DESC:TECHNICAL FIELD OF THE INVENTION
The invention relates to a solid oral pharmaceutical composition comprising liothyronine or pharmaceutically acceptable salt thereof, an antioxidant and one or more pharmaceutically acceptable excipients, wherein said pharmaceutical composition has water activity ranging from about 0.4 to about 0.75, measured at 25°C. The invention also relates to a process of preparation of such composition.
BACKGROUND OF INVENTION
Hypothyroidism is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as poor ability to tolerate cold, a feeling of tiredness, constipation, depression, and weight gain. Occasionally there may be swelling of the front part of the neck due to goitre.
In young and otherwise healthy people with overt hypothyroidism, a full replacement dose (adjusted by weight) can be started immediately; in the elderly and people with heart disease a lower starting dose is recommended to prevent over supplementation and risk of complications. Lower doses may be sufficient in those with subclinical hypothyroidism, while people with central hypothyroidism may require a higher than average dose.
Thyroid hormone drugs are natural or synthetic preparations containing tetraiodothyronine (T4, levothyroxine) sodium or triiodothyronine (T3, liothyronine) sodium or both. T4 and T3 are produced in the human thyroid gland by the iodination and coupling of the amino acid tyrosine. T4 contains four iodine atoms and is formed by the coupling of two molecules of diiodotyrosine (DIT). T3 contains three atoms of iodine and is formed by the coupling of one molecule of DIT with one molecule of monoiodotyrosine (MIT). Both hormones are stored in the thyroid colloid as thyroglobulin.
Liothyronine is used to treat an underactive thyroid (hypothyroidism). It replaces or provides more thyroid hormone, which is normally made by the thyroid gland. Liothyronine is a man-made form of thyroid hormone. Low thyroid hormone levels can occur naturally or when the thyroid gland is injured by radiation/medications or removed by surgery. It is marketed as the sodium salt under the brand name Cytomel®.
Liothyronine sodium is described chemically as sodium (S)-2-amino-3-[4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]propanoate. The molecular formula is
C15H11I3NNaO4 and the molecular weight is 672.96 gm/mole. The chemical structure of liothyronine sodium is:

In the Federal Register Vol. 62, No. 157, Aug. 14, 1997; page 43535, the Department of Health and Human. Services, Food and Drug Administration, published the facts that the products available on the U.S. market which comprise levothyroxine sodium and are orally administered have stability problems and therefore must be present in an up to 20% excess dose and that manufacturers must develop appropriate novel administration forms.
U.S.Patent No. 5,225,204 proposed to use water-soluble polyvinylpyrrolidone in addition to the respective sodium salts and adsorb the resulting mixture on a cellulose carrier to form a tablet, powder or capsule. In U.S. Patent No. 5,635,209, also sodium iodide as well as a wetting agent and a lubricant are used in addition to the sodium salt of levothyroxine. In U.S. Patent No. 5,958,979, sodium thiosulfate is proposed as a stabilizing component. From U.S. Patent No. 6,399,101 it can be taken that the use of siliconized microcrystalline cellulose is to be of advantage. U.S. Patent No. 8,293,272 discloses composition of levothyroxine compounds with certain adjusted water activity values of composition. Another thyroxine-containing formulation which contains thyroxine/cyclodextrin complexes is described in WO 1997/19703. Thyroxine-containing preparations with other additives such as glycine, a carbohydrate and an inorganic salt are disclosed in WO 1997/17951. WO 03/041699 discloses combination of levothyroxine active drug with antioxidant butylated hydroxyanisole. WO 2014/029464 discloses liothyronine sodium composition with tocopherol as antioxidant.
The inventors of the invention have overcome the stability problems of thyroxine compounds. The inventors have surprisingly found that preparation of a pharmaceutical composition comprising thyroxine compound along with an antioxidant and specific water activity provides a stable composition.
SUMMARY OF THE INVENTION
In an aspect, there is provided a solid oral pharmaceutical composition comprising i) liothyronine or pharmaceutically acceptable salt thereof, ii) an antioxidant and iii) one or more pharmaceutically acceptable excipients.
In another aspect, there is provided a solid, oral pharmaceutical composition comprising (a) about 0.01 % w/w to about 0.05 % w/w of liothyronine or a pharmaceutically acceptable salt thereof; (b) about 0.05% % w/w to about 0.25 % w/w of an antioxidant selected from a group consisting of alpha tocopherol, ascorbic acid, sodium metabisulfite, butylated hydroxyanisole and butylated hydroxytoluene; and (c) one or more pharmaceutically acceptable excipients; wherein the weight ratio of liothyronine to the antioxidant is in the range of about 1:1 to about 1:9, and wherein said pharmaceutical composition has water activity ranging from about 0.4 to about 0.75, measured at 25°C.
In another aspect, there is provided a solid oral pharmaceutical composition comprising i) liothyronine or pharmaceutically acceptable salt thereof, ii) an antioxidant and iii) one or more pharmaceutically acceptable excipients; wherein said pharmaceutical composition has water activity ranging from about 0.45 to about 0.7 measured at 25°C.
In another aspect, there is provided a pharmaceutical composition, wherein amount of liothyronine present in the composition is in the range of about 0.01% w/w to about 0.05 % w/w of the composition.
In another aspect, there is provided a pharmaceutical composition, wherein amount of antioxidant present in the composition is in the range of about 0.05% w/w to about 0.25 % w/w of the composition.
In another aspect, there is provided a pharmaceutical composition, wherein weight ratio of liothyronine to the antioxidant is in the range of about 1:1 to about 1:9
In another aspect, there is provided a pharmaceutical composition, wherein said pharmaceutical composition has water activity ranging from about 0.4 to about 0.75 measured at 25°C.
In another aspect, there is provided a pharmaceutical composition, wherein the antioxidant is alpha tocopherol present in an amount of about 0.11% w/w to about 0.15% w/w of the composition.
In another aspect, there is provided a pharmaceutical composition, wherein the composition is present in the form of powder, tablet, dispersible tablet, pellets, capsule, granules or pellets filled in capsule, tablet in capsule, multilayer tablet, bilayer tablet, trilayer tablet, mini-tablet or premixed powder filled in capsule.
In another aspect, there is provided a pharmaceutical composition, wherein the composition is present in the form of dispersible tablet.
In another aspect, there is provided a pharmaceutical composition, wherein the composition is stable when stored at condition of 25°C for at least 1 month, or at least 3 months, or atleast 9 months.
In another aspect, there is provided a pharmaceutical composition, wherein the pharmaceutically acceptable salt of liothyronine is liothyronine sodium.
In another aspect, there is provided an oral pharmaceutical tablet composition comprising (a) about 0.025 % w/w liothyronine sodium, (b) about 0.13 % w/w alpha tocopherol and (c) one or more pharmaceutically acceptable excipients comprising microcrystalline cellulose and croscarmellose sodium; wherein said pharmaceutical composition has water activity ranging from about 0.4 to about 0.75 measured at 25°C.
In another aspect, there is provided a solid oral pharmaceutical composition comprising (a) about 0.025 % w/w of liothyronine sodium (b) about 0.13 % w/w of alpha tocopherol, and (c) one or more pharmaceutically acceptable excipients; wherein said pharmaceutical composition has water activity ranging from about 0.5 to about 0.7 measured at 25°C.
In another aspect, there is provided an oral pharmaceutical tablet composition comprising (a) about 0.025 % w/w liothyronine sodium, (b) about 0.13 % w/w alpha tocopherol and (c) one or more pharmaceutically acceptable excipients comprising microcrystalline cellulose, magnessium sterate and croscarmellose sodium; wherein said pharmaceutical composition has water activity ranging from about 0.4 to about 0.75 measured at 25°C.
In another aspect, there is provided a process of preparation of solid oral pharmaceutical composition comprising liothyronine or pharmaceutically acceptable salt thereof, wherein the process comprises the steps of:
a) co-sifting pharmaceutically acceptable excipients including microcrystalline cellulose and croscarmellose sodium through sieve and then loading said mixture into rapid mixer granulator,
b) dissolving liothyronine sodium and alpha tocopherol in granulating solvent absolute ethanol,
c) adding solution prepared in step b) to step a) in rapid mixture granulator,
d) drying of granules and sifting through sieves,
e) adding extra granular excipients including microcrystalline cellulose, magnessium sterate and blending, and
f) compressing the final blend to form a tablet.

DETAILED DESCRIPTION OF THE INVENTION
The term "liothyronine" used throughout the specification refers to not only liothyronine per se, but also their other pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
“Pharmaceutical composition” or “pharmaceutical formulation” or “pharmaceutical dosage form” can be used interchangeably and refers to the combination of one or more active ingredients and one or more excipients.
“Pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art and includes any pharmaceutically acceptable salt soluble in water to form an aqueous solution.
“Pharmaceutically acceptable excipient” refers to non-active pharmaceutical ingredient substances which are within the scope of sound medical judgment suitable for use in formulating pharmaceutical products.
“An antioxidant” or “stabilizer” is a substance capable of inhibiting oxidation and that may be added for this purpose to pharmaceutical products subject to deterioration by oxidative processes.
The term “stability,” or “stable” with respect to a drug dosage form, refers to the chemical and physical integrity of the dosage unit and, when appropriate, the ability of the dosage unit to maintain protection against microbiological contamination. The shelf life of the dosage form is the time lapse from initial preparation to the specified expiration date. The monograph specifications of identity, strength, quality, and purity apply throughout the shelf life of the product.
The compositions of the invention can be prepared together with at least one pharmaceutically acceptable excipient or as oral, parental, inhalation dosage forms comprising the active agent. The pharmaceutical compositions of the invention can be prepared in solid forms comprising tablet; capsule; enterically coated or modified-release tablets; controlled-release tablet, extended-release tablet; delayed-release tablet; slow or fast-release tablet; fast soluble tablet; effervescent tablet; effervescent granule; fast soluble powder mixture; water-soluble powder, tablet, or granule; granule; pellet; mini tablet; micro tablet; granule in capsule; pellet in capsule; mini tablet in capsule; micro tablet in capsule or dry powder mixture to prepare syrup; orodispersible tablet; film tablet or combinations thereof; or in any one of liquid forms such as syrup or suspension.
In an embodiment, there is provided a solid oral pharmaceutical composition comprising i) liothyronine or pharmaceutically acceptable salt thereof, ii) an antioxidant and iii) one or more pharmaceutically acceptable excipients.
In another aspect, there is provided a solid, oral pharmaceutical composition comprising (a) about 0.01 % w/w to about 0.05 % w/w of liothyronine or a pharmaceutically acceptable salt thereof; (b) about 0.05% % w/w to about 0.25 % w/w of an antioxidant selected from a group consisting of alpha tocopherol, ascorbic acid, sodium metabisulfite, butylated hydroxyanisole and butylated hydroxytoluene; and (c) one or more pharmaceutically acceptable excipients; wherein the weight ratio of liothyronine to the antioxidant is in the range of about 1:1 to about 1:9, and wherein said pharmaceutical composition has water activity ranging from about 0.4 to about 0.75, measured at 25°C.
In another embodiment, there is provided a solid pharmaceutical composition comprising i) liothyronine or pharmaceutically acceptable salt thereof, ii) an antioxidant and iii) one or more pharmaceutically acceptable excipients; and wherein the pharmaceutically acceptable salt of liothyronine is liothyronine sodium present in the composition in the range of about 0.01 % to about 0.05 %, preferably about 0.02 % to about 0.04 %, or about 0.025% w/w of the composition.
An antioxidant preferably selected from the group consisting of tocopherol, sodium ascorbate, propyl gallate, tertiary butylhydroquinone, butylated hydroxyanisole and butylated hydroxytoluene, butylated hydroxyanisole and butylated hydroxytoluene, preferably alpha tocopherol. In another aspect, there is provided a pharmaceutical composition, wherein the antioxidant is alpha tocopherol present in an amount of about 0. 11% w/w to about 0.15% w/w, preferably about 0.12% w/w to about 0.14% w/w, or about 0.13% w/w of the composition.
In another embodiment, there is provided a pharmaceutical composition, wherein the weight ratio of liothyronine to the antioxidant is in the range of about 1:1 to about 1:9, preferably about 1:4 to about 1:7, or about 1:5.
The pharmaceutically acceptable excipients for composition can be selected from a group comprising one or more binding agents (binders), disintegrants, lubricants, one or more diluents, glidants, wetting agents, coating agents, anti-adhesive agents, swelling agent, viscosity enhancing agents, filling agents, drying agents, rate controlling polymer agent, surfactants, cosolvents, acidifier, alkaliser, stabilizing agents, pH regulators, flavouring agent, sweeteners, emulgators, antifoaming agents, protective agents, solvents or solvent combinations, colouring agents and complexing agents or the combinations thereof.
The disintegrants that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate or combinations thereof. Preferably the disintegrant is croscarmellose sodium.
The binders that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, methyl cellulose, povidone, copovidone, starch or combinations thereof.
The diluents that can be used in the pharmaceutical compositions according to the invention can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch and starch derivatives, sodium chloride, sucrose, talc, xylitol or the combinations thereof. Preferably the diluent is microcrystalline cellulose.
The lubricants that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate or combinations thereof. Preferably the lubricant is magnesium stearate.
The glidants that can be used in the pharmaceutical compositions according to the invention can be selected from but not limited to colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, magnesium trisilicate, cornstarch, talc and the like or combinations thereof.
In another embodiment, there is provided a solid pharmaceutical composition comprising i) liothyronine or pharmaceutically acceptable salt thereof, ii) an antioxidant and iii) one or more pharmaceutically acceptable excipients; wherein said pharmaceutical composition has water activity ranging from about 0.4 to about 0.75, or about 0.45 to about 0.7, or about 0.5 to about 0.65, or about 0.55 to about 0.6, measured at 25°C.
“Water activity” of pharmaceutical solids (proteins, drugs, and excipients) is essential to obtain a solid dosage form with optimal chemical, physical, microbial, and shelf life properties. Water activity (aw) influences the chemical stability, microbial stability, flow properties, compaction, hardness, and dissolution rate of dosage forms of pharmaceuticals, proteins, biopharmaceuticals, nutraceuticals, and phytochemicals.

Water activity (aw), or equilibrium relative humidity (ERH), is a measure of the free water in a pharmaceutical dosage form. It is defined as the ratio of the water vapor pressure of the substance (p) to the vapor pressure of pure water (p0) at the same temperature; a = p/p0 Equilibrium relative humidity is water activity expressed as a percentage; ERH = aw x 100. Water associated with a substance is classified as either free or bound. Free water (sometimes called mobile or unbound) is loosely adsorbed on the surface of the substance and has properties of bulk water. Bound water is directly or tightly associated with a material and is not readily available for chemical interaction with other species. Additionally, some water is less tightly bound, with properties reflecting a much higher level of structure than bulk water but less than that of tightly bound water. Thus, the amount of free water rather than the amount of total water is critical to the chemical and physical stability of a drug substance that is moisture sensitive.
Water activity is a critical factor in determining the shelf life of products. Rates of exchange of moisture through the package and the rate of change in aw of the product towards a critical limit will determine the shelf life of a product. Knowledge of the temperature, ambient relative humidity and critical aw values will aid in selection of a package with the correct barrier properties to optimize quality and shelf life.
There are different means by which to assess water activity. Traditional readings can be obtained using a resistive electrolytic (based on a liquid electrolyte sensor); a capacitance (using dual charged plates divided between a polymer membrane dielectric); a dew point hygrometer (based on the physicochemical understanding that the temperature at which dew forms is directly proportional to the vapour pressure of the air). More advanced instruments include dew point technology; or relative humidity sensors that change electrical resistance or capacitance. The water activity of pharmaceutical composition of the invention is measured with the help dew point technology method using Aqua Lab equipment of Decagon at temperature of 25°C.
In another embodiment, there is provided a pharmaceutical composition, wherein the composition is present in the form of powder, tablet, dispersible tablet, pellets, capsule, granules or pellets filled in capsule, tablet in capsule, multilayer tablet, bilayer tablet, trilayer tablet, mini-tablet or premixed powder filled in capsule.
In another embodiment, there is provided a pharmaceutical composition, wherein the composition is present in the form of tablet.

In another embodiment, there is provided a pharmaceutical composition, wherein the composition is present in the form of dispersible tablet which disperse in 20 seconds, or in 10 seconds in water.
In another embodiment, there is provided a pharmaceutical composition, wherein the composition is stable when tested at condition of 25°C for at least 1month, or at least 3 months or at least 9 months.
In another embodiment, there is provided an oral pharmaceutical tablet composition comprising (a) about 0.025 % w/w liothyronine sodium, (b) about 0.13 % w/w alpha tocopherol and (c) one or more pharmaceutically acceptable excipients comprising microcrystalline cellulose and croscarmellose sodium; wherein said pharmaceutical composition has water activity ranging from about 0.4 to about 0.75 measured at 25°C.
In another embodiment, there is provided a solid oral pharmaceutical composition comprising (a) about 0.025 % w/w of liothyronine sodium (b) about 0.13 % w/w of alpha tocopherol, and (c) one or more pharmaceutically acceptable excipients; wherein said pharmaceutical composition has water activity ranging from about 0.5 to about 0.7 measured at 25°C.
In another embodiment, there is provided an oral pharmaceutical tablet composition comprising (a) about 0.025 % w/w liothyronine sodium, (b) about 0.13 % w/w alpha tocopherol and (c) one or more pharmaceutically acceptable excipients comprising microcrystalline cellulose, magnessium sterate and croscarmellose sodium; wherein said pharmaceutical composition has water activity ranging from about 0.4 to about 0.75, measured at 25°C.
In another embodiment, there is provided a solid oral pharmaceutical composition, wherein a composition with antioxidant as alpha tocopherol is more stable than composition without alpha tocopherol; wherein stability tested at condition of 25°C for period of 1, 3 or 6 months.
In another general embodiment, there is provided a process of preparation of solid composition comprising liothyronine or pharmaceutically acceptable salt thereof.
The pharmaceutical compositions of the invention are prepared by wet or dry processing methods. In general aspect of the invention the pharmaceutical compositions are prepared by wet processing methods. In a class of this aspect the pharmaceutical compositions are prepared by wet granulation methods. With wet granulation either high-shear granulation or fluid-bed granulation may be used. In this aspect high shear granulation with non aqueous solvent is employed which has the advantage of affording tablets with higher diametric strength.
In another general aspect the pharmaceutical compositions are prepared by dry processing methods. In a class of this aspect the pharmaceutical compositions are prepared by direct compression or dry granulation methods. Dry granulation is done by using roller compaction.
In one embodiment, there is provided a process of preparation of solid composition comprising liothyronine or pharmaceutically acceptable salt thereof, wherein the process comprises the steps of:
a) co-sifting pharmaceutically acceptable excipients including microcrystalline cellulose and croscarmellose sodium through sieve and then loading said mixture into rapid mixer granulator,
b) dissolving liothyronine sodium and Alpha tocopherol in granulating solvent absolute ethanol,
c) adding solution prepared in step b) to step a) in rapid mixture granulator,
d) drying of granules and sifting through sieves,
e) adding extra granular excipients including microcrystalline cellulose, magnessium sterate and blending, and
f) compressing the final blend to form a tablet.
The pharmaceutical compositions obtained by the dry or wet processing methods and may be compressed into tablets, encapsulated, or metered into sachets.
The term "tablet" as used herein is intended to encompass compressed pharmaceutical dosage formulations of all shapes and sizes, whether coated or uncoated.
In another embodiment, there is provided a method of treating hypothyroidism in a patient which method comprising administering the pharmaceutical composition in accordance with the invention.
The invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
EXAMPLES
EXAMPLE 1: Composition of stable formulation of Liothyronine Sodium 20µg Tablets (with alpha tocopherol)
Sr. No. Ingredients Formula
(% w/w)
Intra granular materials
1 Liothyronine sodium 0.025
2 Microcrystalline cellulose 77.03
3 Croscarmellose sodium 3.54
4 Alpha tocopherol 0.13
Granulating agent
5 Ethanol (Absolute) q.s
Extra granular materials
6 Microcrystalline cellulose 19.29
Total weight 100
Manufacturing process:
a) Microcrystalline cellulose (Ceolus UF 711) of intragranular part and croscarmellose sodium were co-sifted through # 40 sieve.
b) Step (a) material loaded into rapid mixer granulator and mixed for 5 minutes keeping impeller at slow speed and chopper off.
c) Alpha tocopherol was dissolved in absolute ethanol and then liothyronine sodium.
d) Step (c) solution was added slowly over dry mixed material in rapid mixture granulator keeping impellor slow and chopper off.
e) The wet mass was granulated further keeping impeller and chopper at fast speed.
f) The wet granules were dried in rapid dryer at inlet temperature of 30 to 45°C till desired LOD (limit NMT 3.5%) was achieved.
g) The dried granules sifted through 30 # sieve.
h) Ceolus UF 711(extra granular part) was reweighed as per yield of the dried granules and sifted through # 40 sieve.
i) Blending: Approximately 50% of dried granules of step (g) loaded into a double cone blender then added step (h) material and remaining quantity of dried granules of step (g) and mixed for 25 minutes at 16 RPM.
j) Above blend was compressed into tablets using 6.2 mm, round FFBE punches with a target assay of 105 %.

EXAMPLE 2: Comparative Composition of Liothyronine Sodium 20µg Tablets with alpha tocopherol and without alpha tocopherol
Sr. No. Ingredients Composition with alpha tocopherol Composition without alpha tocopherol
Formula
(% w/w) Formula
(% w/w)
Intra granular materials
1 Liothyronine sodium 0.025 0.025
2 Microcrystalline cellulose 77.03 77.15
3 Croscarmellose sodium 3.54 3.54
4 Alpha tocopherol 0.13 - -
Granulating agent
5 Ethanol (Absolute) q.s. q.s.
Extra granular materials
6 Microcrystalline cellulose 19.29 19.29
Total weight 100 100
Manufacturing process was similar to that given in Example 1.
Table 1: Comparative stability data of Composition of Liothyronine Sodium 20µg Tablets with alpha tocopherol and without alpha tocopherol
Composition Period Assay Total Impurities Water Activity
[with dl-alpha tocopherol]
Initial 106.8% 0.508% 0.42
1 M, 25°C/60%RH 105.5% 0.572% 0.43
[without dl-alpha tocopherol] Initial 104.0% 0.342% 0.56
1 M, 25°C/60%RH 102.2% 0.677% 0.57

EXAMPLE 3: Composition of Liothyronine Sodium Tablets (20 µg)
Sr. No. Ingredients Formula
(% w/w)
Intra granular materials
1 Liothyronine sodium 0.025
2 Microcrystalline cellulose 77.03
3 Croscarmellose sodium 3.54
4 Alpha tocopherol 0.13
Granulating agent
5 Ethanol (Absolute) q.s.
Extra granular materials
6 Microcrystalline cellulose 18.28
7 Magnesium stearate 1
Total weight 100

Manufacturing process:
a) Microcrystalline cellulose (Ceolus UF 711) of intragranular part and croscarmellose sodium were co-sifted through # 40 sieve.
b) Step (a) material loaded into rapid mixer granulator and mixed for 5 minutes keeping impeller at slow speed and chopper off.
c) Alpha tocopherol was dissolved in absolute ethanol and then liothyronine sodium.
d) Step (c) solution was added slowly over dry mixed material in rapid mixture granulator keeping impellor slow and chopper off.
e) The wet mass was granulated further keeping impeller and chopper at fast speed.
f) The wet granules were dried in dryer at inlet temperature of 35°C to 55°C till desired LOD was achieved.
g) The dried granules sifted through 30 # sieve.
h) Microcrystalline cellulose and magnesium stearate (extra granular part) were weighed as per yield of the dried granules and sifted through # 40 sieve.
i) Blending: Approximately 50% of dried granules of step (g) loaded into a double cone blender then added step (h) material and remaining quantity of dried granules of step (g) and mixed for 25 minutes at 16 RPM.
j) Above blend was compressed into tablets using 6.2 mm, round FFBE punches with a target assay of 105 %.

EXAMPLE 4: Stability Study of Example 3
Stability Study performed at 25°C/60%RH
Sr No Study Initial 3 months 9 months
1 %Assay 106.7 106.1 105.7
2 Water Activity 0.42 0.44 0.45

EXAMPLE 5: Composition of Liothyronine Sodium 20µg Tablets
Example
5A Example 5B Example
5C
Sr. No. Ingredients Formula
(% w/w) Formula
(% w/w) Formula
(% w/w)
Intra granular materials
1 Liothyronine sodium 0.03 to 0.04 0.025 0.04 to 0.05
2 Microcrystalline cellulose 60 to 70 77.03 85 to 95
3 Croscarmellose sodium 1.2 to 2.5 3.54 4.2 to 6.4
4 Alpha tocopherol 0.21 to 0.32 0.13 0.4 to 0.5
Granulating agent
5 Ethanol (Absolute) q.s. q.s. q.s.
Extra granular materials
6 Microcrystalline cellulose 10 to 15 20 to 25 30 to 40
7 Magnesium stearate 3 to 5 6 to 8 10 to 13
Total weight 100 100 100
Manufacturing process: Manufacturing process is similar as mentioned in Example 3.
,CLAIMS:We claim:
1. A solid oral pharmaceutical composition comprising (a) about 0.01% w/w to about 0.05 % w/w of liothyronine or a pharmaceutically acceptable salt thereof; (b) about 0.05% % w/w to about 0.25 % w/w of an antioxidant selected from a group consisting of alpha tocopherol, ascorbic acid, sodium metabisulfite, butylated hydroxyanisole and butylated hydroxytoluene; and (c) one or more pharmaceutically acceptable excipients; wherein the weight ratio of liothyronine to the antioxidant is in the range of about 1:1 to about 1:9, and wherein said pharmaceutical composition has water activity ranging from about 0.4 to about 0.75, measured at 25°C.

2. The pharmaceutical composition according to claim 1, wherein the composition has water activity ranging from about 0.45 to about 0.7 measured at 25°C.

3. The pharmaceutical composition according to claim 1, wherein the antioxidant is alpha tocopherol present in an amount of about 0. 11% w/w to about 0.15% w/w.

4. The pharmaceutical composition according to claim 1, wherein the weight ratio of liothyronine to the antioxidant is about 1:5.

5. The pharmaceutical composition according to claim 1, wherein the composition is present in the form of powder, tablet, dispersible tablet, pellets, capsule, granules or pellets filled in capsule, tablet in capsule, multilayer tablet, bilayer tablet, trilayer tablet, mini-tablet or premixed powder filled in capsule.

6. The pharmaceutical composition according to claim 1, wherein the composition remains stable when stored at condition of 25°C for at least 6 month.

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

8. A solid oral pharmaceutical composition comprising (a) about 0.025 % w/w of liothyronine sodium (b) about 0.13 % w/w of alpha tocopherol, and (c) one or more pharmaceutically acceptable excipients; wherein said pharmaceutical composition has water activity ranging from about 0.5 to about 0.7 measured at 25°C.

9. An oral pharmaceutical tablet composition comprising (a) about 0.025 % w/w liothyronine sodium, (b) about 0.13 % w/w alpha tocopherol and (c) one or more pharmaceutically acceptable excipients comprising microcrystalline cellulose and croscarmellose sodium; wherein said pharmaceutical composition has water activity ranging from about 0.4 to about 0.75 measured at 25°C.

10. A process of preparation of an oral pharmaceutical tablet composition according to claim 9, wherein the process comprises the steps of:
a) co-sifting pharmaceutically acceptable excipients including microcrystalline cellulose and croscarmellose sodium through sieve and then loading said mixture into rapid mixer granulator,
b) dissolving liothyronine sodium and alpha tocopherol in granulating solvent absolute ethanol,
c) adding solution prepared in step b) to step a) in rapid mixture granulator,
d) drying of granules and sifting through sieves,
e) adding extra granular excipients including microcrystalline cellulose, magnesium stearate and blending, and
f) compressing the final blend to form a tablet.