WO2008057464A2

WO2008057464A2 - Compositions and methods for improving the bioavailability of liothyronine

Info

Publication number: WO2008057464A2
Application number: PCT/US2007/023220
Authority: WO
Inventors: Michael Lamson; M. King Jolly
Original assignee: King Pharmaceuticals Research And Development, Inc.
Priority date: 2006-11-01
Filing date: 2007-11-01
Publication date: 2008-05-15
Also published as: WO2008057464A3

Abstract

The present invention is directed to sustained release pharmaceutical compositions that include a thyroid hormone, such as liothyronine or a pharmaceutically acceptable salt thereof. More specifically, the present invention is directed to sustained release pharmaceutical compositions that include liothyronine, or a pharmaceutically acceptable salt thereof that are capable of maintaining the plasma concentration of liothyronine above the baseline concentration over an extended period of time while mitigating or even eliminating the initial, acute plasma concentration peak of liothyronine, characteristic of immediate release formulations.

Description

COMPOSITIONS AND METHODS FOR IMPROVING THE BIOAVAILABILITY OF LIOTHYRONINE

FIELD OF THE INVENTION The present invention is directed to sustained release pharmaceutical compositions that include a thyroid hormone, such as liothyronine or a pharmaceutically acceptable salt thereof. More specifically, the present invention is directed to sustained release pharmaceutical compositions comprising liothyronine, or a pharmaceutically acceptable salt thereof that are capable of maintaining the plasma concentration of liothyronine above the baseline concentration of liothyronine over an extended period of time while mitigating or even eliminating the initial, acute plasma concentration peak of liothyronine, characteristic of immediate release formulations.

BACKGROUND

More than eight million Americans suffer from hypothyroidism. Hypothyroidism occurs when the thyroid gland produces insufficient amounts of thyroid hormone. Low levels of thyroid hormone can result in a slower metabolism rate, causing an individual to feel cold, run down, sluggish, and tired. Low levels of thyroid hormone can also cause hair to become brittle and skin to become dry and itchy.

It is estimated that 17% of women and 8% of men, who are 60 years of age or older, suffer from hypothyroidism. The most common cause of low thyroid production is an autoimmune disease called Hashimoto's Thyroiditis which occurs when lymphocytes make antibodies which slowly and gradually disable the hormone- producing cells in the thyroid gland. Hypothyroidism can also be caused by deficient levels of iodine in the body. For example, diets low in iodine can contribute to the development of hypothyroidism and the many serious physical and mental problems associated with it.

Unfortunately, hypothyroidism is frequently under diagnosed even though there is a simple blood test that measures the amount of thyroid stimulating hormone (TSH) in the body. A high TSH indicates that the thyroid gland is not producing sufficient amounts of thyroid hormone.

Once properly diagnosed, however, treatment is straightforward. The missing thyroid hormone is replaced with thyroxine (T4), currently available in tablet dosage form. For many patients, however, administration of thyroxine alone is insufficient, due to the body's limited capacity to convert thyroxine to liothyronine (T3), which is biologically more active than thyroxine. Research suggests that for such individuals a mixture of thyroid hormones thyroxine and liothyronine maybe a more effective form of treatment than thyroxine alone. Currently, liothyronine is available in an immediate release form under the name

Cytomel^® (King Pharmaceuticals, Inc. Bristol, TN). Though clinically useful, Cytomel , however, is not without its drawbacks. For example, administration of Cytomel^® results in an undesired, initial, acute plasma level peak of liothyronine. Such an abrupt change in the plasma level of liothyronine can cause adverse, short-term side effects such as increased heart rate, nervousness, anxiousness and irritability and long- term side effects such as a decrease in bone density. Also, when administered in an immediate release form, liothyronine has a half-life of about 10 hours and, therefore, must be administered twice daily. This twice daily administration places an added burden on patients and exposes the patient to two undesired initial, acute plasma level peaks of liothyronine.

Therefore, a sustained release pharmaceutical composition provides many advantages over conventional immediate release pharmaceutical compositions. By providing a slow and steady release of a therapeutic agent, absorbed concentration peaks are mitigated or even eliminated by affecting a smoother and more sustained blood level response. Other advantages include less frequent dosing, increased patient compliance and fewer side effects.

However, effective oral sustained release compositions of a therapeutic agent must also take into consideration any absorption window that the therapeutic agent may have. A therapeutic agent's absorption window is the area in the body where the therapeutic agent is absorbed. Some absorption windows are large and can, for example, include the entire gastrointestinal tract. Other absorption windows are small and can, for example, be limited to the duodenum or the jejunum. Thus, sustained release compositions that do not account for a therapeutic agent's absorption window and therefore, do not release the therapeutic agent within the absorption window cannot effectively deliver the therapeutic agent. Such sustained release formulations tend to pass through the absorption window of the therapeutic agent before being able to release a therapeutically effective amount of the therapeutic agent, thus allowing the plasma concentration of the therapeutic agent to return to pre-administration levels. Therefore, it is desirable in the treatment of hypothyroidism, as well as other diseases, both therapeutically and prophylactically, to provide a therapeutic agent, preferably one suitable for the treatment of hypothyroidism, in sustained release pharmaceutical compositions that provide a release rate of the therapeutic agent that mitigates any undesired, initial, acute plasma level peak, and maintains plasma level concentrations of the therapeutic agent above the pre-administration concentration levels over an extended period of time. It is also desirable to provide a therapeutic agent; preferably one suitable for the treatment of hypothyroidism, in oral sustained release pharmaceutical compositions that provide a release rate of the therapeutic agent that mitigates any undesired, initial, acute plasma level peak and is capable of releasing the therapeutic agent within the absorption window of the therapeutic agent.

SUMMARY

Definitions As used herein and unless otherwise defined, the phrase "upper gastrointestinal tract" means the portion of the gastrointestinal tract that includes the stomach and small intestine.

As used herein, and unless otherwise indicated, the phrase "baseline concentration" or "baseline plasma level" means, for subjects capable of producing any amount of liothyronine, the circulating endogenous concentration of liothyronine in a subject immediately prior to the administration of the sustained release pharmaceutical compositions of the present invention. Additionally, for subjects not capable of producing any amount of liothyronine, i.e. athyreotic subjects, who are being treated with a thyroid hormone, such as, liothyronine and/or thyroxine, the phrase "baseline concentration" or "baseline plasma level" means, the steady-state trough concentration (Cmin ss) of liothyronine.

As used herein, and unless otherwise indicated, the terms "controlled release", "sustained release" and "modified release" can be used interchangeably and are used to describe pharmaceutical compositions of the present invention wherein the release of the therapeutic agent is such that an immediate, acute plasma level peak is mitigated or eliminated as compared to immediate release pharmaceutical compositions of the same drug. As used herein, and unless otherwise indicated, the terms "individual", "subject" or "patient" can be used interchangeably and are not limited to an individual under the care of a physician. In certain embodiments, a patient is a human.

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc and organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acids. Examples of specific salts thus include hydrochloride and mesylate salts. Others are well-known in the art. See, e.g., Remington ' s Pharmaceutical Sciences (18th ed., Mack Publishing, Easton PA: 1990) and Remington: The Science and Practice of Pharmacy (19th ed., Mack Publishing, Easton PA: 1995).

As used herein, and unless otherwise specified, the phrase "optimal plasma level concentration", means a plasma level concentration of liothyronine wherein the subject no longer suffers from hypothyroidism or the symptoms associated with hypothyroidism are reduced. The optimal plasma level concentration will vary by subject and will depend, in large part, on the age, height, weight, and sex of the subject. In general, however, when testing for or monitoring hypothyroidism a TSH range between 0.5 to 5.0 uIU/ml is likely to indicate optimal plasma level concentrations of liothyronine. As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or condition, or to delay or minimize one or more symptoms associated with the disease or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the disease or condition or symptom thereof. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or eliminates symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent. The terms "treat," "treating" and "treatment," as used herein, contemplate an action that occurs while a patient is suffering from the specified disease or disorder, which reduces the severity of the disease or disorder, or retards or slows the progression of the disease or disorder.

Without being limited by theory, the inventors of the present invention have made the surprising discovery that liothyronine has an absorption window where, once administered, it is absorbed at certain points in the gastrointestinal tract as opposed to being passively absorbed throughout the entire gastrointestinal tract, as previously thought. Specifically, liothyronine is believed to be absorbed in the upper gastrointestinal tract, mainly in the duodenum and the jejunum. In view of such discovery, the present invention is directed to sustained release pharmaceutical compositions that provide a release rate of liothyronine that mitigates or even eliminates any undesired, initial, acute plasma level peak, and maintains liothyronine plasma concentrations above the baseline liothyronine plasma concentration over an extended period of time. The present invention is also directed to oral sustained release pharmaceutical compositions that provide a release rate of liothyronine that mitigates or even eliminates any undesired, initial, acute plasma level peak and is capable of releasing liothyronine within the absorption window of liothyronine.

In certain embodiments, the invention described herein includes sustained release pharmaceutical compositions comprising liothyronine, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient, wherein the composition releases a therapeutically effective amount of liothyronine over an extended period of time.

In other embodiments, the invention described herein includes sustained release pharmaceutical compositions comprising liothyronine, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient, wherein the composition releases a therapeutically effective amount of liothyronine over a period of four hours or more.

In yet other embodiments, the invention described herein includes sustained release pharmaceutical compositions comprising liothyronine, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient, wherein the plasma concentration of liothyronine remains above the baseline concentration of liothyronine for at least four hours, and wherein within two hours of administration, the plasma concentration of liothyronine does not exceed the baseline concentration of liothyronine by more than 3.5 times that of the baseline concentration of liothyronine.

In still other embodiments, the invention described herein includes sustained release pharmaceutical compositions comprising liothyronine, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient, wherein the sustained release pharmaceutical compositions release a therapeutically effective amount of the liothyronine in a period of less than about five hours after administration of the pharmaceutical composition, and wherein the C_max of the liothyronine is less than about 4 ng/ml.

In still other embodiments, the invention described herein includes sustained release pharmaceutical compositions comprising liothyronine, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition remains in the upper gastrointestinal tract over an extended period of time.

The present invention is also directed to methods of improving the bioavailability and/or the pharmacokinetic profile of liothyronine. In certain embodiments, provided herein are methods of improving the bioavailability and/or the pharmacokinetic profile of liothyronine comprising administering to a patient in need thereof a sustained release pharmaceutical composition comprising liothyronine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition releases a therapeutically effective amount of liothyronine for an extended period of time.

In other embodiments provided herein, are methods of improving the bioavailability and/or the pharmacokinetic profile of liothyronine comprising administering to a patient in need thereof a sustained release pharmaceutical composition comprising liothyronine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition remains in the upper gastrointestinal tract for an extended period of time.

In yet other embodiments provided herein, are methods of improving the bioavailability and/or the pharmacokinetic profile of liothyronine comprising administering to a patient in need thereof a sustained release pharmaceutical composition comprising liothyronine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the plasma concentration of liothyronine remains above the baseline concentration of liothyronine for at least four hours, and wherein within two hours of administration, the plasma concentration of liothyronine does not exceed the baseline concentration of liothyronine by more than 3.5 times that of the baseline concentration of liothyronine.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the mean plasma liothyronine concentration in subjects following a single dose of liothyronine in either an immediate release or sustained release dosage form.

Figure 2 shows the semi-log plot of the mean plasma liothyronine concentration in subjects following a single dose of liothyronine in either an immediate release or sustained release dosage form. Figure 3 shows the cumulative absorption of liothyronine over a period of eight hours.

Figure 4 shows the mean in vivo input rate of liothyronine over a period of 24 hours.

Figure 5 shows the mean in vivo input rate of liothyronine over a period of eight hours.

Figure 6 shows a comparison between in vivo cumulative absorption and in vitro dissolution of liothyronine over a period of eight hours.

DESCRIPTION The compositions and methods of the present invention take advantage of the inventors' discovery of the absorption window of liothyronine. Compositions described herein include liothyronine or a pharmaceutically acceptable salt thereof, wherein, once administered, the plasma concentration of liothyronine remains above the baseline concentration of liothyronine for an extended period of time. Such compositions include oral sustained release formulations, as well as, transdermal and intravenous compositions.

Certain sustained released compositions described herein take advantage of the discovery of the absorption window of liothyronine by remaining in the upper gastrointestinal tract, enabling liothyronine to be absorbed within the absorption window.

Compositions described herein can remain in the upper gastrointestinal tract by utilizing various techniques. In certain embodiments, the pharmaceutical compositions of the present invention have a density that is less than that of gastric juices; therefore, the compositions remain in the upper gastrointestinal tract by floating on gastric juices in the stomach. In other embodiments, the compositions described herein, once administered, swell or expand to a size that allows the compositions to remain in the upper gastrointestinal tract. In yet other embodiments, the compositions described herein include a bioadhesive material that enables the composition to adhere to body tissue located along the upper gastrointestinal tract, such as the tissue lining the stomach or duodenum.

Methods described herein are directed to improving the bioavailability of liothyronine by mitigating or even eliminating the undesired, acute liothyronine plasma peak that is characteristic of commercially available liothyronine formulations, as well as, releasing liothyronine so that the concentration of liothyronine remains above the baseline concentration of liothyronine. Some methods comprise administering to a patient in need thereof liothyronine compositions described herein. Liothyronine Absorption Window The inventors of the present invention have discovered that liothyronine has an absorption window, wherein liothyronine is absorbed in certain sections of the upper gastrointestinal tract as opposed to being passively absorbed throughout the entire intestinal tract, as previously believed.

The absorption window of liothyronine was determined by conducting an open- label, randomized, single-dose, 4-way, crossover pharmacokinetic study in healthy young adult (age 18-45 years) male and female volunteers. Twenty-four (24) subjects (40%-60% female) were enrolled and randomly assigned to a treatment sequence. Subjects completed a Screening Phase, a Treatment Phase consisting of 4 dosing periods, and an End of Study Phase. The Screening Phase was conducted on an outpatient basis within 30 days prior to the start of Dosing Period I.

During Dosing Period I, eligible subjects were admitted to the clinical research unit (CRU) on the evening before dosing (Day -1) and randomized to one of the following treatment sequences: Treatment A: Triostat^® 2.5 mL (25 μg per 2.5 mL) mixed with 50 mL of normal saline and infused intravenously over 15 minutes. Treatment B: Cytomel^® 50 μg (1 x50 μg tablet) administered orally with

240 mL of water. Treatment C: An 8-hour modified-release 50 μg tablet (1x50 μg tablet) administered orally with 240 mL of water. Treatment D: A 12-hour modified-release 50 μg (1x50 μg tablet) administered orally with 240 mL of water.

The Treatment Phase included serial sampling of venous blood samples (10 mL) obtained from an indwelling catheter (with saline flush as needed) or by direct venipuncture for the purpose of determining the concentrations of total T₄ and T₃ in serum. Blood samples were collected at the following times: -0.5 and -0.25 hours pre- dose, 0 hours (pre-dose), and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3, 4, 6, 8, 10, 12, 18, 24, 36, and 48 hours post-dose. Samples were allowed to clot at room temperature for 20 minutes, then processed in a refrigerated centrifuge and stored frozen (-2O⁰C) until analysis.

Vital signs, adverse event (AE) assessments, clinical laboratory assessments, ECGs, and physical examinations were done at specified times. Subjects were discharged from the CRU at the end of the 48-hour post-dosing serum sampling on Day 3, provided all available clinical assessments were completed and acceptable to the Investigator.

Following a washout period of 14 days between doses, subjects crossed-over and entered Dosing Periods II, III, and IV, and underwent the same procedures and assessments performed in Dosing Period I (excluding randomization). A final safety assessment was done at End of Study. During each dosing period, subjects were confined to the CRU for approximately 60 hours (3 nights and 2 days).

Figures 1 and 2 show the mean plasma liothyronine concentration and the semilog plot of the mean plasma liothyronine concentration in 23 volunteers following a single dose of an immediate release, intravenous dose of liothyronine (Triostat^®), an immediate release oral formulation of liothyronine (Cytomel), an 8-hour modified release oral formulation of liothyronine (MR8) and a 12-hour modified release oral formulation of liothyronine (MR12), respectively. The mean concentration profiles indicate that the oral bioavailability of liothyronine from Cytomel^® is nearly complete after three hours when compared to the reference dose of Triostat^®. The profiles also indicate that the absorption of liothyronine from the 8-hour and 12-hour modified release formulations is incomplete when compared to Triostat , with a sharp departure from the absorptive phase (indicating a fall-off in absorption) at about four hours post dose. The decline in liothyronine plasma concentrations from the modified release oral dosage forms seems to parallel the decline in liothyronine concentrations from the intravenous dose after four hours post dose, indicating that little or no drug was absorbed after about the 4-hour time point.

Figure 3 shows the cumulative absorption, i.e. the ratio of oral bioavailability to intravenous bioavailability of liothyronine, of an immediate release oral formulation of liothyronine (Cytomel^®), an 8-hour modified release oral formulation of liothyronine (MR8) and a 12-hour modified release oral formulation of liothyronine (MRl 2) over a period of eight hours. As shown in Figure 3, about 80% of the liothyronine in the immediate release formulation has been absorbed after three hours. However, only about 30% of the liothyronine in the 8-hour modified release formulation and about 20% of the liothyronine in the 12-hour modified release formulation has been absorbed after about four hours, showing that both modified release formulations exhibit little or a lack of further absorption after about four hours.

Figures 4 and 5 shows the mean in vivo input rate of an immediate release oral formulation of liothyronine (Cytomel^®), an 8-hour modified release oral formulation of liothyronine (MR8) and a 12-hour modified release oral formulation of liothyronine (MR 12) over period of 24 hour and eight hour period, respectively. Figures 4 and 5, again show that the immediate release formulation has released most of the liothyronine within a period of three hours and that most of the liothyronine has been absorbed. In contrast, little or no liothyronine from the two modified release formulations was absorbed after about four hours even though a large percent of the liothyronine had not been released after about four hours.

Figure 6 shows a comparison between in vivo cumulative absorption and in vitro dissolution of an immediate release oral formulation of liothyronine (Cytomel^®), an 8- hour modified release oral formulation of liothyronine (MR8) and a 12-hour modified release oral formulation of liothyronine (MRl 2) over a period of eight hours. As shown in Figure 6, 100% of the liothyronine in the immediate release formulation of liothyronine is released in vitro within 30 minutes and about 90% of the liothyronine is absorbed in vivo after three hours. In contrast, 100% of the 8-hour modified release formulation is released in vitro in eight hours but only about 39% is absorbed in vivo in eight hours with little or no liothyronine being absorbed in vivo after about four hours and about 60% of the 12-hour modified release formulation is released in vitro in eight hours and only about 29% of liothyronine is absorbed in vivo in eight hours with little or no liothyronine being absorbed in vivo after about four hours. Thus, supporting the observation that little or no liothyronine is absorbed after about four hours.

Additionally, Table 1 summarizes pharmacokinetic parameters of the immediate release oral formulation of liothyronine (Cytomel) the 8-hour modified release oral formulation of liothyronine (MR8) and the 12-hour modified release oral formulation of liothyronine (MR 12).

TABLE 1

As shown in Table 1, the T_max of the 8-hour modified release and the 12 hour modified release formulation was about three to four hours and only about 39% and 29% of the liothyronine was absorbed, respectively. Thus, showing that the absorption of liothyronine decreases after about four hours.

Without being held to any one theory, it is believed that the limited or lack of absorption of liothyronine after about four hours, demonstrated by Figures 1-6, and Table 1 can be explained by liothyronine having an absorption window, wherein liothyronine is absorbed in the upper gastrointestinal tract. In the fasted state, the stomach exhibits cyclic activity wherein between about every about 60-120 minutes the stomach is swept clean of any particles. Then, under normal conditions material can take between 2-3 hours to pass through the small intestine. Thus, a pharmaceutical dosage form can pass through the stomach and small intestine between about 3 to 5 hours. Therefore, it is believed that since the above study demonstrates that even though the modified release dosage forms were capable of releasing liothyronine over a period of eight and 12 hours, but yet there was little or no absorption of liothyronine after a four hour period, the modified release dosage forms were being passed through the upper gastrointestinal tract in about four hours. Therefore, since the modified release dosage forms could no longer release liothyronine within the absorption window after the modified dosage forms were passed through the upper gastrointestinal tract, no additional liothyronine could be absorbed and one would expect to see the plasma concentration to fall back to the baseline concentration. Compositions

The sustained release pharmaceutical compositions described herein comprise liothyronine or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof. Liothyronine is the synthetic form of a natural hormone. The preferred form of liothyronine is a liothyronine salt and, in the present invention, the preferred salt is liothyronine sodium.

The sustained release pharmaceutical compositions of the present invention can contain about 0.001% to about 10% of liothyronine by weight. Preferably, the compositions of the present invention contain about 0.01% to about 1% of liothyronine by weight. More preferably, the compositions of the present invention contain about 0.01 % to about 0.06% of liothyronine by weight.

The pharmaceutical compositions of the present invention may contain any therapeutically effective amount of liothyronine, such as from about 0.001 μg or less to about 200 μg or more, or preferably from about 0.01 μg to about 100 μg or preferably from about 0.1 μg to about 50 μg. Preferably, the dosage will be 5 μg, 10 μg, 25 μg or 50 μg.

Though the present invention encompasses sustained release pharmaceutical compositions of liothyronine and pharmaceutical salts thereof, the present invention is not limited to sustained release pharmaceutical compositions of liothyronine. The sustained release pharmaceutical compositions of the present invention can also be used in connection with other active pharmaceutical ingredients ("APIs"), such as other hormones (either natural or synthetic) and, in particular, other thyroid hormones. Examples of other thyroid hormones include, but are not limited to, L-thyroxine and triiodothyronine. The sustained release liothyronine pharmaceutical compositions described herein mitigate or even eliminate the initial plasma concentration peak exhibited by immediate release formulations, as well as, maintain the plasma level of liothyronine above the baseline level of liothyronine over an extended period of time. The present invention is directed towards sustained release pharmaceutical compositions that release liothyronine over an extended period of time. An extended period of time can be greater than two hours, greater than four hours, greater than six hours, greater than eight hours, greater than twelve hours, greater than sixteen hours, greater than twenty hours or greater than twenty four hours. In certain embodiments, the pharmaceutical compositions of the present invention release a therapeutically effective amount of liothyronine over a period of 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 hours or longer. Preferred pharmaceutical compositions release an effective amount of liothyronine over a period of 8, 12, 20 or 24 hours. For example, the sustained release pharmaceutical compositions described herein include a sustained release pharmaceutical composition comprising liothyronine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the composition releases a therapeutically effective amount of liothyronine over a period of four hours or longer.

Without being limited to theory, it is believed that in certain embodiments, the pharmaceutical compositions described herein achieve the desired pharmacokinetic (pK) profiles by releasing a therapeutic amount of liothyronine within the absorption window of liothyronine. The sustained release pharmaceutical compositions of the present invention can release liothyronine, or a pharmaceutically acceptable salt thereof, in the upper gastrointestinal tract over an extended period of time so that the liothyronine is absorbed within the absorption window of liothyronine. The compositions described herein can release the liothyronine, or a pharmaceutically salt thereof, within any portion of the absorption window of liothyronine, the stomach or any portion of the small intestine, including the duodenum, jejunum and the ileum.

The sustained release pharmaceutical compositions of the present invention can release at least about 60%-95% of the liothyronine or a pharmaceutically acceptable salt thereof over an extended period of time. For example, pharmaceutical compositions of the present invention can release about 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of the liothyronine, or a pharmaceutically acceptable salt thereof, over an extended period of time. In certain embodiments, the sustained release pharmaceutical compositions of the present invention can release 80% of the liothyronine, or a pharmaceutically acceptable salt thereof, over a period of about 8, 12, 15, 17, 19, 20, 22, or 24 hours. In other embodiments, the sustained release pharmaceutical compositions of the present invention can release 85% of the liothyronine or a pharmaceutically acceptable salt thereof, over a period of about 8, 12, 15, 17, 19, 20, 22, or 24 hours. In certain embodiments, the release rate of liothyronine from the sustained release pharmaceutical compositions can be about 0.001 μg/hour to about 100 μg/hour of liothyronine. In other embodiments, the release rate of liothyronine from the sustained release pharmaceutical compositions can be about 0.01 μg/hour to about 10 μg/hour, or about 0.1 μg/hour to about 10 μg/hour, or about 1 μg/hour to about 5 μg/hour.

Additionally, the release of liothyronine from the sustained release pharmaceutical compositions can follow zero-order or first order kinetics. Zero-order kinetics is attained by a constant rate of release of liothyronine, while first-order kinetics is attained by an initial fast release rate which is followed by a slower release rate.

The sustained release pharmaceutical compositions described herein also include compositions comprising liothyronine, or a pharmaceutically acceptable salt thereof, wherein the composition remains in the upper gastrointestinal tract over an extended period of time, including the stomach, or any portion of the small intestine including the duodenum, jejunum and the ileum.

The pharmaceutical compositions of the present invention can remain in the upper gastrointestinal tract for greater than two hours, greater than four hours, greater than six hours, greater than eight hours, greater than twelve hours, greater than sixteen hours, greater than twenty hours or greater than twenty four hours. In certain embodiments, the pharmaceutical compositions of the present invention can remain in the upper gastrointestinal tract over a period of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 hours or longer. Preferred pharmaceutical compositions can remain in the upper gastrointestinal tract over a period of 4, 8, 12, 20 or 24 hours. The sustained release pharmaceutical compositions described herein also include compositions comprising liothyronine or pharmaceutically acceptable salt thereof, wherein, when administered, provide a plasma concentration of liothyronine that remains above the baseline concentration of liothyronine over an extended period of time. An extended period of time wherein plasma concentration of liothyronine remains above the baseline concentration of liothyronine can be greater than two hours, greater than four hours, greater than six hours, greater than eight hours, greater than twelve hours, greater than sixteen hours, greater than twenty hours or greater than twenty four hours. In certain embodiments, the plasma concentration of liothyronine remains above the baseline over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 hours or longer upon administration of the pharmaceutical compositions described herein.

Additionally, the sustained release pharmaceutical compositions of the present invention can release liothyronine such that the initial liothyronine plasma concentration peak that is characteristic of currently available immediate release liothyronine formulations is mitigated or even eliminated. In certain embodiments, the C_maχ of the liothyronine is at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% less than that of commercially available immediate release dosage forms of liothyronine, such as Cytomel®. In certain embodiments, the sustained release pharmaceutical compositions of the present invention can release liothyronine such that the C_max of the sustained released liothyronine compositions described herein is less than about 4 ng/ml, less than about 3.5 ng/ml, less than about 3 ng/ml, less than about 2.5 ng/ml. For example, the pharmaceutical compositions of the present invention can release a therapeutically effective amount of liothyronine in a period five hours or less after the administration of the pharmaceutical composition, wherein the C_max of the liothyronine is less than about 4 ng/ml. It should be noted that though the plasma concentration of liothyronine is expressed in units of ng/ml, the plasma concentration can also be expressed in other units. For example, 4 ng/ml can also be expressed as 400 ng/100 ml, 400 ng/dL or 400 ng%.

In other embodiments, within 1 hour of administration of a pharmaceutical composition of the present invention, the plasma concentration of liothyronine does not exceed the baseline concentration of liothyronine by more than 3.5 times that of the baseline concentration. In other embodiments, within 1 hour of administration, the concentration of liothyronine does not exceed the baseline concentration of liothyronine by more than 3.0 times, or more than 2.5 times, or more than 2.0 times, or more than 1.5, or more than 1.0 times that of the baseline concentration of liothyronine.

In other embodiments, within two hours of administration of the pharmaceutical compositions of the present invention, the plasma concentration of liothyronine does not exceed the baseline concentration of liothyronine by more than 3.5 times that of the baseline concentration. In other embodiments, within two hours of administration, the concentration of liothyronine does not exceed the baseline concentration of liothyronine by more than 3.0 times, or more than 2.5 times, or more than 2.0 times, or more than 1.5, or more than 1.0 times that of the baseline concentration of liothyronine.

Additionally, the sustained release compositions of the present invention are directed to compositions of liothyronine that have an improved pharmacokinetic profile

® as compared to currently available immediate release formulations, such as Cytomel .

In certain embodiments, the pharmaceutical compositions of the present invention can have the same AUC (i.e. area under the plasma curve) but have a lower C_maχ or a delayed T_max or both as compared to currently available immediate release formulations. In other embodiments, the pharmaceutical compositions of the present invention can have a similar AUC but have a lower C_max or a delayed T_max or both as compared to currently available immediate release formulations. In such embodiments, the AUC of the pharmaceutical compositions described herein can be within 1%, 5%, 10% or 20% of

® the AUC of currently available immediate release formulations, such as Cytomel . In alternative embodiments, the pharmaceutical compositions of the present invention can have a different AUC, as well as, a lower C_max or a delayed T_max or both as compared to currently available immediate release formulations. In such embodiments, the AUC of the pharmaceutical compositions described herein can be within 30%, 40%, 50%, 60%,

70%, 80%, 90% of the AUC of currently available immediate release formulations, such

® as Cytomel .

Additionally, the sustained release compositions of the present invention are directed to compositions of liothyronine that have the same or similar AUC of liothyronine as compared to currently available immediate release formulations, such as Cytomel^®, but have the added advantage of reducing the frequency or intensity of the side effects observed with immediate release formulations. Such side effects include, but are not limited to, short-term side effects such as increased heart rate, nervousness, anxiousness and irritability and long-term side effects such as a decrease in bone density. In certain embodiments, the AUC of the pharmaceutical compositions described herein can be the same i.e. equal to currently available immediate release

® formulations, such as Cytomel . Sustained release pharmaceutical compositions of the present invention also reduce fluctuations of liothyronine plasma concentrations during treatment as compared with currently available immediate release liothyronine formulations. Also, the sustained release pharmaceutical compositions of the present invention are designed to achieve an optimal plasma level concentration of liothyronine and reduce or eliminate undesired plasma level fluctuations above or below the subject's optimal plasma level concentration of liothyronine. In most subjects the optimal plasma level concentration of liothyronine is 80-180 ng/dL. In certain embodiments, the pharmaceutical compositions of the present invention, prevent or reduce plasma level concentration fluctuations that exceed 80%, 75%, 70%, 65%, 60% or 55%, 50%, 45%, 40%, 35%,

30%, 35%, 20%, 25%, 20%, 15%, 10%, 5% of the optimal plasma level concentration of liothyronine.

In certain embodiments, after 1 hour after administration of the pharmaceutical compositions of the present invention, the plasma concentration of liothyronine does not fluctuate more than 80%, 75%, 70%, 65%, 60% or 55% per hour. In other embodiments, the plasma concentration of liothyronine does not fluctuate more than 50% per hour. For example, if 1 hour after administration of the pharmaceutical compositions of the present invention, the liothyronine concentration is 0.209 ng/ml, then the plasma concentration of liothyronine at two hours after administration will be between 0.104 ng/ml to 0.314 ng/ml. In other embodiments, 1 hour post administration of the pharmaceutical compositions of the present invention, the plasma concentration of liothyronine does not fluctuate more than 45%, 40%, 35%, 30%, 35%, 20%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2% or 1% per hour.

In some embodiments of the present invention, 1 hour post administration of the pharmaceutical compositions of the present invention, the plasma concentration of liothyronine does not fluctuate more than ± 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1 or 0.5 ng/dL/hr. In other embodiments, 1 hour post administration of the pharmaceutical compositions of the present invention, the plasma concentration of liothyronine does not fluctuate more than ± 50, 45, 40, 35, 30, 25, 20, 15, or 10 ng/dL/hr. Additionally, the sustained release compositions of the present invention are directed to compositions of liothyronine that are able to delay the C_max of liothyronine as compared to currently available immediate release formulations. The C_max of liothyronine can occur at least 1, 2, 3, 4, 5, 6, 7, 8 hours or more after administration of the pharmaceutical compositions of the present invention. In certain embodiments the C_1113x of liothyronine occurs about 3 to 8 hours after administration of the pharmaceutical compositions of the present invention. In preferred embodiments of the present invention the C_max of liothyronine occurs about 3, 4 or 5 hours after administration of the pharmaceutical compositions of the present invention. The sustained release compositions of the present invention are also directed to compositions of liothyronine that are able to prolong the T_max of liothyronine. T_max is the time at which C_maχ is achieved. The T_max of liothyronine can be greater than one hour post administration. In certain embodiments the T_max can be greater than 2, 3, 4, 5, 6, 7 or 8 hours post administration. In other embodiments the T_max can be greater than 10, 12, 16, 24, 36 or 48 hours post administration of the sustained release compositions of the present invention. Ideally the T_max of liothyronine occurs between 6 to 12 hours post administration of the sustained release compositions of the present inventions. In some preferred embodiments the T_max of liothyronine occurs between two to four hours post administration of the sustained release composition of the present invention. Sustained release pharmaceutical compositions described herein can also reduce the frequency or eliminate the occurrence of undesirable side effects. Such undesirable side effects include adverse cardiac effects. Such adverse cardiac effects include, but are not limited to, fluctuations in heart rate, fast or irregular heartbeat, heart palpitations, increased blood pressure, increased risk of heart attack, chest pain, and congestive heart failure. Other undesirable side effects may include headaches, skin rash or hives, confusion, mood swings, irritability, muscle weakness, psychosis, restlessness, nervousness, sweating, sensitivity to heat, anxiousness, excessive sweating, flushing, shortness of breath, osteoporosis and deceased bone density.

Upon administration of the sustained release compositions of the present invention, the frequency of such undesirable side effects can be reduced by about 10% or more, as compared to currently available immediate release formulations. In certain embodiments, the frequency of undesirable side effects can be reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%, as compared to immediate release formulations of liothyronine. For some side effects, a reduction in the frequency or occurrence of undesirable side effects associated with immediate release formulations can be measured within the first hour post administration of the sustained release formulations of the present invention. As for other side effects a reduction in side effects can be measured within 24 or 48 hours, or longer post administration of the sustained release formulations of the present invention.

The reduction in frequency or elimination of the occurrence of undesirable side effects can be measured by any means known in the art. For example scales similar to the Crooks scale and the Klein Hyperthyroid Symptom Scale, which are used to measure hyperthyroidism symptoms, can be used to measure a reduction of the undesirable side effects associated with currently available immediate release liothyronine formulations. See Klein el al., Symptom Rating Scale for Assessing Hyperthyroidism, 148 Arch. Intern. Med. 387(1988). Also, side effects such as increased blood pressure and fluctuations in heart rate can be measured directly using methods known in the art. Excipients

Pharmaceutical compositions of the present invention may also include at least one pharmaceutically acceptable excipient. Suitable pharmaceutically acceptable excipients include, but are not limited to, polymers, diluents, binders, glidants, vehicles, carriers, disintegrating agents, lubricants, swelling agents, solubilizing agents, wicking agents, cooling agents, preservatives, stabilizers, sweeteners, flavors, etc. While any pharmaceutically acceptable excipient is contemplated by the present invention, it should be understood that the excipient(s) selected for formulating with liothyronine should not defeat the sustained release objectives of the present invention. Examples of suitable polymers include, but are not limited to, polysaccharides, celluloses, and organic moieties such as polyvinyl pyrrolidines and plastics.

Examples of celluloses include, but are not limited to, hydroxypropylcellulose, hydroxypropylmethylcellulose (a.k.a. hypromellose), hydroxyethylcellulose, ethylcellulose, cellulose acetate phthalate, cellulose acetate, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxylpropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methylcellulose acetate succinate phthalate, hydroxypropyl methyl cellulose succinate phthalate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimelllitate succinate, cellulose propionate trimellitate, cellulose butryrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridine dicarboxylate, salicylic acid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic acid, cellulose acetate, ethyl picolinic acid cellulose acetate. These polymers can be used individually or in combination. Other polymers that may be suitable for use with the present invention include, but are not limited to, acrylate and methacrylate copolymers. Exemplary commercial grades of such copolymers include the EUDRAGIT^® series.

Other suitable polymers include, but are not limited to, proteins such as gelatin and albumin; starches such as carboxylic acid functionalized starches, starch glycolate, and cross-linked high amylose starch such as CONTRAMID^®; carboxylic acid functionalized polymethyacrylates; carboxylic acid functionalized polyacrylate; amine- functionalized polyacrylates; amine-functionalized polymethacrylates; vinyl polymers and copolymers having at least one substituent selected from the group consisting of hydroxyl, alkylacyloxy, and cyclicamido; polyvinyl alcohols that have at least a portion of their repeat units in the unhydrolyzed (vinyl acetate) form; polyvinyl alcohol polyvinyl acetate copolymers; polyvinyl acetate phthalate; polyvinyl pyrrolidone; polyethylene polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene copolymers, polyethylene oxide, alkylacyloxy-containing repeat units, or cyclicamido- containing repeat units; polyvinyl alcohols that have at least a portion of their repeat units in the unhydrolyzed form; polyvinyl alcohol polyvinyl acetate copolymers; polyethylene glycol, polyethylene glycol polypropylene glycol copolymers, polyvinyl pyrrolidone polyethylene polyvinyl alcohol copolymers, and polyoxyethylene- polyoxypropylene block copolymers.

In certain embodiments, the preferred polymer is hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxymethyl cellulose, ethyl cellulose or a combination thereof. In other embodiments of the invention of the present invention the pharmaceutical composition includes hydroxypropyl methylcellulose and polyethylene oxide. Suitable combinations of hydroxypropyl methylcellulose and polyethylene oxide can be found in U.S. Patent 6,723,340 incorporated herein by reference. The sustained release pharmaceutical compositions of the present invention can contain about 1% to about 99% of polymer by weight, or between 10% to about 90% of polymer by weight, or between about 20% to about 80% of polymer by weight, or between about 30% to about 70% of polymer by weight, or between about 40% or about 60% of polymer by weight.

In certain embodiments of the present invention, the pharmaceutical compositions can contain about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of polymer by weight.

Examples of stabilizers or preservatives include, but are not limited to, parahydroxybenzoic acid alkyl esters, antioxidants, antifungal agents, and other stabilizers/preservatives known in the art.

Examples of coloring agents include, but are not limited to, water soluble dye, Aluminum Lake, ion oxide, natural colors, titanium oxide, and the like. Suitable Aluminum Lake coloring agents include, but are not limited to, FD&C Blue #1 Aluminum Lake, FD&C Red #30 Aluminum Lake, FD&C Red #40 Aluminum Lake, FD&C Yellow #6 Aluminum Lake, FD&C Yellow #10 Aluminum Lake or combinations thereof.

Examples of diluents or fillers include, but are not limited to, water-soluble and/or water-insoluble tabletting fillers. The water-soluble diluent agent may be constituted from a polyol of less than 13 carbon atoms, in the form of directly compressible material (the mean particle size being about 100 and about 500 microns), in the form of a powder (the mean particle size being less than about 100 microns) or a mixture thereof. The polyol is preferably chosen from the group comprising of mannitol, xylitol, sorbitol and maltitol. The water-insoluble filler maybe a cellulosic derivative, such as, microcrystalline cellulose or a starch, such as, pre-gelatinized starch. Preferred diluents are lactose monohydrate, microcrystalline cellulose, silicified microcrystalline cellulose, calcium sulfate and magnesium oxide.

Examples of disintegrating agents include, but are not limited to, cross-linked sodium carboxymethylcellulose, crospovidone and their mixtures. Examples of lubricating agents include, but are not limited to, magnesium stearate, stearic acid and its pharmaceutically acceptable alkali metal salts, sodium stearyl fumarate, Macrogol 6000, glyceryl behenate, talc, colloidal silicon dioxide, calcium stearate, sodium stearate, Cab-O-Sil, Syloid, sodium lauryl sulfate, sodium chloride, magnesium lauryl sulfate, talc and mixtures thereof. Examples of swelling agents include, but are not limited to, starches; polymers; cellulosic materials such as, microcrystalline cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose and ethyl cellulose; waxes such as, bees wax; natural materials, such as, gums and gelatins; or mixtures of any of the above. Examples of glidants include, but are not limited to, silicone dioxide.

A flavoring may be advantageously chosen to give a combination of fast onset and long-lasting sweet taste and get a "round feeling" in the mouth with different textures or additives. Cooling agents can also be added in order to improve the mouth feeling and provide a synergy with flavors and sweetness. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets or capsules may be coated with shellac, sugar or both. Administration

Pharmaceutical compositions of the invention comprise liothyronine, or a pharmaceutically acceptable salt, which can be effectively administered to patients by various routes. Examples of routes of administration include parenteral (e.g., subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, intradermal, intraperitoneal, intraportal, intra-arterial, intrathecal, transmucosal, intra-articular, and intrapleural,), transdermal (i.e., topical), epidural, and mucosal (e.g., intranasal) injection or infusion, as well as oral, inhalation, pulmonary, and rectal administration. The compositions of the present invention can take the form of solutions, suspensions, emulsions, tablets, caplets, capsules, powders, granules, beads and patches depending on the route of administration.

Oral pharmaceutical compositions of the present invention are generally in the form of individualized or multiunit doses, such as coated or uncoated tablets, caplets or capsules. When the pharmaceutical compositions of the present invention are formed into tablets or caplets, it is to be understood that the tablets or caplets may be scored, and that they may be of any suitable shape and size, such as round, square, rectangular, oval, diamond, pentagon, hexagon or triangular, so long as the objectives of the present invention are not defeated. In certain embodiments of the present invention, the pharmaceutical composition is a tablet, caplet or capsule that swells upon exposure to gastric juices or other aqueous medium which allows the composition to remain in the upper gastrointestinal tract over an extended period of time. Tablets or caplets can be single layer, bilayer or multilayer tablet of caplets. In the case of bilayer or multilayer tablets or caplets one, two or more layers can swell. Examples of suitable swelling tablets are disclosed in U.S. Patent No. 6,488,962 to Berner et al. and U.S. Patent No. 6,797,283 to Edgren et al, both of which are incorporated by reference in their entirety.

In certain embodiments, the composition can swell to a length of about 3 mm to about 50 mm and a width of about 3 mm to about 50 mm.

In other embodiments of the present invention, the pharmaceutical composition is a tablet or caplet that has a density of less than 1 g/ml so that the composition floats on gastric juices or other aqueous medium such that the composition remains in the upper gastrointestinal tract. The pharmaceutical compositions of the present invention can also be in the form of granules or beads that once released in the upper gastrointestinal tract get trapped in the folds of the small intestine and release liothyronine in the upper gastrointestinal tract.

In still other embodiments of the present invention, the pharmaceutical composition can comprise a bioadhesive material that is capable of adhering to the lining of the stomach, duodenum or the jejunum and release liothyronine in the upper gastrointestinal tract.

The pharmaceutical compositions described herein can be administered to a patient in the fed or fasted state. Additionally, the pharmaceutical compositions described herein can be taken at any time of the day, with or without food. In certain embodiments, the compositions described herein are administered to a patient in the fasted state. For example, the pharmaceutical compositions can be administered to a patient prior to going to bed, for the sustained, overnight release of liothyronine while the patient is in a fasted state.

The pharmaceutical compositions described herein can be administered, multiple times a day, once daily, weekly, or monthly. Pharmaceutical compositions of the present invention can be administered to a patient such that the patient receives from about 0.001 μg/day or less to about 200 μg/day or more, or preferably from about 0.01 μg/day to about 100 μg/day or preferably from about 0.1 μg/day to about 50 μg/day of liothyronine. Preferably, the dosage will be 1 μg/day, 5 μg/day, 10 μg/day, 25 μg/day or 50 μg/day of liothyronine. Methods of Use

The present invention also provides methods for improving the bioavailability of liothyronine. In certain embodiments, provided herein are methods of improving the bioavailability of liothyronine, or a pharmaceutically acceptable salt thereof, comprising administering to a patient in need thereof a sustained released pharmaceutical composition comprising liothyronine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the composition releases liothyronine over an extended period of time. In other embodiments, provided herein are methods of improving the bioavailability of liothyronine comprising administering to a patient in need thereof a sustained released pharmaceutical composition comprising liothyronine, or a pharmaceutically acceptable salt thereof, wherein the plasma concentration of liothyronine remains above the baseline concentration of liothyronine for a period of at least four hours, and wherein within two hours of administration, the plasma concentration of liothyronine does not exceed the baseline concentration of liothyronine by more than 3.5 times that of the baseline concentration of liothyronine.

The present invention is also directed to methods of preventing, treating and managing disease and conditions caused by deficient thyroid hormone, including, but not limited to, thyroid hormone deficiency and hypothyroidism. Additionally, preferred pharmaceutical compositions of the present invention can be administered to a patient to treat or prevent congestive heart failure (CHF) comprising administering a sustained release pharmaceutical composition described herein to a patient in need thereof. The description contained herein is for purposes of illustration and not for purposes of limitation. Changes and modifications may be made to the embodiments of the description and still be within the scope of the invention. Furthermore, obvious changes, modifications or variations will occur to those skilled in the art. Also, all references cited above are incorporated herein, in their entirety, for all purposes related to this disclosure.

Claims

WHAT IS CLAIMED:

1. A sustained release pharmaceutical composition comprising: liothyronine or a pharmaceutically acceptable salt thereof, wherein the plasma concentration of liothyronine in a human remains above the baseline concentration of liothyronine for a period of at least four hours, and wherein within two hours of administration to a human, the plasma concentration of liothyronine does not exceed the baseline concentration of liothyronine by more than 3.5 times that of the baseline concentration of liothyronine.

2. The pharmaceutical composition of claim 1, wherein the plasma concentration of liothyronine remains above the baseline concentration of liothyronine for a period of at least eight hours.

3. The pharmaceutical composition of claim 1, wherein the plasma concentration of liothyronine remains above the baseline concentration of liothyronine for a period of at least twelve hours.

4. The pharmaceutical composition of claim 1, wherein the plasma concentration of liothyronine remains above the baseline concentration of liothyronine for a period of at least twenty hours.

5. The pharmaceutical composition of claim 1, wherein within 1 hour of administration of the pharmaceutical composition, the plasma concentration of liothyronine does not exceed the baseline concentration of liothyronine by more than 3.5 times that of the baseline concentration.

6. The pharmaceutical composition of claim 1, wherein upon administration, the plasma concentration of liothyronine does not exceed the baseline concentration by more than 3 times that of the baseline concentration.

7. The pharmaceutical composition of claim 1 , wherein upon administration, the plasma concentration of liothyronine does not exceed the baseline concentration by more than 2.5 times that of the baseline concentration.

8. The pharmaceutical composition of claim 1, wherein upon administration, the plasma concentration of liothyronine does not exceed the baseline concentration by more than two times that of the baseline concentration.

9. The pharmaceutical composition of claim 1, wherein upon administration, the plasma concentration of liothyronine does not exceed the baseline concentration by more than 1.5 times that of the baseline concentration.

10. The pharmaceutical composition of claim 1 , wherein the amount of liothyronine is between about 1 μg to 100 μg.

1 1. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of liothyronine is liothyronine sodium.

12. The pharmaceutical composition of claim 1, wherein the route of administration of the pharmaceutical composition is oral, transdermal, or intravenous.

13. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is in the form of a tablet, caplet or capsule.

14. A sustained release pharmaceutical composition comprising: liothyronine or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient, wherein the sustained release pharmaceutical composition releases a therapeutically effective amount of the liothyronine in a period of less than about five hours after administration of the pharmaceutical composition to a human, and wherein the C_max of the liothyronine is less than about 4 ng/ml.

15. The pharmaceutical composition of claim 14, wherein the amount of liothyronine is between about 1 μg to 100 μg.

16. The pharmaceutical composition of claim 14, wherein the pharmaceutically acceptable salt of liothyronine is liothyronine sodium.

17. The pharmaceutical composition of claim 14, wherein the C_max of the liothyronine is less than about 3.5 ng/ml.

18. The pharmaceutical composition of claim 14, wherein the C_max of the liothyronine is less than about 3 ng/ml.

19. The pharmaceutical composition of claim 14, wherein the C_max of the liothyronine is less than about 2.5 ng/ml.

20. The pharmaceutical composition of claim 14, wherein within two hours of administration, the plasma concentration of liothyronine does not exceed the baseline concentration of liothyronine by more than 3.5 times that of the baseline concentration.

21. The pharmaceutical composition of claim 14, wherein within 1 hour of administration of the pharmaceutical composition, the plasma concentration of liothyronine does not exceed the baseline concentration of liothyronine by more than 3.5 times that of the baseline concentration.

22. The pharmaceutical composition of claim 14, wherein upon administration, the plasma concentration of liothyronine does not exceed the baseline concentration by more than 3 times that of the baseline concentration.

23. The pharmaceutical composition of claim 14, wherein upon administration, the plasma concentration of liothyronine does not exceed the baseline concentration by more than 2.5 times that of the baseline concentration.

24. The pharmaceutical composition of claim 14, wherein upon administration, the plasma concentration of liothyronine does not exceed the baseline concentration by more than two times that of the baseline concentration.

25. The pharmaceutical composition of claim 14, wherein upon administration, the plasma concentration of liothyronine does not exceed the baseline concentration by more than 1.5 times that of the baseline concentration.