DESC:STABLE PHARMACEUTICAL COMPOSITIONS OF LEVOTHRYOXINE

FIELD OF THE INVENTION

The invention relates to a stable pharmaceutical composition comprising levothyroxine or a pharmaceutically acceptable salt thereof, along with one or more pharmaceutically acceptable excipients. The present invention further provides a stable pharmaceutical composition comprising about 325 mcg to about 1000 mcg levothyroxine for once weekly administration for treatment of hypothyroidism. Moreover, the present invention also relates to the process of preparation of the said composition thereof.

BACKGROUND OF THE INVENTION

Hypothyroidism is a common disorder, which is mainly treated in primary rather than secondary care. Hypothyroidism is common in the general population with an incidence of 4.1/1000 per year in women and 0.6/1000 per year in men. In treatment of thyroid hormone deficiency very low daily doses of levothyroxine sodium are used in the range from 25 to 300 mcg. Commercial preparations currently marketed include Unithyroid®, Levothroid®, Levoxyl®, Synthroid®, and Levo-T® are for daily administration. Non-compliance is the most common cause of lack of response to thyroxine treatment.

Once weekly thyroxine replacement seems to be a good option to prevent lack of response to thyroxine treatment due to non-compliance with once daily dosing regimen. However, pharmaceutical preparations containing levothyroxine hormone are known to exhibit deficiencies with regard to uniformity, stability, and shelf life. More specifically, levothyroxine sodium hormone is hygroscopic and degrades rapidly under conditions of high humidity or in the presence of other moisture sources or light and under conditions of high temperature. A few attempts have been made in the art to prepare stable thyroxine compositions.

U.S. Pat. No. 5,225,204, describes a dosage composition complex of hydrated levothyroxine sodium which includes poloxamer or polyvinylpyrrolidone and is granulated with a polar organic solvent before being uniformly adsorbed on a cellulose compound.

U.S. Pat. No. 5,955,105, describes thyroid hormone preparations comprising an inorganic salt, a carbohydrate having a molecular weight of greater than 500, or glycine. Suitable carbohydrate binders include microcrystalline cellulose, maltodextrin, starch and hydroxypropyl cellulose having a molecular weight between 80,000 and 1,150,000.

U.S. Pat. No. 5,225,204, describes compositions comprising polyvinyl pyrrolidone, hydroxypropyl cellulose with subsequent combination of this mixture with a microcrystalline cellulose carrier.

U.S. Pat. No. 5,635,209, describes a composition of levothyroxine sodium containing potassium iodide and microcrystalline cellulose. This composition may also include a disintegrant, a lubricant and a dye.

U.S. Pat. No. 5,753,254, describes a solid fast dispersing dosage form comprising a disintegrating agent, a flavoring agent and a lubricating agent. The disintegrating agent may be starch, agar, bentonite, cellulose, microcrystalline cellulose, methylcellulose, carmellose, croscarmellose sodium, alginic acid, guar gum, silicon dioxide and sodium lauryl sulphate. The flavoring agent may be a sweetening agent, a peppermint oil and/or fruit flavor, a flavor enhancing agent or an ingredient which induces the formation of saliva, such as an organic acid like citric and malic acid. The lubricating agent may be magnesium stearate, calcium stearate, stearic acid and mixtures thereof. Optional ingredients may also be present.

Thyroid hormone drugs like levothyroxine or salts thereof are known for its poor stability. Such poorly stable or fast degradation prone drugs may lose its potency over the period of shelf life which may result in under-dosing. Also, there is a common practice to add overages in order to compensate probable potency loss. All such variations of under-dosing or over-dosing of the drug may result in undesirable clinical outcomes. Therefore, storage stability and content uniformity of levothyroxine or salts thereof in the pharmaceutical preparations is a critical issue making it further difficult for the formulators to develop a stable composition containing higher amounts of levothyroxine as achieved by the present invention.

Thus, there is still a need in the art for stable compositions of levothyroxine containing higher amounts of levothyroxine which can be readily formed into dosage forms for once weekly administration and which is substantially free of the disadvantages, defects, and limitations of the compositions disclosed in the art.

The present invention provides levothyroxine compositions for once weekly administration that are optimal, stable, and safe, in particular, present invention provides stable pharmaceutical compositions comprising about 325 mcg to about 1000 mcg levothyroxine or a pharmaceutically acceptable salt thereof, along with one or more pharmaceutically acceptable excipients.

OBJECTIVE OF THE INVENTION

The principal objective of the present invention is to provide a stable pharmaceutical composition comprising levothyroxine or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

Another objective of the present invention is to provide a process for the preparation of the stable pharmaceutical composition comprising levothyroxine or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

Another objective of the present invention is to provide a stable composition of levothyroxine containing higher amount of levothyroxine which can be readily formed into dosage forms for once weekly administration.

Another objective of the present invention is to provide a stable pharmaceutical composition of levothyroxine which is substantially free of the disadvantages and defects.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a stable pharmaceutical composition comprising levothyroxine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

According to one aspect, the present invention provides a stable pharmaceutical composition comprising levothyroxine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein said composition comprises from about 325 mcg to about 1000 mcg of levothyroxine or a pharmaceutically acceptable salt thereof.

According to another aspect, the present invention provides a stable pharmaceutical composition comprising levothyroxine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients selected from the group consisting of diluent(s), disintegrant(s), binder(s), lubricant(s), glidant(s), pH modifier(s), and anti-oxidant(s), or a combination thereof, wherein said composition comprises 350 mcg, 525 mcg, or 700 mcg of levothyroxine or a pharmaceutically acceptable salt thereof.

According to another aspect, the present invention provides a stable pharmaceutical composition comprising 350 mcg, 525 mcg, or 700 mcg of levothyroxine or a pharmaceutically acceptable salt thereof; wherein the pharmaceutical composition comprises:
- 1 - 99 % w/w diluent(s),
- 1 - 50% w/w of disintegrant(s),
- 0 - 25% w/w of binder(s), and
- 0.01 - 5% w/w lubricant(s) or glidant(s), based on the total weight of the composition.

According to another aspect, the stable pharmaceutical composition of the present invention is a tablet or a capsule dosage form.

According to another aspect, the present invention provides a stable pharmaceutical composition comprising: (a) a core comprising levothyroxine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, and (b) optionally, a coating over said core, wherein said coating comprises one or more film forming polymers.

According to one more aspect, the present invention provides a stable pharmaceutical composition comprising levothyroxine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients; wherein the composition is prepared by direct compression, dry granulation, wet granulation, melt granulation, or extrusion process.

According to another aspect, the present invention provides a process of preparation of a stable pharmaceutical composition comprising levothyroxine or a pharmaceutically acceptable salt thereof, wherein said process comprises: (a) blending levothyroxine or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients to obtain a blend; (b) optionally granulating and lubricating the blend; (c) compressing the blend or granules to form a tablet or filling the blend or granules in a capsule.

According to one more aspect, the present invention provides a dosing schedule comprising administering one tablet or capsule comprising 350 mcg, 525 mcg, or 700 mcg levothyroxine or a pharmaceutically acceptable salt thereof once weekly for the treatment of hypothyroidism.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description.

DETAIL DESCRIPTION OF THE INVENTION

The present invention provides a “stable pharmaceutical composition comprising levothyroxine” or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

As used in this specification, the singular forms “a”, “an”, and “the” include plural references unless the context dictates otherwise. Thus, for example, a reference to “a method” or “a process” includes one or more methods, one or more processes, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

The term “composition” or “compositions” or “oral composition” or oral composition” “dosage form” or “pharmaceutical composition” or “pharmaceutical composition” as used herein synonymously include solid or liquid dosage form, i.e., tablets such as mono-layered tablets, bi-layered tablets, tri-layered tablets, multilayer tablets, caplets, minitablets, capsules, tablet in tablet, tablets in a capsule, granules in a capsule, pellets, pellets in a capsule, powder, granules, solid dispersion, drug coated inert cores, beads, spheroids, suspension, solution, or any other suitable dosage form meant for oral administration. The pharmaceutical composition includes immediate release, fast release, orally disintegrating, extended release, modified release, delayed release, pulsed release compositions and the like.

Levothyroxine, L-thyroxine, or Thyroxine is used interchangeably in the context of the present invention.

The term “pharmaceutically acceptable salt” or “salt” is used interchangeably in the context of the present invention. “Pharmaceutically acceptable salts” or “salts” as used in the context of the present invention refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt, carbonate salts; organic acids such as succinic acid, formic acids, acetic acid, diphenyl acetic acid, palmoic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, p-chlorobenzoic acid, dibenzoyl tartaric acid, oxalic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid and the like. The inorganic salts may further include alkali metal and alkaline earth metal salts such as sodium, potassium, barium, lithium, calcium, magnesium, rhodium, zinc, cesium, selenium, and the like. In a particular embodiment, the salt is a sodium salt of levothyroxine.

The term “excipient” or “pharmaceutically acceptable excipients” means a pharmacologically inactive component such as a diluent(s), disintegrant(s), binder(s), and the like, of a pharmaceutical product. The excipients that are useful in preparing a dosages form are generally safe, non-toxic, and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one excipient and more than one excipient. Due to the varying properties of the active drug substance to be formulated, dosage forms typically require pharmaceutical excipients that are uniquely tailored for the active drug substance in order to achieve advantageous physical and pharmaceutical properties.

The term "desiccant" is referred herein to a substance used to remove or suppress or decrease the odour or to absorb moisture which prevents degradation and/or decomposition of the active agent(s), wherein the desiccants are selected from, but not limited to, silicon dioxide (silica gel), silicon dioxide, alumina oxide, a mixture of silica gel and activated carbon, a mixture of silica gel and clay, a mixture of silica alumina and activated carbon; a synthetic zeolite, silica gel, silica-alumina, an active carbon, metallic oxide such as calcium oxide and the like used either alone or in combinations thereof.

The desiccant may be placed in the internal space of the package containing the composition (e.g. HDPE bottle, carton or sealed closed container) in an amount sufficient (1 to 20 gm) to remove the odorous material or to absorb moisture which prevents degradation and/or decomposition of the active agent(s) or to suppress or reduce the smell.

The “stable” according to present invention refers to a pharmaceutical composition comprising levothyroxine or pharmaceutically acceptable salts thereof, in which the amount of impurity(ies) remains below FDA acceptable intake limit after exposure of the pharmaceutical composition to 40 °C ± 2 °C and 75% ± 5% RH for a period of six months or 25 °C ± 2 °C and 60% ± 5% RH for a period of at least 12 months. In particular, the “stable” according to present invention refers to a pharmaceutical composition comprising levothyroxine or pharmaceutically acceptable salts thereof, wherein the composition retains at least 95% of the potency of levothyroxine in the composition after storage at 40 °C ± 2 °C and 75% ± 5% RH for a period of at least six months or at 25 °C ± 2 °C and 60% ± 5% RH for a period of at least twelve months.

According to one aspect, the present invention provides a stable pharmaceutical composition comprising levothyroxine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein said composition comprises from about 325 mcg to about 1000 mcg of levothyroxine or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the present invention provides a stable pharmaceutical composition comprising levothyroxine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein said composition comprises 350 mcg, 525 mcg, or 700 mcg of levothyroxine or a pharmaceutically acceptable salt thereof.

Suitable “excipients” or “pharmaceutically acceptable excipients” include, without limitation, diluent(s), binder(s), disintegrant(s), glidant(s), surfactant(s), solubilizer(s), extended release or delayed release excipient(s), pH modifier(s), anti-oxidant(s), preservative(s), lubricant(s), flavoring agent(s), plasticizer(s), colorant(s), opacifier(s), carrier(s), and like. Specifically, the composition of the present invention contains diluent(s), disintegrant(s), binder(s), glidant(s), and/or lubricant(s) that are used for the preparation of stable composition of levothyroxine or pharmaceutically acceptable salts thereof.

Suitable diluent(s) include, without limitation, organic and inorganic diluents such as celluloses and cellulose derivatives, starches and modified starches, polyols, carbohydrates, inorganic phosphates, carbonates, silicates, sulfates etc. In particular, microcrystalline cellulose, silicified microcrystalline cellulose, polyols and sugar alcohols selected from but not limited to alditols, mannitol, D-mannitol, meglumine, xylitol, isomalt, sorbitol, lactitol, pentitol, arabitol, ribitol, galactitol, erythritol, glycerol, and the like; Carbohydrate selected from but not limited to monosaccharides, oligosaccharides polysaccharides, dextrins, maltodextrin, pullulan, arabinose, dextrose, dextrates, lactose, sucrose, sucralose, saccharin, fructose, maltose, trehalose, psicose, tagatose, sorbose, cellulose derivatives, cellobiose, starches, modified starches, sucrose fatty acid esters, and the like; inorganic diluents selected from but not limited to dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, kaolin, calcium sulfate, and the like; or combinations thereof. Diluents may include co-processed excipients such as microcrystalline cellulose and colloidal silicon dioxide (Prosolve SMCC), D-mannitol and starch (Pearlitol® Flash), lactose and microcrystalline cellulose (Cellactose®), D-mannitol, xylitol, microcrystalline cellulose, Crospovidone, dibasic calcium phosphate anhydrous (F-MELT®, Fujicalin®, Neusilin®) in its composition. When present, a diluent may be employed in an amount ranging from about 1% to about 99% by weight of the pharmaceutical composition. In one embodiment of the present invention, the diluent is present in an amount of more than 50%, more than 60%, more than 70%, more than 80% by weight of the pharmaceutical composition. In one embodiment of the present invention, the composition is free of reducing saccharide(s).

Suitable binder(s) include, without limitation, natural and synthetic polymers, natural and synthetic gums, hydrocolloids, celluloses and cellulose derivatives, starches and modified starches, carbohydrates, vinyl polymers etc. In particular, polyvinylpyrrolidone (PVP), e.g., PVP K30 or PVP K90, polyvinyl acetate, polyvinyl alcohol, polyethylene glycols (PEG), e.g., PEG 400, PEG 4000, PEG 6000, copolymers of PEG, polyvinyl alcohol, polyvinylacetate, and PVP, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, both preferably of medium to high viscosity, e.g. viscosity grades 3 or 6 cps, copovidone, maltodextrins, pregelatinized starch, microcrystalline cellulose, acacia, alginic acid, tragacanth, gelatin, liquid glucose, corn starch, sugars, ethyl cellulose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium alginate, used either alone or combinations. When present, a binder may be employed in an amount ranging from about 0.1% to about 25%, by weight of the pharmaceutical composition. In one embodiment of the present invention, the composition is free of binder(s). In one embodiment of the present invention, the composition comprises dry binder(s).

Suitable disintegrant(s) include, without limitation, natural and synthetic polymers, natural and synthetic gums, celluloses and cellulose derivatives, starches and modified starches etc. In particular, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone, corn starch, cross-linked sodium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium starch glycolate, crosslinked CMC (Ac-Di-Sol), Sodium carboxymethyl starch, ion-exchange resins, formalin-casein, used either alone or combinations thereof. When present, a disintegrant may be employed in an amount ranging from about 0.1% to about 50%, by weight of the pharmaceutical composition.

Suitable lubricant(s) include, without limitation, zinc stearate, magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid, colloidal silica, aluminium or calcium silicate, stearic acid, cutina, PEG 4000-8000, talc and combinations thereof. When present, a lubricant may be employed in an amount ranging from about 0.01% to about 10%, preferably from about 0.1% to about 5%, by weight of the pharmaceutical composition.

Suitable glidant(s) include, without limitation, colloidal silicon dioxide (e.g., Aerosil 200), mesoporous silica, stearates, magnesium trisilicate, powdered cellulose, starch, talc, and combinations thereof. When present, a glidant may be employed in an amount ranging from about 0.01% to about 10%, preferably from about 0.1% to about 5%, by weight of the pharmaceutical composition.

Suitable pH modifier(s) include, without limitation, an acid selected from an organic or inorganic acid such as ascorbic acid, fumaric acid, citric acid, malic acid, succinic acid, adipic acid, maleic acid, lactic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, and the like or a base selected from organic bases such as pyridine, alkanamines, such as methylamine, diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, pyridine, imidazole, histidine, guanidine, poly ethyleneimine, poly(vinylpyridine), diethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane (Tris), sodium glycine, 1-methylimidazole, 2-methylimidazole, and 4(5)-methylimidazole, and 1,2-diaminoethane, 2-(bis(2-hydroxyethyl)amino)-2-(hydroxymethyl)propane-1,3-diol, sodium lysine, sodium histidine, and sodium arginine, polyvinyl imidazole, and copolymers thereof (e.g., a copolymer of poly ethyleneimine and one or more of poly(vinylpyridine) and polyvinylimidazole, or a copolymer of poly(vinylpyridine) with polyvinyl imidazole) or inorganic bases such as sodium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, magnesium oxide, sodium citrate, sodium hydroxide, potassium hydroxide, ammonium salts, and the like.

Suitable antioxidant(s) include, without limitation, natural and synthetic compounds, organic and inorganic acids etc. In particular, ascorbic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, citric acid, malic acid, lactic acid, benzenesulfonic acid, oxalic acid, triphenylacetic acid, 1-hydroxy-2-naphthoic acid, 3-hydroxy-2-naphthoic acid, sodium ascorbate, alpha-tocopherol, butylated hydroxytoluene, butylated hydroxyanisole, gentisic acid (2,5-dihydroxy benzoic acid), acetyl cysteine, ascorbyl palmitate, cysteine, dithiothreitol, thioglycerol, thiourea, caffeic acid, propyl gallate, ferulic acid, sodium pyrosulfite, edetic acid, edetate salts, 2, 6-di-tert-butyl p-cresol, gallic acid and esters thereof, nordihydroguaiaretic acid, benzoic acid, benzoates, sorbic acid, sorbates, guaiacol ester, tea polyphenol, curcumin, chlorogenic acid, methionine, proline, biflavonoids, superoxide dismutase, silymarin, grape skin/seed extract, melanin, rosemary extract, sodium sulfite, sodium thiosulfate, sodium bisulfite, sodium metabisulfite, tert-butylhydroquinone, sodium citrate, magnesium ascorbyl phosphate, sodium ascorbyl phosphate, 3,4-dihydroxybenzoic acid, butylated hydroxybenzoic acid and salts thereof, erythorbic acid and sodium salts thereof, sorbic acid and salts thereof, sodium formaldehyde sulfoxylate, glutathione, lipoic acid, dihydroxy fumaric acid, and the like.

Suitable extended release or delayed release excipient(s) include, without limitation, hydrophilic or hydrophobic agents, natural and synthetic poylmers, natural and synthetic gums, In particular, polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, a fatty acid, a fatty acid ester, an alkyl alcohol, a wax, xanthan gum, gellan gum, shellac, rosin, zein (prolamine from corn), povidone, kollidon SR (polyvinyl acetate and povidone), a poly(meth)acrylate, poly(ethylene oxide), polyuronic acid salts, cellulose ethers, xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan gum locust bean gum, alkali metal salts of alginic acid or pectic acid, sodium alginate, potassium alginate, ammonium alginate, polyethylene oxide, carbomer homopolymer, hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxypropyl methyl cellulose, carboxyvinyl polymers, polymerized gelatin, shellac, methacrylic acid copolymer type C NF, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propionate phthalate, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate, hydrogenated castor oil, stearic acid, hydrogenated vegetable oil, glyceryl behenate, glyceryl monostearate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethyl cellulose (CMEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and acrylic acid polymers and copolymers like methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate with copolymers of acrylic and methacrylic acid esters (Eudragit NE, Eudragit RL, Eudragit RS) and the like. Polymer may be used from 0.1- 50% by weight of the composition, preferably 10-50% by weight of the composition.

Suitable coating agent(s) according to present invention may be selected from immediate release, extended release, or delayed release coatings but not limited to, Shellac, cellulose acetate phthalate (CAP), polyvinylacetate phthalate (PVAP), hyroxylpropyl cellulose, hyroxypropyl methylcellulose (HPMC), acrylates, phthalates, and Zein (a corn protein derivative), Hydroxypropyl methyl cellulose, Methyl hydroxyethyl cellulose, Ethylcellulose, Povidone, polyvinyl acetate, polyvinyl alcohol, Opadry, and the like.

In one embodiment of the present invention, the composition is free of excipient(s) that adversely affect the stability of levothyroxine or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a stable pharmaceutical composition comprising levothyroxine or a pharmaceutically acceptable salt thereof, wherein levothyroxine or pharmaceutically acceptable salt thereof is having a particle size of D90 less than 200 µm, preferably, D90 less than 150 µm, D90 less than 100 µm, D90 less than 75 µm, D90 less than 50 µm, D90 less than 25 µm, D90 less than 10 µm.

In another embodiment, the present invention provides a stable pharmaceutical composition comprising about 325mcg to about 1000 mcg of levothyroxine or a pharmaceutically acceptable salt thereof; wherein the pharmaceutical composition comprises:
- 1 – 99 % w/w diluent(s),
- 1 - 50% w/w of disintegrant(s),
- 0 - 25% w/w of binder(s), and
- 1 - 5% w/w lubricant(s) or glidant(s), based on the total weight of the composition.

In another embodiment, the present invention provides a stable pharmaceutical composition comprising 350 mcg, 525 mcg, or 700 mcg of levothyroxine or a pharmaceutically acceptable salt thereof; wherein the pharmaceutical composition comprises:
- 1 – 99 % w/w diluent(s),
- 1 - 50% w/w of disintegrant(s),
- 0 - 25% w/w of binder(s), and
- 1 - 5% w/w lubricant(s) or glidant(s), based on the total weight of the composition.

In another embodiment, the present invention provides a stable pharmaceutical composition comprising 350 mcg, 525 mcg, or 700 mcg of levothyroxine or a pharmaceutically acceptable salt thereof; wherein the pharmaceutical composition comprises:
- 50 – 95 % w/w diluent(s),
- 1 - 20% w/w of disintegrant(s),
- 0 - 5% w/w lubricant(s) or glidant(s), based on the total weight of the composition.

In another embodiment, the present invention provides a pharmaceutical composition according to the invention is a tablet or a capsule. The weight of the dosage form, in particular a tablet according to the invention is 100mg to 500mg. In one embodiment, the pharmaceutical composition according to the present invention is an immediate release composition. In one embodiment, the pharmaceutical composition according to the present invention is an extended release composition. In another embodiment, the pharmaceutical composition according to the present invention comprises an immediate release portion and extended release portion.

In another embodiment, the present invention provides a stable pharmaceutical composition comprising: (a) a core comprising levothyroxine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, and (b) optionally, a coating over said core, wherein said coating comprises one or more film forming polymers.

In another embodiment, the present invention provides a stable pharmaceutical composition comprising levothyroxine or a pharmaceutically acceptable salt thereof, wherein the particle size of levothyroxine or pharmaceutically acceptable salts thereof is D90 between 5 µm and 100 µm.

In another embodiment, the present invention provides a stable pharmaceutical composition comprising levothyroxine or a pharmaceutically acceptable salt thereof, wherein the particle size of levothyroxine or pharmaceutically acceptable salts thereof is D50 between 5 µm and 50 µm.

In another embodiment, the present invention provides a stable pharmaceutical composition comprising levothyroxine or a pharmaceutically acceptable salt thereof, wherein the particle size of levothyroxine or pharmaceutically acceptable salts thereof is D10 between 1 µm and 25 µm.

In another embodiment, the present invention provides a stable pharmaceutical composition comprising levothyroxine, wherein the pharmaceutical composition is having total degradation impurity is less than 4%, when stored at 40°C ± 5°C & 75% ± 5% RH for a period of at least three months.

In another embodiment, the present invention provides a stable pharmaceutical composition comprising levothyroxine and one or more pharmaceutically acceptable excipients, wherein the said composition further comprises one or more impurity selected from the group comprising Livothyronin, T4 Hydro acetic acid, N- acetamide, N- Formyl, N-Acetyl, N-Acetic acid, Benzoic acid or combinations thereof.

In another embodiment, the present invention provides a stable pharmaceutical composition comprising levothyroxine, wherein the pharmaceutical composition is having total degradation impurity is less than 0.5%, preferably less than 0.25%, more preferably less than 0.1%, when stored at 40°C ± 5°C & 75% ± 5% RH for a period of at least six months.

In another embodiment, the present invention provides a stable pharmaceutical composition comprising levothyroxine or a pharmaceutically acceptable salt thereof, one or more disintegrants, and optionally one or more pharmaceutically acceptable excipients; wherein the composition is administered for treatment of hypothyroidism.

In another embodiment, the present invention provides a dosing schedule comprising administering one tablet or capsule comprising 350 mcg, 525 mcg, or 700 mcg levothyroxine or a pharmaceutically acceptable salt thereof, once weekly for the treatment of hypothyroidism.

In another embodiment, the present invention provides a kit comprising (a) a pharmaceutical composition comprising levothyroxine and one or more pharmaceutically acceptable excipients; (b) a desiccant.

In another embodiment, the present invention provides a kit comprising (a) a pharmaceutical composition comprising levothyroxine and one or more pharmaceutically acceptable excipients; (b) a desiccant selected from the group silicon dioxide (silica gel), alumina oxide, a mixture of silica gel and activated carbon, a mixture of silica gel and clay, a mixture of silica alumina and activated carbon; a synthetic zeolite, silica gel, silica-alumina, an active carbon, metallic oxide such as calcium oxide and the like used either alone or in combinations thereof.

In another embodiment, the present invention provides a stable pharmaceutical composition comprising levothyroxine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients; wherein the composition is prepared by direct compression, dry granulation, wet granulation process, melt granulation, or extrusion process.

In another embodiment, the present invention provides a process of preparation of stable pharmaceutical composition comprising levothyroxine or a pharmaceutically acceptable salt thereof, wherein said process comprises: (a) blending levothyroxine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients to obtain a blend; (b) optionally granulating and lubricating the blend; (c) compressing the blend or granules to form a tablet or filling the blend or granules in a capsule.

In another embodiment, the present invention provides a direct compression process for preparation of a stable pharmaceutical composition comprising levothyroxine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein said process comprises the steps of:
(1) Premixing levothyroxine or a pharmaceutically acceptable salt thereof and the main portion of the excipients in a mixer to obtain a pre-mixture;
(2) optionally dry screening the pre-mixture through a screen in order to segregate cohesive particles and to improve content uniformity;
(3) mixing the pre-mixture of step (1) or (2) in a mixer, optionally by adding remaining excipients to the mixture and continuing mixing;
(4) tableting the final mixture of step (3) by compressing it on a suitable tablet press to produce the tablet cores;
(5) optionally film-coating of the tablet cores of step (4) with a film coat.

In another embodiment, the present invention provides a dry granulation process for preparation of a stable pharmaceutical composition comprising levothyroxine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein said process comprises the steps of:
(1) mixing levothyroxine or a pharmaceutically acceptable salt thereof with either all or a portion of the excipients in a mixer;
(2) compaction of the mixture of step (1) on a suitable roller compactor;
(3) reducing the ribbons obtained during step (2) to granules by suitable milling or sieving steps;
(4) optionally mixing the granules of step (3) with the remaining excipients in a mixer to obtain the final mixture;
(5) tabletting the granules of step (3) or the final mixture of step (4) by compressing it on a suitable tablet press to produce the tablet cores; (6) optionally film-coating of the tablet cores of step (5) with a film coat.

In another embodiment, the present invention provides a wet granulation process for preparation a stable pharmaceutical composition comprising levothyroxine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein said process comprises the steps of:
(1) Premixing levothyroxine or a pharmaceutically acceptable salt thereof and the main portion of the excipients in a mixer to obtain a pre-mixture;
(2) granulating the pre-mixture of step (1) by adding a granulation liquid;
(3) drying the granules of step (2) in a fluidized bed dryer or a drying oven;
(4) optionally dry sieving of the dried granules of step (3);
(5) mixing the dried granules of step (4) with the remaining excipients in a mixer to obtain the final mixture;
(6) tableting the final mixture of step (5) by compressing it on a suitable tablet press to produce tablets cores or filling the final mixture of step (5) in capsules;
(7) optionally film-coating of the tablet cores of step (6) with a film coat.

In some embodiments, the compositions may be granulated prior to being compacted. The compositions may comprise an intragranular part and an extra-granular part, wherein the intragranular part has been granulated and the extra-granular part has been added after granulation. In some embodiments, the intragranular part may comprise levothyroxine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. In some embodiments, the extra-granular part may comprise the levothyroxine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The extra-granular part may comprise a diluent, a binder, a disintegrant, a lubricant and/or a glidant.

In some embodiments of the present invention, the process comprises geometric blending/mixing of levothyroxine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients to produce homogenous blends.

The present invention further relates to a process for preparation of an oral pharmaceutical composition comprising levothyroxine or pharmaceutically acceptable salts thereof, wherein the process comprises inert gas purging to reduce the oxygen concentration or substitution with oxygen-free gas or bubbling with oxygen-free gas.

The present invention further relates to a package or storage container for packaging or storing the pharmaceutical composition, wherein the package or container is made up of material that blocks oxygen or is impervious to oxygen or comprises an oxygen scavenger. The present invention further relates to inclusion of a desiccant or an oxygen absorber in the package or storage container for packaging or storing the pharmaceutical formulation.

According to one embodiment, the stable pharmaceutical composition of the present invention is immediate release and releases NLT 80% (Q) at 45 min.

In another embodiment of the present invention, there is provided a stable pharmaceutical composition of levothyroxine or a pharmaceutically acceptable salt thereof, wherein said composition is stable at 40 °C ± 2 °C and 75% ± 5% Relative Humidity (RH) for at least one month, at least three months, at least six months.

In another embodiment, the present invention provides an oral pharmaceutical composition of levothyroxine or a pharmaceutically acceptable salt thereof, wherein said composition is stable at 25 °C ± 2 °C and 60% ± 5% RH for a period of at least three months, at least six months, at least twelve months.

In another embodiment, the present invention provides an oral pharmaceutical composition of levothyroxine or a pharmaceutically acceptable salt thereof, wherein the composition is having impurities below FDA acceptable daily intake limit. The total impurity(ies) of about 10% or less, about 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less at 40 °C ± 2 °C and 75% ± 5% RH for a period of at least six months or at 25 °C ± 2 °C and 60% ± 5% RH for a period of at least twelve months.

While selected embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

EXAMPLES

The invention now will be described in particularity with the following illustrative examples; however, the scope of the present invention is not intended to be, and shall not be, limited to the exemplified embodiments below:

Example 1: Pharmaceutical composition of Levothyroxine
Ingredients Quantity (%w/w of total composition)
Levothyroxine or its pharmaceutically acceptable salt 0.01-10%
Diluent 10-99%
Binder 0-20%
Disintegrant 1-20%
Glidant 0.01-10%
Lubricant 0.01-10%
Optional Film Coating 1-20% weight gain

Example 2: Pharmaceutical composition of Levothyroxine

Ingredient Quantity % w/w
Levothyroxine or its pharmaceutically acceptable salt 0.01-5
Microcrystalline cellulose 1-95
Sodium Starch Glycolate 1-20
Colloidal Silicon Dioxide 0.1-20
Magnesium stearate 0.01-10

Process:
1. sifting Levothyroxine or its pharmaceutically acceptable salt and microcrystalline cellulose and sodium starch Glycolate through # 40 mesh;
2. sifting the blend as obtained in Step 1 with colloidal silicon dioxide through #40 mesh;
3. mixing the blend as obtained in Step 2 in a blender for 10-20 minutes;
4. lubricating blend as obtained in Step 3 in a blender for 3-7 minutes in a blender with magnesium stearate;
5. compressing the final blend as obtained instep 4 on a compression machine to obtain compressed tablets.

Example 3: Pharmaceutical composition of Levothyroxine
Ingredient Quantity % w/w
Levothyroxine or its pharmaceutically acceptable salt 0.01-5
Microcrystalline cellulose 1-95
Crospovidone 1-20
Colloidal Silicon Dioxide 0.1-20
Sodium stearyl fumarate 0.01-10

Process:
1. sifting all the ingredients through appropriate sieves (100% should pass through sieve);
2. dry-mixing the pre-sifted Levothyroxine or its pharmaceutically acceptable salt, microcrystalline cellulose, crospovidone and silicon dioxide in a suitable blender;
3. lubricating the dry mixed ingredients as obtained in step 2 in the blender using sodium stearyl fumarate;
4. passing the blend through roller compactor to obtain compacted mass/ribbons;
5. passing the compacted mass/ribbons through appropriate mesh screen and passing the blend through the required sieve to obtain granules;
6. blending the granules as obtained in step 5 in a suitable blender and lubricating using sodium stearyl fumarate;
7. compressing the blend as obtained in step 6 into tablets;
8. film Coating The tablets as obtained in step 7.

Example 4: Pharmaceutical composition of Levothyroxine
Ingredient Amount in mg per tablet
350 mcg 525 mcg 700 mcg
Levothyroxine Sodium USP 0.350 0.525 0.700
Prosolv SMCC 50 115.800 115.625 115.45
Sodium Starch Glycolate 13.000 13.000 13.000
Magnesium Stearate 0.650 0.650 0.650
Lake blend 0.200 0.200 0.200
Total weight 130.00 130.00 130.00

Process
1. Sifting:
i) sifting together Levothyroxine Sodium, Prosolve SMCC 50 through suitable sieve and collected in polybag;
ii) sifting together a part of Prosolve SMCC 50, Step (i) and Sodium starch glycolate through suitable sieve and collecting in polybag;
iii) sifting together a part of Prosolv SMCC 50 and coloring agent through suitable mesh and collecting in polybag;
iv) sifting together the remaining quantity of Prosolv SMCC 50, step (iii) and step (ii) through suitable mesh and collecting in a polybag;
v) re-sifting the step iv through suitable mesh and collecting in a polybag
vi) sifting Magnesium Stearate through suitable sieve and collecting in polybag.
2. Blending (After Sifting):
loading the material from sifting step (v) in a blender and blend it;
3. Sifting (After Blending):
sifting the blended material as obtained in step 2 through suitable sieve and collecting in polybag;
4. Lubrication: loading the sifted material as obtained in Step 3 in blender, adding the sifted magnesium stearate and blend it;
5. Compression: compressing the above lubricated blend as obtained in step 4 using suitable tooling;
6. Packing: packing the tablets as per requirement.

Content Uniformity:
The content uniformity of compositions of present invention are given in below table:

Content Uniformity
Sample % Assay
Mean 100.4
Min 97.2
Max 102.2
AV 3.7

Stability Data:
The compositions of present invention were subjected to stability studies. The results are provided in below table:

Pack Stability data Levothyroxine Sodium tablets Specification
Initial 3M 40 °C/75%RH 3 M 25 °C/60%RH 6M 40 °C/75%RH 6 M 25 °C/60%RH
Moisture Content (wt%) 5.68 5.54 5.05 5.11 4.7 Not more than (NMT) 8%
Assay (% w/w) 99.5 96.4 97.7 97.4 97.2 95.0 - 105.0 %
Related substances (% w/w, by HPLC)
Livothyronin 0.03 0.04 0.04 0.05 0.04 NMT 2.0
T4 Hydro acetic acid 0.05 0.09 0.08 0.12 0.07 NMT 1.0
N- acetamide 0.01 0.03 0.03 0.04 0.03 NMT 1.0
N- Formyl ND ND ND 0.01 ND NMT 1.0
N-Acetyl ND 0.02 0.08 0.02 0.07 NMT 1.0
N-Acetic acid 0.02 0.02 0.03 0.08 0.06 NMT 1.0
Benzoic acid 0.01 0.02 0.04 0.12 0.09 NMT 1.0
Any highest unspecified degradation product 0.05 0.06 0.07 0.09 0.09 NMT 1.0
Total Degradation product 0.15 0.31 0.37 0.67 0.47 NMT 4.0

Further, the pharmaceutical composition of present invention is packed with the desiccant and the final pack is subjected to the stability study. The results are as follows:

Thyroxine Sodium Tablets 350 mcg
Pack details 30'S counts in 34cc PP Bottle with closure + 1 x 0.25g Silica gel pouch
Storage condition 40°C / 75%RH
Tests Specification Initial 3 M
Description Light Green to Green colored, round, biconvex uncoated tablets debossed with ‘L45’ on one side and breakline on the other side. Complies Complies
Average weight (mg) 100 ± 5.0 % 100.8 101.32
Water (wt%, By KF) NMT 8.0 4.10 3.87
Dissolution: 0.2 % w/v SLS in 0.01 M HCL, 500 mL, RPM 50, IP Apparatus 2 Paddle NLT 70% (Q) in 45 min 100 (99-101) 102(101-103)
Assay 90.0%-110.0% 100.20% 101.04%
Related substances:
Liothyronine sodium NMT 2.0 % 0.04 0.05

Thyroxine Sodium Tablets 700 mcg
Pack details 30'S counts in 34cc PP Bottle with closure + 1 x 0.25g Silica gel pouch
Storage condition 40°C / 75%RH
Tests Specification Initial 3 M
Description Light yellow to yellow colored, round, biconvex uncoated tablets debossed with ‘L46’ on one side and breakline on the other side. Complies Complies
Average weight (mg) 100 ± 5.0 % 101 100.62
Water (wt%, By KF) NMT 8.0 4.34 4.11
Dissolution: 0.2 % w/v SLS in 0.01 M HCL, 500 mL, RPM 50, IP Apparatus 2 Paddle NLT 70% (Q) in 45 min 104(102-108) 98(96-101)
Assay 90.0%-110.0% 101.30% 98.53%
Related substances:
Liothyronine sodium NMT 2.0 % 0.04 0.04 ,CLAIMS:We Claim:

1. A stable pharmaceutical composition comprising levothyroxine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein said composition comprises from about 325 mcg to about 1000 mcg of levothyroxine or a pharmaceutically acceptable salt thereof.

2. The stable pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition comprises 700 mcg of levothyroxine or a pharmaceutically acceptable salt thereof.

3. The stable pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition comprises 525 mcg of levothyroxine or a pharmaceutically acceptable salt thereof.

4. The stable pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition comprises 350 mcg of levothyroxine or a pharmaceutically acceptable salt thereof.

5. The stable pharmaceutical composition as claimed in claim 1, wherein levothyroxine or pharmaceutically acceptable salt thereof is having a particle size of D90 less than 200 µm.

6. A kit comprising (a) a pharmaceutical composition comprising levothyroxine and one or more pharmaceutically acceptable excipients; (b) a desiccant selected from the group silicon dioxide (silica gel), alumina oxide, a mixture of silica gel and activated carbon, a mixture of silica gel and clay, a mixture of silica alumina and activated carbon; a synthetic zeolite, silica gel, silica-alumina, an active carbon, metallic oxide such as calcium oxide and the like used either alone or in combinations thereof, wherein the pharmaceutical composition has water content less than 5% by weight after storage at 40°C / 75%RH for three months.

7. A stable pharmaceutical composition comprising 325mcg to 1000mcg of levothyroxine, 1-99% w/w diluent(s), 1-50% w/w of disintegrant(s), 0-25% w/w of binder(s), and 1-5% w/w lubricant(s) or glidant(s), based on the total weight of the composition, wherein the particle size of levothyroxine or pharmaceutically acceptable salts thereof is D10 between 1 µm and 25 µm.

8. The stable pharmaceutical composition as claimed in claim 7, wherein the pharmaceutical composition comprises: 50 – 95 % w/w diluent(s), 1 - 20% w/w of disintegrant(s), 0 - 5% w/w lubricant(s) or glidant(s), based on the total weight of the composition.

9. The stable pharmaceutical composition as claimed in claim 1, wherein the said composition is administered once weekly for the treatment of hypothyroidism.

10. The stable pharmaceutical composition as claimed in claim 1, wherein the process of preparation of the stable pharmaceutical composition comprising the steps of:
(a) blending levothyroxine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients to obtain a blend;
(b) granulating and lubricating the blend;
(c) compressing the blend or granules or filling the blend or granules in a capsule.

Dated this, 9th Day of August, 2024 For Mankind Pharma Ltd.

Dr. Anil Kumar
Chief Scientific Officer