mal to nil presence these analogues have in endogenous
`secretion. The present inventor believes that using present
`formulations and/or delivery systems With a thyroid hormone
`agent consisting essentially of T4 may alloW achieving a more
`accurate reproduction of thyroid hormone endogenous pro
`duction in exogenous form compared to therapy With T3 and
`T4 analogues.
`[0044] Implicit in previous studies (Rangan, 2006; Bau
`hofer, 1976; Grebe, 1997) may be that reduced ?uctuation in
`delivery of thyroxine results in increased TSH, and decreased
`T4, T3, free T4 and free T3 concentrations, for a give dose per
`unit time of thyroxine. The present inventor believes that
`using present formulations and/or delivery systems With a
`thyroid hormone agent consisting essentially of T4 may alloW
`achieving greater TSH and lesser T4, T3, free T4, and free T3
`concentrations, and therefore increased thyroid hormone vol
`ume of distribution and/or metabolism, for a given dose per
`unit time of thyroxine, compared to conventional current
`therapy.
`[0045] Given the inventor’s understanding of thyroid hor
`mone function, and the diffuse constellation of symptoms and
`physiologic effects associated With hyperthyroid and
`hypothyroid states, the inventor believes that optimal physi
`ology may be reduced, and many diseases may be potentiated,
`by ?uctuation in thyroid hormone volume of distribution and
`metabolism and, therefore, by F as Well.
`[0046] The present formulations and delivery systems may
`be used for treating a condition for Which a thyroid hormone
`therapy may be useful. The present formulations may be
`administered to a subject, Which may be a vertebrate. In many
`embodiments, the subject may be a Warm-blooded animal,
`such as a mammal. In a preferred embodiment, the subject
`may be a human being. The present delivery system may be
`used for administering a thyroid hormone active agent con
`sisting essentially to a subject, Which may be a vertebrate. In
`many embodiments, the subject may be a Warm-blooded ani
`mal, such as a mammal. In a preferred embodiment, the
`subject may be a human being.
`[0047] Applications of the present invention include treat
`ing thyroid disorders such as hypothyroidism, and hyperthy
`roidism. The applications of the present formulations and/or
`delivery systems also may include reducing body fat percent
`age, increasing lean mass (including body Water and blood
`content), increasing tissue perfusion, improving the degree to
`Which thyroid hormone effect is optimally distributed, and
`one or more bene?ts thereof, ultimately fortifying the physi
`ology of a vertebrate organism, making it more resilient to
`and ameliorating the effects of: infectious, traumatic, genetic
`and polygenic multifactorial diseases, such as obesity, diabe
`tes, hypertension, hyperlipidemia, hypercholesterolemia,
`hypertriglyceridemia, atherosclerosis, atopy, asthma, integu
`mentary diseases, cardiovascular diseases, pulmonary dis
`eases, gastrointestinal diseases, musculoskeletal diseases,
`neurologic/endocannabinoid diseases, immunologic dis
`eases, nephrologic diseases, endocrine diseases, and geni
`tourinary diseases.
`[0048] Oral Forms
`[0049] The present inventor developed an oral dosage for
`mulation for thyroxine, Which may reduce/minimize ?uctua
`
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`
`tion in delivery of T4 into the bloodstream, When adminis
`tered to a subject, such as a mammal, Which may be a human.
`The oral dosage formulation disclosed in this section com
`prise a thyroid hormone active agent that consists essentially
`of thyroxine, Which means that the thyroid hormone active
`agent is 3,5,3',5' tetraiodo-L-thyronine, a salt of 3,5,3',5' tet
`raiodo-L-thyronine, a prodrug form of 3,5,3',5' tetraiodo-L
`thyronine, a salt of the prodrug form of 3,5,3',5' tetraiodo-L
`thyronine, or any combination thereof and excludes, as best as
`possible: T3 also knoWn as 3,5,3' triiodo-L-thyronine; ana
`lo gues, such as structural, functional, substrate, and transition
`state analogues of 3,5,3',5' tetraiodo-L-thyronine, and ana
`logues of 3,5,3' triiodo-L-thyronine, such as structural, func
`tional, substrate, and transition state analogues of 3,5,3' tri
`iodo-L-thyronine.
`[0050] In some embodiments, the oral dosage formulation
`may be a sustained, also knoWn as prolonged, extended or
`timed, release formulation, Which may provide a sustained
`release of thyroxine over a prolonged period of time, Which
`may be at least 3 hours, at least 4 hours, at least 5 hours, at
`least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours,
`at least 10 hours, at least 11 hours, at least 12 hours at least 13
`hours, at least 14 hours, at least 15 hours, at least 16 hours, at
`least 17 hours, at least 18 hours, at least 19 hours, at least 20
`hours, at least 21 hours, at least 22 hours, at least 23 hours or
`at least 24 hours.
`[0051] The sustained release formulation may contain a
`controlled release matrix, Which may contain a thyroid hor
`mone active agent consisting essentially of thyroxine. In
`some embodiments, the controlled release matrix may be, for
`example, a polymer matrix. In some embodiments, the con
`trolled release matrix may comprise a biodegradable mate
`rial, such as a biodegradable polymer or a biodegradable
`porous silicon. In some embodiments, the controlled release
`matrix may comprise a porous material, such as a porous
`silicon or porous silica. In such a case, the hormone active
`agent may be contained in pores of the porous material.
`[0052] “Sustained release”, “prolonged release”, and “pro
`longed action” are terms Well knoWn to those skilled in the art,
`see, eg Remington’s at pages 1676 to 1693 Other related
`terms include “controlled release” and also US. Pat. Nos.
`4,666,702 and 5,324,522.
`[0053] Sustained release dosage forms, Which may be used
`With the invention, include those described in the folloWing
`patent documents: US. Pat No. 4,795,642, US. Pat. No.
`4,851,232, US. Pat. No. 4,970,075, GB 2,219,206, US. Pat.
`No. 4,680,323, US. Pat. No. 4,357,469, US. Pat. No. 4,369,
`172, US. Pat. No. 4,389,393, US. Pat. No. 3,344,029, US.
`Pat. No. 4,012,498, US. Pat. No. 3,939,259, US. Pat. No.
`3,065,143, US. Pat. No. 5,324,522, US. Pat No. 6,200,600,
`US. Pat No. 6,500,454, US. Pat No. 6,524,615, US. Pat. No.
`7,083,808, US. Pat. No. 7,674,479, US. Pat. App. No.
`20100136109.
`[0054] The present oral forms may beused in treatment in
`place of conventional oral forms of T4, Where ever they may
`be used.
`[0055] The delivery of drugs as oral preparations in com
`bination With a delivery vehicle that confers controlled
`release is knoWn in the art. It may be desirable to formulate
`drugs in carriers that facilitate oral administration since this is
`less traumatic for subjects in need of drug treatment. In an
`effort to control drug release drug delivery vehicles have been
`designed that release an active agent in a controlled sustained
`manner resulting in a more constant supply rate of the drug
`
`into the blood stream. Means to deliver drugs in a sustained
`manner are knoWn in the art and include sloW release poly
`mers that are formulated With a drug to control its release, see
`eg US patent publication no. 20100136109.
`[0056] In some embodiments, the controlled release matrix
`may comprise drug delivery polymers, such as hydrophilic
`polymers, Which generally are knoWn in the art for alloWing
`the controlled release of active agents either by diffusion out
`of the polymer matrix or by erosion of the polymer or a
`combination thereof. Polymers may be degradable or non
`degradable but degradable may be preferred since they may
`degrade to smaller molecules that may be easily excreted.
`Examples of appropriate polymers include cellulose based
`polymers, such as hydroxypropylmethylcellulose, hydrox
`ypropyl cellulose, methyl cellulose, and sodium carboxym
`ethylcellulose; starch, including pre-gelatinised starch; poly
`methyacrylates and derivatives thereof, such as Eudragit RL
`and RS, polyvinyl pyrrolidone, polyvinyl alcohol, polyethe
`lyene glycol, [poly (lactide-co-glycolide) and polyethylene
`oxide. Polymethyl methacrylate or hydroxypropylmethylcel
`lulose may be preferred polymers.
`[0057] In some embodiments, the polymer may be a non
`hydrophilic polymer, such as Water insoluble ethyl deriva
`tives (e.g., ethyl cellulose), microcrystalline cellulose
`(Avicel), and dicalcium phosphate.
`[0058] The polymer morphology may also affect the
`release properties of the encapsulated drug and typically
`polymer matrices can be in the form of micro/nanoparticles,
`such as micro/nanospheres.
`[0059] Examples of polymers used to obtain sustained drug
`release are also provided in WO99/22724, Which describes
`the use of hydrophilic drug delivery polymers in the sustained
`release of venlafaxine; JP2006335771, Which discloses the
`use of hydroxypropylmethylcellulose in the delivery of a
`number of medicines; W001 10443, Which describes the use
`of hydroxypropylmethylcellulose in the sustained delivery of
`the anti-cancer agent camptothecin.
`[0060] The present oral forms may contain at least 0.125
`micrograms, or at least 0.25 micrograms or at least 0.5 micro
`grams or at least 1 microgram and no more than 1000 micro
`grams or any quantity Within these ranges of T4 in an indi
`vidual dose formulation, such as a tablet or a capsule.
`[0061] The present oral dose forms may be administered at
`least once per day, or at least 2 times per day, or at least 3 times
`per day, or at least 4 times per day, or at least 5 times per day,
`or at least 6 times per day, or at least 7 times per day, or at least
`8 times per day.
`[0062] In some embodiments, the oral formulation may be
`a multiparticulate formulation. Such multiparticulate formu
`lation may contain a thyroid hormone active agent consisting
`essentially of T4 in individual microparticulate units, Which
`may be contained Within a capsule. The multiparticulate for
`mulation may comprise polyvinylpyrrolidone and optionally
`one or more additional components, such as microcrystalline
`cellulose, Which may be Avicel; dicalcium phosphate; and
`lactose. In some embodiments, the multiparticulate may com
`prise polyvinylpyrrolidone and a mixture of tWo or more of
`the folloWing: microcrystalline cellulose (e. g. Avicel), dical
`cium phosphate, lactose. Polyvinylpyrrolidone may provided
`at betWeen 0.5% W/W and 5% W/W; or 1-3% W/W or at about
`1% W/W.
`[0063] The polymer release matrix may also include
`excipients that can be added to one or more polymers to
`further modify drug release, drug stability or polymer degra
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`dation kinetics or combinations thereof. For example, basic
`salts may be added to control polymer degradation thereby
`altering drug release. In some embodiments, hydrophilic
`excipients may be added that accelerate drug release.
`[0064] When administered, the medicament of the present
`invention is administered in pharmaceutically acceptable
`preparations. Such preparations may routinely contain phar
`maceutically acceptable concentrations of salt, buffering
`agents, preservatives, compatible carriers and supplementary
`potentiating agents. The preferred route of administration is
`oral.
`[0065] W