WO2023088976A1

WO2023088976A1 - Orodispersible levothyroxine compositions

Info

Publication number: WO2023088976A1
Application number: PCT/EP2022/082159
Authority: WO
Inventors: Nilesh PARIKH; William CRAWFORD HITE
Original assignee: Tap Pharmaceuticals AG
Current assignee: Tap Pharmaceuticals AG
Priority date: 2021-11-16
Filing date: 2022-11-16
Publication date: 2023-05-25
Anticipated expiration: 2024-05-16

Abstract

Embodiments of the invention provide solid, unit-dose, orodispersible composition that comprise about 50-95% (w/w) of an alditol; about 0.01-10% (w/w) of a vinyl polymer; about 5-50% (w/w) of a granulating solution, which granulating solution comprises an amount of a levothyroxine sodium sufficient to cause the solid, unit-dose, orodispersible composition to comprise 50 µg, 100 µg, 200 µg, 300 µg, 400 µg, 500 µg, 600 µg, 700 µg, 800 µg, 900 µg, or 1 mg of the levothyroxine sodium, about 5%-45% (w/v) of a solvent, about 5%-95% (w/v) of a co-solvent, and about 0.01%- 5% (w/v) of a pH adjusting agent. Such orodispersible composition exhibits, in the Example 3 LT4-Na Dissolution Assay, an extent and rate of input levothyroxine sodium dissolution of at least 70% in five minutes.

Description

ORODISPERSIBLE LEVOTHYROXINE COMPOSITIONS

Cross-Reference to Related Application

[0001] This application claims priority of U.S. Provisional Application No. 63/280,087 filed on November 16, 2022, which is hereby incorporated by reference in its entirety.

Field of the Invention

[0002] Embodiments of the invention relate to orodispersible levothyroxine compositions that comprise alditol, polymer, solvent, cosolvent.

Background of the Invention

[0003] Thyroid hormone active drugs are used for both therapeutic and prophylactic treatment of thyroid disorders. For example, levothyroxine sodium (“LT4-Na”) is prescribed for thyroid hormone replacement therapy in cases of reduced or absent thyroid function in ailments such as myxedema, cretinism, and obesity. (See, e.g., Post and Warren in Analytical Profiles of Drug Substances, Vol. 5, Florey (ed.); Academic Press, New York (1976), pp. 226-281.)

[0004] LT4-Na is relatively stable in pure form, but pharmaceutical preparations containing LT4-Na and various excipients often exhibit instability and a relatively short shelf life. Several brands of LT4-Na drug product have been subjected to recall due to failure to maintain potency through the expiration date. In 1997, the United States Food and Drug Administration (FDA) categorized all orally administered LT4-Na drug products as new drugs due to significant problems relating to storage stability and variable potency. The FDA required manufacturers of LT4-Na drug products who wished to continue marketing them to submit new drug applications. (See, e.g., 62 Fed. Reg. 43535 (Aug. 14, 1997).) In 2012, the United Kingdom's Medicines and Healthcare Products Regulatory Agency issued a recall against EVOTROX 25, 50, and 100 pg LT4-Na solutions because variable stability data failed to provide assurance of product quality.

[0005] U.S. Pat. No. 5,225,204 (“204 patent”) discloses assertedly stable dosage forms of LT4-Na that comprise a complex of LT4-Na and a cellulose compound, polyvinylpyrrolidone (“PVP”), or a poloxamer, which complex is adsorbed on the surface of a cellulose compound carrier. The 204 patent describes four embodiments asserted to provide such stable dosage forms of LT4-Na. Embodiment 1: the stable complex of LT4-Na is prepared by mixing the LT4-Na with the complexing agent PVP, dissolving the resulting mixture in a polar organic solvent such as water, methanol, ethanol, propanol, isopropyl alcohol, methylene dichloride or butanol; adding a cellulose carrier to the liquid; and drying the resulting mixture to obtain a powdery, stabilized complex of LT4-Na and PVP adsorbed on the cellulose carrier. Embodiment 2: only differs from Embodiment 1 by way of the complexing agent being poloxamer instead of PVP. Embodiment 3: LT4-Na is at least partially dissolved directly in the polar organic solvent and a cellulose carrier is added to the solution to produce the stabilized LT4-Na complex. Embodiment 4: LT4-Na is dry mixed with a cellulose complexing agent and a cellulose carrier to produce the stabilized LT4-Na complex. The 204 patent states that such complexes can be mixed with pharmaceutically acceptable excipients for compression into tablets or placed in capsules.

[0006] The 204 patent teaches reduced to practice compositions prepared according to the methods described in the above embodiments. Reduced to practice Example 1 of the 204 patent is according to embodiment 1 ; and reduced to practice Example 2 of the 204 patent is according to embodiment 2. But the 204 patent presents no stability data for those compositions.

[0007] U.S. Pat. No. 5,955,105 (the “105 patent”) observes that, although the 204 patent asserts its pharmaceutical compositions are stable, no stability data was presented. The 105 patent teaches that it repeated Examples 1 and 2 of the 204 patent, and subjected the resulting preparations to stability tests at ambient room temperature (ART), 30°C, and 40°C. The resulting stability data (reproduced below) indicated that the Example 1 and 2 preparations did not provide suitable stability for pharmaceutical preparations of LT4-Na.

EXAMPLE 1 OF U.S. PAT. NO. 5,225,204

Condition Interval % Actual (S.D.)

Initial Initial 100

ART 1 months 92.3 ± (6.1)

ART 2 months 88.1 ± (2.7)

ART 3 months 87.2 ± (11.9)

30°C 1 months 86.1 ± (5.1)

30°C 2 months 95.3 ± (3.9)

30°C 3 months 87.8 ± (5.6)

40°C 1 months 95.0 ± (1.8)

40°C 2 months 94.7 ± (5.7)

40°C 3 months 91.9 ± (4.2) EXAMPLE 2 OF U.S. PAT. NO. 5,225,204

Condition Interval % Actual (S.D.)

Initial Initial 97.0 ± (0.4)

ART 1 months 89.7 ± (2.3)

ART 2 months 68.3 ± (1.9)

ART 3 months 61.4 ± (1.9)

30°C 1 months 88.3 ± (1.6)

30°C 2 months 71.3 ± (1.3)

30°C 3 months 64.2 ± (0.1)

40°C 1 months 89.5 ± (0.6)

40°C 2 months 64.1 ± (0.1)

40°C 3 months 62.5 ± (1.2)

[0008] The 105 patent further teaches that, for the Example 1 preparation of the 204 patent, a non-uniform granulation was obtained that was difficult to convert into solid dosage form. Unknown peaks were visible in the stability samples. And the peaks were contemplated to be due to an adduct formed in solution between LT4-Na and PVP.

[0009] U.S. Pat. No. 9,168,238 (“238 patent”) teaches that conventional LT4-Na formulations for injection are preservative-free lyophilized powders for reconstitution in 5 mL 0.9% NaCl containing 10 mg mannitol, 700 pg of tribasic sodium phosphate, either 200 pg or 500 pg LT4-Na, and sodium hydroxide. It teaches that conventional LT4-Na compositions include 10 mg mannitol and either 200 or 500 pg levothyroxine sodium, corresponding to a mass ratio of mannitol to LT4-Na sodium (M:L) of 50:1 and 20:1, respectively. The 238 patent teaches the desirability of providing a new formulation of LT4-Na that can improve LT4-Na stability; and preferably a new LT4-Na formulation would have acceptable stability above room temperature for an extended period of time.

[0010] The 238 patent teaches that lyophilized LT4-Na compositions having less mannitol than conventional compositions protect against LT4-Na degradation at temperatures of 25°C and higher. The 238 patent teaches that it provides compositions that include from 100 to 500 pg of LT4-Na, and from 1 to 5 mg mannitol. The compositions were lyophilized solids having a mass ratio of mannitol to LT4-Na of at most 40: 1 or 10: 1. The 238 patent further teaches that it provides compositions that: (i) comprise from 100 to 500 pg of LT4-Na and from 1 to 5 mg mannitol, (ii) when stored at 40°C exhibit conversion of LT4-Na into at most 0.19% liothyronine over a period of three months, and (ii) when stored at 25°C exhibit conversion of LT4-Na into at most 0.13% liothyronine over a period of 12 months. In contrast, conventional compositions of lyophilized LT4-Na having 10 mg mannitol and a mannitol to LT4-Na ratio of 100 and exhibit conversion of LT4-Na into 0.57% liothyronine upon three months storage at 40°C. The 238 patent discloses such experimental results in two tables, reproduced here.

Stability of levothyroxine in solid compositions containing different amounts of mannitol.

Levothyroxine Sodium: 100 pg 100 pg 100 pg 100 pg

Dibasic Sodium Phosphate: 500 pg 500 pg 500 pg 500 pg

Mannitol: 10 mg 4 mg 3 mg 2 mg

M:L ratio: 100:1 40:1 30:1 20:1

Time Temp. %T3

0 - 0.17 0.22 0.22 0.22

1 month 40° C. 0.34 0.19 0.18 0.18

2 months 0.30 0.18 0.18 0.19

3 months 0.57 0.18 0.18 0.18

2 weeks 50° C. - 0.18 0.18 0.19

4 weeks - 0.19 0.18 0.19

Stability of levothyroxine in solid compositions containing different amounts of levothyroxine sodium and 3 mg mannitol.

Levothyroxine Sodium: 100 pg 200 pg 500 pg

Dibasic Sodium Phosphate: 500 pg 500 pg 500 pg

Mannitol: 3 mg 3 mg 3 mg

M:L ratio: 30:1 15:1 6:1

^{Ti mC} _x Temp. %T3

(mo.)

0 - 0.12 0.12 0.12

1 40° C. 0.13 0.13 0.13

2 0.13 0.13 0.14

3 0.13 0.13 0.13

4 25° C. 0.13 0.13 0.13

5 0.13 0.13 0.13

6 0.13 0.14 0.13

3 0.13 0.13 0.13

6 0.12 0.12 0.12

9 0.13 0.13 0.13

12 0.13 0.12 0.12 [0011] The most widely used forms of orally administered drugs, including LT4-Na, are solid preparations designed to be swallowed by the patient and subsequently disintegrate in the stomach or gastrointestinal tract. Such conventional solid preparations are most commonly in pill, tablet, or capsule form. But a surprising number of people have trouble in swallowing such solid preparations. For example, one study reports that an estimated 50% of the population suffers from difficulty in swallowing conventional tablets, a condition known as dysphagia (See, e.g., Seager, H., J. Pharm. Pharmacol. 50: 375-382, 1998). Conventional pills, tablets, and capsules are difficult to take by patients who suffer from dysphagia (prevalent in geriatric and/or pediatric populations) or who are water-restricted (e.g., nephropathy patients) or who are bedridden and have difficulty sitting up. Orodispersible pills, tablets or capsules that rapidly disintegrate in the saliva of a patient’s mouth (e.g., buccal and/or sublingual spaces) without need for swallowing, or taking water to assist in swallowing, have the potential to overcome these problems. But formulating drugs in safe and effective orodispersible tablets, pills, or capsules presents difficult technical challenges. Few orodispersible drugs are approved by the United States Food and Drug Administration, and LT4-Na is not among them.

Summary of the Invention

[0012] Embodiments of the invention provide unit-dose, orodispersible compositions that comprise a therapeutically effective amount of a levothyroxine sodium; 50% (w/w) to 95% (w/w) of an alditol; 0.01% (w/w) to 10% (w/w) of a vinyl polymer; 0.5% (w/w) to 5% (w/w) of a polar solvent; and 5% (w/w) to 25% (w/w) of a co-solvent. Such composition exhibit, in the Example 3 LT4-Na Dissolution Assay, an extent and rate of input levothyroxine sodium dissolution of at least 70% in five minutes.

[0013] In some embodiments, the alditol is selected from the group consisting of mannitol, xylitol, dextrose, maltodextrin, sorbitol, and a combination thereof. In some embodiments, the solvent is selected from the group consisting of water, ethanol, and a combination thereof. In some embodiments, the co-solvent is selected from the group consisting of glycerin, propylene glycol, polyethylene glycol, and a combination thereof.

[0014] In some embodiments, the solid, unit-dose, orodispersible compositions comprise from 0.01% (w/w) to 5% (w/w) of a pH adjusting agent. In some embodiments, the alditol is mannitol, the vinyl polymer is polyvinylpyrrolidone, the solvent is water; and the co-solvent is glycerin. In some embodiments, the pH adjusting agent is Na2COs and the composition comprises 12.5 pg to 2.5 mg of the levothyroxine sodium; 75% (w/w) to 95% (w/w) of the mannitol; 0.05% (w/w) to 5% (w/w) of the polyvinylpyrrolidone; 1% (w/w) to 2.5% (w/w) of the water;7.5% (w/w) to 20% (w/w) of the glycerin; and 0.05% (w/w) to 2.5% (w/w) of the Na2COs. In some embodiments, the polyvinylpyrrolidone has a K-value of 27.0 to 32.4, a 2-pyrrolidone content of no more than 3.0g/100g, a vinylpyrrolidone content of no more than 10 mg/kg, a heavy metals content of no more than 10 mg/kg, a lead content of no more than 10 mg/kg, a water content of no more than 5.0 g/lOOg, a formic acid content of no more than 0.5 g/lOOg, a sulfite content of no more than 500 mg/kg, a nitrogen (anhydrous basis) content of no 11.5-12.8 g/lOOg, and a peroxide content of less than 400 ppm.

[0015] In some embodiments, the unit-dose, orodispersible composition exhibit, in the Example 3 LT4-Na Dissolution Assay, an extent and rate of input levothyroxine sodium dissolution of at least 80% in five minutes, at least 90% in five minutes, or at least 95% in five minutes.

[0016] Certain embodiments of the invention provide unit-dose, orodispersible compositions that consist essentially of a therapeutically effective amount of a levothyroxine sodium; 50% (w/w) to 95% (w/w) of an alditol; 0.01% (w/w) to 10% (w/w) of a vinyl polymer; 0.5% (w/w) to 5% (w/w) of a polar solvent; and 5% (w/w) to 25% (w/w) of a co-solvent. Such composition exhibit, in the Example 3 LT4-Na Dissolution Assay, an extent and rate of input levothyroxine sodium dissolution of at least 70% in five minutes.

[0017] In some embodiments, the alditol is selected from the group consisting of mannitol, xylitol, dextrose, maltodextrin, sorbitol, and a combination thereof. In some embodiments, the solvent is selected from the group consisting of water, ethanol, and a combination thereof. In some embodiments, the co-solvent is selected from the group consisting of glycerin, propylene glycol, polyethylene glycol, and a combination thereof.

[0018] In some embodiments, the unit-dose, orodispersible compositions consist essentially of from 0.01% (w/w) to 5% (w/w) of a pH adjusting agent. In some embodiments, the alditol is mannitol, the vinyl polymer is polyvinylpyrrolidone, the solvent is water; and the cosolvent is glycerin. In some embodiments, the pH adjusting agent is Na2COs and the composition comprises 12.5 pg to 2.5 mg of the levothyroxine sodium; 75% (w/w) to 95% (w/w) of the mannitol; 0.05% (w/w) to 5% (w/w) of the polyvinylpyrrolidone; 1% (w/w) to 2.5% (w/w) of the water;7.5% (w/w) to 20% (w/w) of the glycerin; and 0.05% (w/w) to 2.5% (w/w) of the Na2COs. In some embodiments, the polyvinylpyrrolidone has a K-value of 27.0 to 32.4, a 2-pyrrolidone content of no more than 3.0g/100g, a vinylpyrrolidone content of no more than 10 mg/kg, a heavy metals content of no more than 10 mg/kg, a lead content of no more than 10 mg/kg, a water content of no more than 5.0 g/lOOg, a formic acid content of no more than 0.5 g/lOOg, a sulfite content of no more than 500 mg/kg, a nitrogen (anhydrous basis) content of no 11.5-12.8 g/lOOg, and a peroxide content of less than 400 ppm.

[0019] In some embodiments, the unit-dose, orodispersible composition exhibit, in the Example 3 LT4-Na Dissolution Assay, an extent and rate of input levothyroxine sodium dissolution of at least 80% in five minutes, at least 90% in five minutes, or at least 95% in five minutes.

[0020] Certain embodiments of the invention provide unit-dose, orodispersible compositions that consist essentially of levothyroxine sodium in an amount selected from the group consisting of 25 pg, 50 pg, 100 pg, 150 pg, 200 pg, 250 pg, 300 pg, 350 pg, 400 pg, 500 pg, 600 pg, 700 pg, 800 pg, 900 pg, 1 mg, 1.5 mg, 2 mg, or 2.5 mg; 75% (w/w) to 95% (w/w) mannitol; 0.05% (w/w) to 5% (w/w) polyvinylpyrrolidone; 1% (w/w) to 2.5% (w/w) water; 7.5% (w/w) to 20% (w/w) glycerin; and 0.05% (w/w) to 2.5% (w/w) Na2COs. In such embodiments, the composition exhibits, in the Example 3 LT4-Na Dissolution Assay, an extent and rate of input levothyroxine sodium dissolution of at least 70% in five minutes, and the polyvinylpyrrolidone has a K-value of 27.0 to 32.4, an aldehyde content of no more than 500 mg/kg, a hydrazine content of no more than 1 mg/kg, a 2-pyrrolidone content of no more than 3.0g/100g, a vinylpyrrolidone content of no more than 10 mg/kg, a heavy metals content of no more than 10 mg/kg, a lead content of no more than 10 mg/kg, a water content of no more than 5.0 g/lOOg, a formic acid content of no more than 0.5 g/lOOg, a sulfite content of no more than 500 mg/kg, a nitrogen (anhydrous basis) content of no 11.5-12.8 g/lOOg, and a peroxide content of less than 400 ppm. In some embodiments, the unit-dose, orodispersible composition exhibit, in the Example 3 LT4-Na Dissolution Assay, an extent and rate of input levothyroxine sodium dissolution of at least 80% in five minutes, at least 90% in five minutes, or at least 95% in five minutes.

[0021] Certain embodiments of the invention provide solid, unit-dose, orodispersible composition that comprise about 50-95% (w/w) of an alditol; about 0.01-10% (w/w) of a vinyl polymer; about 5-50% (w/w) of a granulating solution, which granulating solution comprises an amount of a levothyroxine sodium sufficient to cause the solid, unit-dose, orodispersible composition to comprise the therapeutic equivalent of 12.5 pg, 25 pg, 50 pg, 100 pg, 200 pg, 300 pg, 400 pg, 500 pg, 600 pg, 700 pg, 800 pg, 900 pg, or 1 mg of the levothyroxine sodium, about 5%-45% (w/v) of a solvent, about 5%-95% (w/v) of a co-solvent, and about 0.01%-5% (w/v) of a pH adjusting agent. Such orodispersible composition exhibits, in the Example 3 LT4-Na Dissolution Assay, an extent and rate of input levothyroxine sodium dissolution of at least 70% in five minutes.

[0022] In certain embodiments, solid, unit-dose, orodispersible composition further comprises a pH adjusting agent, the alditol is selected from the group consisting of mannitol, sorbitol, xylitol, dextrose, maltodextrin and a combination thereof; the solvent is selected from the group of polar solvents consisting of water, ethanol, and a combination thereof; and the co-solvent is selected from the group consisting of glycerin, propylene glycol, polyethylene glycol, and a combination thereof.

[0023] In certain embodiments, the alditol is mannitol; the vinyl polymer is polyvinylpyrrolidone; the solvent is water; the co-solvent is glycerin; and the pH adjusting agent is Na2COs.

[0024] In certain embodiments, the orodispersible composition comprises: from about 70% (w/w) to about 90% (w/w) of the mannitol, from about 0.1% (w/w) to about 5% (w/w) of the polyvinylpyrrolidone; and from about 5% (w/w) to about 30% (w/w) of the granulating solution; and the granulating solution comprises: from about 5% (w/v) to about 15% (w/v) of the water, from about 80% (w/v) to about 95% (w/v) of the glycerin, and from about 1 % (w/v) to about 5% (w/v) of the Na2COs. In certain embodiments, the solid, unit-dose, orodispersible composition exhibits in the Example 3 LT4-Na Dissolution Assay, an extent and rate of input levothyroxine sodium dissolution of at least 80%, 85%, 90%, or 95% in five minutes.

Detailed Description of the Invention

[0025] LT4-Na demonstrates pH dependent aqueous solubility and has an intrinsic pH of around 8.5. The LT4-Na drug substance is less soluble in the environment pH range of 4 to 8 with a significant increase in drug solubility at environmental pH above pH 9. Solubility is a critical step in the absorption of any drug product, where drug molecules have to disperse from their carrier systems, solubilize, and only then become available to be absorbed into any biological system. In the case of LT4-Na, a potential target orodispersible formulation would have the environmental pH of saliva which is between pH 6.5 to pH 7.5 at which the maximum tolerable pH range of the buccal or sublingual cavity is between pH 4.5 to 8.5. This presents a problem for any orodispersible formulation of LT4-Na in which the molecule LT4-Na is not readily soluble within this pH range.

[0026] The present inventors have investigated several technical aspects of formulating safe and effective orodispersible LT4-Na compositions. One such technical aspect studied by the present inventors was the extent and rate of LT4-Na dissolution from a variety of formulations into simulated salivary fluid (SSF). The dissolution assay is described in Example 3. The LT4-Na HPLC assay is described in Example 4. And the results of the dissolution assays are reported in Example 5. As a control, the LT4-Na granulating solution described in Example 1 was studied in the Example 3 dissolution assay. The average of three replicate experiments on the granulating solution batch (#220-23) indicated a dissolution extent and rate of 96 pg LT4-Na (out of a total input of 100 pg LT4-Na) in five minutes. (See Example 5.) Indeed, a highly efficient extent and rate of LT4-Na dissolution.

[0027] Turning to the LT4-Na triturate compositions that contain granulating solution and mannitol (but no added PVP), the present inventors identified a problem in that the extent and rate of LT4-Na dissolution was unsuitably low for purposes of an orodispersible tablet. The average LT4-Na dissolution for three replicate experiments was only 68 pg (out of a total input of 100 pg LT4-Na) in five minutes for one batch (#220-24.1) and 57 pg LT4-Na (out of a total input of 100 pg LT4-Na) in five minutes for the other batch (#220-24.2). (See Example 5.) This result was unexpected since prior compositions of LT4-Na for injection were formulated as lyophilized powders comprising LT4-Na and significant amounts of mannitol, which were to be reconstituted in saline solution prior to injection. An expected property of such powders of LT4-Na and mannitol would have been a highly efficient extent and rate of LT4-Na dissolution. At least in part because a healthcare workers administering LT4-Na injections are doing so under emergency circumstances in which the patient is most commonly under severe distress of myxedema coma. Those circumstances would demand that the healthcare worker administer an accurate dose of LT4-Na (since it is a narrow therapeutic index drug) in a highly time efficient manner (since myxedema coma patients suffer injuries that compound with time). Two requirements that conflict with a composition of LT4-Na and mannitol that must be reconstituted prior to use but exhibits a low extent and rate of LT4-Na dissolution. [0028] Though mannitol may have the significant drawback stated above, it also has several desirable properties as a diluent and disintegrant in a orodispersible tablet, capsule, or pill. For instance, and without limitation, mannitol is highly soluble in salivary fluid such that it disintegrates rapidly in sublingual and buccal spaces without the need for a patient to take additional water. Mannitol also has a slightly sweet flavor and provides a cooling effect, each of which are palatable to patients and promotes patient compliance dosing regimens. Further, mannitol is widely recognized by regulatory authorities as a safe pharmaceutical excipient; and it is commercially available at reasonable cost in pharmaceutical grades. Mannitol is highly compactible and shows favorable friability and hardness properties favorable for forming into tablets, capsules, and pills.

[0029] Multiple classes of excipients, each comprising tens to hundreds or thousands of member compounds, polymers, etc. possessing a staggeringly broad diversity of chemical structures and properties, could potentially be employed as an agent for increasing the extent and rate of LT4-Na dissolution from the triturate compositions comprising LT4-Na granulating solution and mannitol. Such classes include, without limitation, diluents, disintegrants, glidants, lubricants, solvents, etc. It was, however, a priori, unpredictable which of such excipients, if any, would effectively increase the rate and/or extent of LT4-Na dissolution from the triturate composition. In no small part because of the enormous complexity of potential chemical interactions among the compounds of the system, including LT4-Na, glycerol, Na2COs, H2O, mannitol, and excipients.

[0030] Indeed, the present inventors tested several excipients for their ability to increase the extent and rate of LT4-Na dissolution from triturate compositions comprising LT4-Na granulating solution and mannitol, as well as other bulking agents. Most all of those tests failed to achieve compositions having LT4-Na dissolution properties acceptable for orodispersible formulations. In addition, many of those compositions were characterized by unacceptable LT4- Na stability profiles.

[0031] The present inventors discovered that adding 0.1% w/w PVP, 0.5 % w/w PVP, 1.0 % PVP or 3.0% w/w PVP to the LT4-Na triturate composition comprising granulating solution and mannitol significantly increased the extent and rate of LT4-Na dissolution. The average LT4- Na dissolution for three replicate experiments of batch No. 220-26A (0.1% w/w PVP) was 97 pg (out of a total input of 100 pg LT4-Na) in five minutes. The average LT4-Na dissolution for three replicate experiments of batch No. 220-26B (0.5% w/w PVP) was 96 pg (out of a total input of 100 pg LT4-Na) in five minutes. The average LT4-Na dissolution for three replicate experiments of batch No. 220-26C (1.0 % w/w PVP) was 98 pg (out of a total input of 100 pg LT4-Na) in five minutes. The average LT4-Na dissolution for three replicate experiments of batch No. 220-26C (3.0% w/w PVP) was 95 pg (out of a total input of 100 pg LT4-Na) in five minutes. (See Example 5.)

[0032] The extent and rate of LT4-Na dissolution from PVP-comprising triturate batch Nos. 220-26A, 220-26B, 220-26C, and 220-26D was even greater than required for an orodispersible formulation. These results are surprising and unexpected not only in view of the unpredictability in the system described above, but also because the 105 patent teaches that, for the Example 1 preparation of the 204 patent comprising LT4-Na and PVP, a non-uniform granulating was obtained that was difficult to convert into solid dosage form. Unknown peaks were visible in the stability samples. The peaks were hypothesized to be due to an adduct formed in solution between LT4-Na and PVP, which would be expected to be stable complex from which the LT4-Na would not release.

[0033] It is well known in chemistry that an adduct can be a product of a direct addition of two or more distinct molecules, resulting in a single reaction product containing all atoms of all components. Such adducts include the combination of Lewis acids and Lewis bases into a single molecule. But adducts are not necessarily molecular in nature. Exemplary adducts from include those of ethylene or carbon monoxide and CuAlCu. The latter is a solid with an extended lattice structure. Upon formation of the adduct, a new extended phase is formed in which the gas molecules are incorporated (inserted) as ligands of the copper atoms within the structure. In the present case, it the present inventors contemplate, without being bound to any particular theory, that the adduct taught by the 105 patent is the network of PVP polymers having LT4-Na incorporated therein as ligands of the PVP polymers.

[0034] The orodispersible compositions of the present invention may be administered by routes that include sublingual, buccal, and transmucosal, as well as rectal and vaginal routes. Pharmaceutically acceptable excipients suitable for use in such compositions include, but are not limited to preservatives, buffers, antioxidants, fillers, extenders, carriers, binders, diluents, disintegrants, glidants, lubricants, suspending agents, and solvents. Compounds such as dyes, colorants, sweeteners, flavorings, perfuming agents, and taste-masking agents also may be included in compositions according to the present invention. In addition, active ingredients in addition to LT4-Na may be included to produce a dual or multiple ingredient medication.

[0035] Exemplary disintegrants may be selected from known pharmaceutical excipients such as, for example, crospovidone, crosscarmelose sodium, sodium starch glycolate, partially gelatinized starches, polacrilin potassium.

[0036] Exemplary lubricants and/or glidants may be selected from known pharmaceutical excipients such as, for example, talc, calcium stearate, sodium stearyl fumarate, stearic acid, magnesium stearate, solid polyethylene glycols, cocoa butter, hydrogenated vegetable oil, mineral oil, sodium lauryl sulfate, glyceryl palmitostearate, and a glyceryl behenate.

[0037] Exemplary binders and/or fillers may be selected from known pharmaceutical excipients such as, for example, polyvinylpyrrolidone, sodium citrate, dicalcium phosphate, alkaline inorganic salts, alginates, gelatins, chitosan, kaolin, magnesium carbonate, calcium carbonate, acacia, methyl cellulose, liquid glucose tragacanth, ethyl cellulose, gelatin, microcrystalline cellulose, hydroxypropylmethyl cellulose, starch paste, hydroxypropyl cellulose, starch, pregelatinized starch, sodium carboxymethyl cellulose, alginic acid, polyvinylpyrrolidone (PVP), cellulose, polyethylene glycol, polyvinyl alcohols, and polymethacrylates.

[0038] Solid dosage forms which may be prepared according to the present invention include tablets, capsules, pills, pellets, and powders, as well as rectal or vaginal suppositories, or any combination thereof.

[0039] The preferred active ingredient in the orodispersible compositions of the present invention is LT4-Na. Therapeutically effective dosage amounts for this drug that may be used in the orodispersible compositions of the present invention generally range from about 0.1 pg to about 5000 pg LT4-Na and are most preferably from about 12.5 pg to about 300 pg LT4-Na. Exemplary dosages therefore include, but are not limited to 12.5 pg LT4-Na, 25 pg LT4-Na, 50 pg LT4-Na, 75 pg LT4-Na, 88 pg LT4-Na, 100 pg LT4-Na, 112 pg LT4-Na, 125 pg LT4-Na, 150 pg LT4-Na, 175 pg LT4-Na, 200 pg LT4-Na, 300 pg LT4-Na, 400 pg, LT4-Na 500 pg, 600 pg LT4-Na, 700 pg LT4-Na, 800 pg LT4-Na, 900 pg LT4-Na, 1 mg LT4-Na, 2 mg LT4-Na, 3 mg LT4-Na, 4 mg LT4-Na, or 5 mg LT4-Na.

[0040] In certain embodiments, the orodispersible compositions of the present invention comprise alditols that, without limitation, may be selected from the group consisting of mannitol, sorbitol, erythritol, lactitol, maltitol, xylitol, and combinations thereof. The orodispersible compositions of the present invention may comprise such alditols, individually or in combination, in (w/w) percentages of the composition ranging from about 10% to about 95%, such as about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and ranges therebetween.

[0041] In certain embodiments, the orodispersible compositions of the present invention comprise PVP in (w/w) percentages of the composition ranging from 0.001% to about 10%, such as about 0.001%, about 0.005%, about 0.01%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 7.5%, about 10%, and ranges therebetween. In certain embodiments, the PVP is PVP K 30 low peroxide characterized by having the following properties: pH 3.0-5.0, K-value 27.0-32.4, aldehydes no more than 500 mg/kg, hydrazine no more than 1 mg/kg, 2-pyrrolidone no more than 3.0 g/lOOg, vinylpyrrolidone no more than 10 mg/kg, heavy metals no more than 10 mg/kg, lead no more than 10 mg/kg, water no more than 5.0 g/lOOg, residue on ignition / sulphated ash no more than 0.1 g/lOOg, formic acid no more than 0.5 g/lOOg, sulfite no more than 500 mg/kg, nitrogen (anhydrous basis) 11.5-12.8 g/lOOg, total aerobic microbial count test method Ph. Eur. 2.6.12 no more than 20 CFU/g, total combined yeasts/molds count test method Ph. Eur. 2.6.12 no more than 20 CFU/g, a peroxide content of less than 400 ppm, less than 300 ppm, less than 200 ppm, less than 100 ppm, less than 50 ppm, less than 40 ppm, less than 30 ppm, less than 20 ppm, or less than 10 ppm.

[0042] In certain embodiments, the orodispersible compositions of the present invention comprise antioxidants that, without limitation, may be selected from the group consisting of butylated hydroxyanisole, vitamin E (alpha tocopherol), butylated hydroxytoluene, ascorbic acid, sodium ascorbate, sodium bisulfate, sodium metabisulfite, cysteine, propyl gallate, beta mercaptoethanol, lutein, lycopene, and combinations thereof. The orodispersible compositions of the present invention may comprise such antioxidants, individually or in combination, in (w/w) percentages of the composition ranging from about 0.001% to about 5%, such as about 0.001%, about 0.005%, about 0.01%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, and ranges therebetween. [0043] The orodispersible compositions of the present invention may comprise lubricants, individually or in combination, in (w/w) percentages of the composition ranging from about 0.1% to about 10% such as about 0.1%, about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10% and ranges therebetween.

[0044] The orodispersible compositions of the present invention may comprise binders and/or fillers, individually or in combination, in (w/w) percentages of the composition ranging from about 0.001% to about 10% such as about 0.001%, about 0.005%, about 0.01%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10% and ranges therebetween.

[0045] The orodispersible compositions of the present invention may comprise lubricants, individually or in combination, percentages, in (w/w) percentages of the composition ranging from about 0.01% to about 10% such as about 0.01%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10% and ranges therebetween.

[0046] The orodispersible compositions of the present invention may comprise disintegrants, individually or in combination, percentages, in (w/w) percentages of the composition ranging from about 0.01% to about 10% such as about 0.01%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10% and ranges therebetween.

[0047] Examples of pharmaceutically acceptable pH adjusting agents and/or buffers suitable for use in compositions of the present invention include, but are not limited to, hydrochloric acid, acetic acid, sodium acetate, formic acid, sodium formate, oxalic acid, sodium oxalate, nitrous acid, sodium nitrite, hydrofluoric acid, sodium bifluoride, sulfurous acid, phosphoric acid, benzoic acid, sodium benzoate, citric acid, sodium citrate, sodium bicarbonate, sodium phosphate, sodium biphosphate, dibasic sodium phosphate, disodium hydrogen phosphate, trisodium phosphate, magnesium oxide, calcium carbonate, sodium carbonate, bicarbonate, calcium bicarbonate, sodium bicarbonate, ammonium chloride, sodium hydroxide, magnesium hydroxide, acetate buffers, citrate buffers, phosphate buffers, lactic acid buffers, TRIS buffers, HEPES buffers, and borate buffers. Such pH adjusting agents and/or buffers are included in compositions according to the present invention in amounts, either individually or in aggregate, required to maintain the pH of a composition between a pH of about 6 and about 10 or a pH between about 7.0 to about 9.0, or a pH at or about any one of 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.

[0048] As used herein, the terms “therapeutically effective amount” or “effective amount” refer to an amount of a composition or formulation of this invention that elicits a therapeutically useful response in a subject. Those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject.

[0049] In certain embodiments, the orodispersible compositions of the invention comprise LT4-Na and/or excipients that have not been subjected to techniques that reduce their particle size such as, without limitation, dry, wet, jet, or ball milling; sonication; microfluidizing; rapid expansion of supercritical solutions, supercritical anti-solvent, or particles from gas saturated solutions. In certain embodiments, the orodispersible compositions of the invention are free of added type-C methacrylic acid copolymer. In certain embodiments, the orodispersible compositions of the invention are not effervescent.

[0050] In certain embodiments, orodispersible compositions of the invention are characterized by exhibiting an extent and rate of input LT4-Na dissolution in the LT4-Na Dissolution Assay described in Example 3 of at least 70%, at least 75%, at least 80%, at least 85%, at least 90% at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the input LT4-Na in five minutes, in some embodiments 4 minutes, in some embodiments 3 minutes, in some embodiments 2 minutes, and in some embodiments 1 minute.

[0051] As used herein, the terms “stable” and “stability” encompass any characteristic of an orodispersible composition of the present invention that may be affected by storage conditions including, without limitation, LT4-Na assay and/or potency, LT4-Na total impurities and/or degradation products, composition water content, appearance, friability, hardness, or color. The storage conditions which may affect stability include, for example, duration of storage, temperature, humidity, and/or light exposure. [0052] In certain embodiments of the invention, a stable LT4-Na composition maintains at least about 90%, at least about 95%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the labeled and/or starting concentration of LT4-Na after storage at 20°C to 30°C (or any integer temperature therebetween) for at least four months, at least six months, at least nine months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In certain embodiments, a stable LT4-Na composition maintains at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% of the labeled and/or starting concentration of LT4-Na after storage at 40°C to 50°C (or any integer temperature therebetween) for at least one week, at least two weeks, at least three weeks, at least one month, at least two months, at least three months, at least four months, at least six months, at least nine months, or at least 12 months. In certain embodiments, a stable LT4-Na composition maintains at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% of the labeled and/or starting concentration of LT4- Na after storage at 60°C to 70°C (or any integer temperature therebetween) for at least one day, at least two days, at least three days, at least four days, at least five days, at least six days, at least seven days, at least eight days, at least nine days, or at least 10 days. Relative humidity at which the orodispersible compositions of the present invention may demonstrate the preceding LT4-Na stability properties can be from 20% to 88% (or any integer percentage therebetween), in dark or light conditions.

[0053] The following examples further illustrate the invention and are not to be construed to limit the claims.

EXAMPLE 1

[0054] Placebo and Granulating Solution. Levothyroxine sodium triturates according to the present invention were made by manufacturing a granulating solution and incorporating it into a triturate blend by a liquid solid dispersion process. As a first step in the process evothyroxine sodium was directly dissolved in a solution composed of glycerin, sodium carbonate and water. First, 100 mL of bulk granulating solution was prepared. Sodium carbonate was dissolved in purified water, to which glycerin was added in a quantity sufficient to achieve a total volume of 100 mL. This solution was split into two equal parts: (i) a 50 mL portion designated, placebo, to which nothing was added and (ii) another 50 mL portion, designated, granulating solution, to which levothyroxine sodium was added in a quantity sufficient to yield a concentration of 100 mg/mL, which corrected for purity and water content amounts to 75.2 mg/g LT4-Na. Table 1 provides the compositions of the placebo and granulating solution.

[0055] Suitable techniques for dissolving sodium carbonate and levothyroxine sodium in the granulating solution include mixing by homogenization, magnetic stirring, shaking, swirling, and the like. The mixing and dissolving steps performed in forming the placebo and granulating solutions were conducted at room temperature 25°C ± 5°C.

[0056] Placebo. In greater detail, bulk solution was made by weighing 2 g of sodium carbonate, NF into a 100 mL volumetric flask. 8mL of purified water were added and the contents were dissolved by shaking. 111.6 g of glycerin, equivalent to 90mL, were transferred to the volumetric flask and a magnetic stir bar was added for mixing. After 10 minutes of stirring, the solution was ready for use.

[0057] Granulating solution. In greater detail, granulating solution was made by weighing 5.5 g of LT4-Na and transferring it to a 50 mL volumetric flask. Placebo was added up to the neck and the contents were dissolved by agitation. The volume was adjusted to 50 mL with placebo, and the resulting granulating solution was mixed with a magnetic stir bar. After 1 hour of mixing, the granulating solution was ready for use.

Table 1

Ingredient Placebo Granulating Solution

LT4-Na, USP 0% (w/w) 10% (w/w)*

Glycerin 99.7%, USP 90% (w/w) 80% (w/w)

Na₂CO₃, NF 2% (w/w) 2% (w/w)

Purified Water 8% (w/w) 8% (w/w)

*7.52% (w/v) when corrected for impurities and water content.

EXAMPLE 2

[0058] LT4-Na Triturates. LT4-NA sodium triturates according to the present invention were made by incorporating the granulating solution into a triturate blend by liquid solid dispersion. The resulting blend was apparently dry, free-flowing, and compressible. First, 500 g of mannitol (particle size distribution by laser diffraction: dvlO = 3.5 pm dv50 = 24 pm dv90 = 55 pm, melting temperature 169°C, water content less than 0.5%, bulk density 0.48 g/ml, tapped density: 0.74 g/ml, true density: 1.514 g/ml, specific surface area: 0.8 m²/g, very soluble in water (216 mg/ml at 25 °c), practically insoluble in ethanol) were pre-treated by pulverizing and passing thorough 10 and 20 mesh. The pulverized mannitol was transferred to a 3 -dimensional, shakermixer machine mixing vessel and set to the lowest speed. 83 g of the granulating solution prepared in Example 1 were then slowly added to the pulverized mannitol, by pouring. The mixture was passed through mesh 10 and 20. The resulting material was transferred to a stainless-steel vessel for additional mixing in a 3 -dimensional, shaker- mixer machine, which yielded the LT4-Na sodium triturates.

[0059] Suitable techniques for performing the process steps for liquid solid dispersion of LT4-Na granulating solution into the mannitol-based triturate include orbital stand mixing and 3- dimensional, shaking-mixing. The mixing steps performed in forming mannitol-based LT4-Na triturate of the preset invention were conducted at 25±5°C. Table 2 states the composition of the LT4-Na triturate.

Table 2

Ingredient Triturate % (w/w)

Granulating solution (w/w) 14.24%

Mannitol (w/w) 85.76%

Total batch size (g) 583g

[0060] Additional LT4-Na triturate compositions were made by adding to the composition stated in Table 2 PVP to an amounts 0.1% w/w, 0.5% w/w, 1.0% w/w PVP, or 3.0% w/w PVP. The batch numbers for the granulating solution and LT4-Na triturates are set forth in Table 3.

Table 3

Composition Batch No.

Granulating solution 220-23

LT4-Na Triturate 220-24.1

LT4-Na Triturate 220-24.2

LT4-Na Triturate + 0.1% w/w PVP 220-26A

LT4-Na Triturate + 0.5% w/w PVP 220-26B

LT4-Na Triturate + 1.0% w/w PVP 220-26C

LT4-Na Triturate + 3.0% w/w PVP 220-26D

EXAMPLE 3

[0061] LT4-Na Dissolution Assay. Rate of solubility studies were conducted on samples of granulating solution and LT4-Na triturate formulations containing 0.0% (w/w), 0.1% (w/w), 0.5% (w/w), 1% (w/w), and 3% (w/w) PVP K30LP. Each sample was tested in triplicate. LT4-Na triturates were packaged in airtight, amber glass containers. An identification label was placed on the outer packaging. Dissolution of the granulating solution and the LT4-Na triturates were tested in simulated saliva fluid (SSF), pH adjusted to 8.5. To prepare 1 liter of SSF pH 8.5, 8 g of sodium chloride, 0.19 g of potassium phosphate monobasic, and 2.38 g of sodium phosphate dibasic were dissolved in 900 mL purified water. The pH was adjusted to 8.50 ± 0.05 with IN sodium hydroxide, and the solution was diluted to final volume of 1 L.

[0062] The dissolution experiments were conducted using a Franz diffusion apparatus equipped with vertical diffusion chambers and magnetic stirring, at a rate of 600 RPM. 10 mL of SSF were pipetted into each chamber and allowed to equilibrate to a temperature of 37°C ± 1°C for 1 hour prior to testing. The top portion of the receptor chambers were sealed off to prevent evaporation of the medium.

[0063] Once equilibrated, a suitable amount of triturate, based on label claim, was accurately weighed to deliver a test concentration of (100 pg LT4-NA/mL). For example, the control triturate without any PVP added has a label claim of 10.7 mg LT4-Na/g. To test the control triturate, approximately 95 mg of triturate must be transferred into the chamber to yield a theoretical maximum solubility of 100 pg/mL. The receptor chamber was sealed off and a single collection timepoint was performed at 5 minutes. The aliquoted sample was filtered through a 0.22 pm PVDF filter into HPLC vials and quickly transferred into the HPLC vial tray controlled at 37°C ± 1°C.

EXAMPLE 4

[0064] LT4-Na HPLC Assay. The equipment used to determine the concentration of LT4- Na in the collected aliquots is a high-performance liquid chromatography (HPLC) system equipped variable wavelength and/or PDA (DAD) detector, column heater and chiller, sample compartment heater and chiller, binary or a tertiary solvent pump; column: Zorbax Eclipse Plus, C18, 150 x 4.6 mm, 3.5pm, PN: 959963-902 or equivalent and Empower software. Reagents, chromatographic parameters, and reference solutions employed in the HPLC stability studies are set forth in Tables 4, 5, and 6.

Table 4

_ HPLC Reagents _

LT4-Na Reference Standard

Acetonitrile (HPLC grade)

Methanol (HPLC grade or equivalent)

Potassium Dihydrogen Phosphate (KH2PO4, ACS grade)

Phosphoric Acid, 85% (H3PO4, HPLC grade) Triethylamine (CeHisN, HPLC grade) Phosphoric Acid, 85% (H3PO4, HPLC grade) Purified Water

Diluent: Methanol: Water (80:20 %v/v)

Mobile Phase A:

0.02M KH2PO4 Buffer + 0.2% Triethylamine pH 2.5+0.1 with orthophosphoric acid Mobile Phase B: 100% Acetonitrile

Needle Wash: 100% Acetonitrile

Table 5

Chromatographic Parameters

System HPLC System with UV Detector

Zorbax Eclipse Plus,

Column C18, 150 x 4.6 mm, 3.5pm,

PN: 959963-902

Column T emperature 45⁰ C

S ample T emperature 10⁰ C

Detector/Wavelength UV @ 225 nm

Flow Rate 1.0 ml/min

Isocratic: On-line Mixing.

Pump Mode Mobile Phase A: Mobile Phase B

(65:35)

Injection Volume 10 pL

Run Time 10 minutes

Retention Times Between 5-6 minutes for LT4-Na Peak

Limit of Quantitation LOQ about 0.05 pg/mL

Table 6

HPLC Suitability and Reference Solutions

Weigh and transfer about 5.5 mg of LT4-Na reference standard into LT4-Na Assay Working 200 mL amber colored volumetric Standard (“AWS”) flask. Add about 50 ml of diluent.

Sonicate to dissolve. Dilute to volume with Diluent and mix well. , _ . . _ , . Prepare in the same manner as

Check Standard Solution .

AWS

Blank solution Diluent

[0065] The HPLC system was deemed suitable for assay of LT4-Na if the following criteria are met: (1) No significant interfering peaks, from the diluent (blank) injection, should be detected at the retention time of LT4-Na. (2) The tailing factor of LT4-Na peak, in AWS, should be NMT 2.0. (3) The %RSD of LT4-Na peak areas, from five replicate injections of AWS, should be NMT 2.0%. (4) Similarity factor between AWS and Check Standard Solution should be within 0.98 and 1.02. (5) The overall %RSD of LT4-Na peak areas, from AWS injections, should be NMT 2.0%.

[0066] The following calculations were used in the HPLC Assay Method for the system suitability and assay determination of LT4-Na sodium.

[0067] Similarity Factor Equation:

Avg. area of Working Standard Weight of Check Standard

Similarity Factor = - - X

Avg. area of Check Standard Weight of Working Standard

[0068]Assay Calculation:

% Assay

Where:

Ru = LT4-Na peak area response obtained from Sample Solution.

Rs = average LT4-Na peak area response obtained from the AWS.

Cu = Concentration of AWS.

Cs = Concentration of sample solution.

EXAMPLE 5

[0069] Dissolution Experimental Results.

Table 7

Composition LT4-Na (mg/g)

Granulating solution 220-23 76.14

Triturate 220-24.1 10.84

Triturate 220-24.2 10.75

Triturate + 0.1% w/w PVP 220-26A 10.53

Triturate + 0.5% w/w PVP 220-26B 10.50

Triturate + 1.0% w/w PVP 220-26C 10.12

Triturate + 3.0% w/w PVP 220-26D 9.52

Table 8

Dissolved

Sample 220-23 220-24.1 220-24.2 220-26A 220-26B 220-26C 220-26D

68 57 96 97 98 92 Sample 2 95 68 57 97 96 96 97 Sample 3 98 71 59 97 97 99 95 Average 96 69 58 97 96 98 95 SD 2.157 1.906 1.355 0.508 0.762 1.746 3.474 % RSD 2.3 2.8 2.3 0.5 0.8 1.8 3.7

[0070] Although the disclosure has been provided in the context of certain embodiments and examples, it will be understood by those skilled in the art that the disclosure extends beyond the specifically described embodiments to other alternative embodiments and/or uses and obvious modifications and equivalents thereof. Accordingly, the disclosure is not intended to be limited by the specific disclosures of embodiments herein.

Claims

WHAT IS CLAIMED IS:

1. A unit-dose, orodispersible composition comprising:

- a therapeutically effective amount of a levothyroxine sodium;

- 50% (w/w) to 95% (w/w) of an alditol;

- 0.01% (w/w) to 10% (w/w) of a vinyl polymer;

- 0.5% (w/w) to 5% (w/w) of a polar solvent; and

- 5% (w/w) to 25% (w/w) of a co-solvent, wherein the composition exhibits, in the Example 3 LT4-Na Dissolution Assay, an extent and rate of input levothyroxine sodium dissolution of at least 70% in five minutes.

2. The unit-dose, orodispersible composition of claim 1, wherein:

- the alditol is selected from the group consisting of mannitol, xylitol, dextrose, maltodextrin, sorbitol, and a combination thereof;

- the solvent is selected from the group consisting of water, ethanol, and a combination thereof; and

- the co-solvent is selected from the group consisting of glycerin, propylene glycol, polyethylene glycol, and a combination thereof.

3. The unit-dose, orodispersible composition of claim 2, further comprising 0.01% (w/w) to 5% (w/w) of a pH adjusting agent, wherein:

- the alditol is mannitol;

- the vinyl polymer is polyvinylpyrrolidone;

- the solvent is water; and

- the co- solvent is glycerin.

4. The unit-dose, orodispersible composition of claim 3, wherein the pH adjusting agent is Na2COs and the composition comprises:

- 12.5 pg to 2.5 mg of the levothyroxine sodium;

- 75% (w/w) to 95% (w/w) of the mannitol;

23 - 0.05% (w/w) to 5% (w/w) of the polyvinylpyrrolidone;

- 1% (w/w) to 2.5% (w/w) of the water;

- 7.5% (w/w) to 20% (w/w) of the glycerin; and

- 0.05% (w/w) to 2.5% (w/w) of the Na2COs. The unit-dose, orodispersible composition of claim 4, wherein the composition exhibits, in the Example 3 LT4-Na Dissolution Assay, an extent and rate of input levothyroxine sodium dissolution of at least 80% in five minutes. The unit-dose, orodispersible composition of claim 4, wherein the composition exhibits, in the Example 3 LT4-Na Dissolution Assay, an extent and rate of input levothyroxine sodium dissolution of at least 90% in five minutes. The unit-dose, orodispersible composition of claim 4, wherein the composition exhibits, in the Example 3 LT4-Na Dissolution Assay, an extent and rate of input levothyroxine sodium dissolution of at least 95% in five minutes. The unit-dose, orodispersible composition of claim 4, wherein the 0.05% (w/w) to 5% (w/w) polyvinylpyrrolidone has a K-value of 27.0 to 32.4, an aldehyde content of no more than 500 mg/kg, a hydrazine content of no more than 1 mg/kg, a 2-pyrrolidone content of no more than 3.0g/100g, a vinylpyrrolidone content of no more than 10 mg/kg, a heavy metals content of no more than 10 mg/kg, a lead content of no more than 10 mg/kg, a water content of no more than 5.0 g/lOOg, a formic acid content of no more than 0.5 g/lOOg, a sulfite content of no more than 500 mg/kg, a nitrogen (anhydrous basis) content of no 11.5-12.8 g/lOOg, and a peroxide content of less than 400 ppm. A unit-dose, orodispersible composition consisting essentially of: a therapeutically effective amount of a levothyroxine sodium;

50% (w/w) to 95% (w/w) of an alditol;

0.01% (w/w) to 10% (w/w) of a vinyl polymer;

0.5% (w/w) to 5% (w/w) of a polar solvent; and 5% (w/w) to 25% (w/w) of a co- solvent, wherein the composition exhibits, in the Example 3 LT4-Na Dissolution Assay, an extent and rate of input levothyroxine sodium dissolution of at least 70% in five minutes.

10. The unit-dose, orodispersible composition of claim 9, wherein:

11. The solid, unit-dose, orodispersible composition of claim 10, further comprisingO.01% (w/w) to 5% (w/w) of a pH adjusting agent, wherein:

- the alditol is mannitol;

- the vinyl polymer is polyvinylpyrrolidone;

- the solvent is water; and

- the co- solvent is glycerin.

12. The unit-dose, orodispersible composition of claim 11, wherein the pH adjusting agent is Na2COs and the composition comprises:

- 12.5 pg to 2.5 mg of the levothyroxine sodium;

- 75% (w/w) to 95% (w/w) of the mannitol;

- 0.05% (w/w) to 5% (w/w) of the polyvinylpyrrolidone;

- 1% (w/w) to 2.5% (w/w) of the water;

- 7.5% (w/w) to 20% (w/w) of the glycerin; and

- 0.05% (w/w) to 2.5% (w/w) of the Na2COs.

13. The unit-dose, orodispersible composition of claim 12, wherein the composition exhibits, in the Example 3 LT4-Na Dissolution Assay, an extent and rate of input levothyroxine sodium dissolution of at least 80% in five minutes.

14. The unit-dose, orodispersible composition of claim 12, wherein the composition exhibits, in the Example 3 LT4-Na Dissolution Assay, an extent and rate of input levothyroxine sodium dissolution of at least 90% in five minutes.

15. The unit-dose, orodispersible composition of claim 12, wherein the composition exhibits, in the Example 3 LT4-Na Dissolution Assay, an extent and rate of input levothyroxine sodium dissolution of at least 95% in five minutes.

16. The unit-dose, orodispersible composition of claim 12, wherein the polyvinylpyrrolidone has a K-value of 27.0 to 32.4, an aldehyde content of no more than 500 mg/kg, a hydrazine content of no more than 1 mg/kg, a 2-pyrrolidone content of no more than 3.0g/100g, a vinylpyrrolidone content of no more than 10 mg/kg, a heavy metals content of no more than 10 mg/kg, a lead content of no more than 10 mg/kg, a water content of no more than 5.0 g/lOOg, a formic acid content of no more than 0.5 g/lOOg, a sulfite content of no more than 500 mg/kg, a nitrogen (anhydrous basis) content of no 11.5-12.8 g/lOOg, and a peroxide content of less than 400 ppm.

17. A unit-dose, orodispersible composition consisting essentially of:

- levothyroxine sodium in an amount selected from the group consisting of 25 pg, 50 pg, 100 pg, 150 pg, 200 pg, 250 pg, 300 pg, 350 pg, 400 pg, 500 pg, 600 pg, 700 pg, 800 pg, 900 pg, 1 mg, 1.5 mg, 2 mg, and 2.5 mg;

- 75% (w/w) to 95% (w/w) mannitol;

- 0.05% (w/w) to 5% (w/w) polyvinylpyrrolidone;

- 1% (w/w) to 2.5% (w/w) water;

- 7.5% (w/w) to 20% (w/w) glycerin; and

- 0.05% (w/w) to 2.5% (w/w) Na2COs, wherein the composition exhibits, in the Example 3 LT4-Na Dissolution Assay, an extent and rate of input levothyroxine sodium dissolution of at least 70% in five minutes, and

26 wherein the 0.05% (w/w) to 5% (w/w) polyvinylpyrrolidone has a K-value of 27.0 to 32.4, an aldehyde content of no more than 500 mg/kg, a hydrazine content of no more than 1 mg/kg, a 2-pyrrolidone content of no more than 3.0g/100g, a vinylpyrrolidone content of no more than 10 mg/kg, a heavy metals content of no more than 10 mg/kg, a lead content of no more than 10 mg/kg, a water content of no more than 5.0 g/lOOg, a formic acid content of no more than 0.5 g/lOOg, a sulfite content of no more than 500 mg/kg, a nitrogen (anhydrous basis) content of no 11.5-12.8 g/lOOg, and a peroxide content of less than 400 ppm.

18. The unit-dose, orodispersible composition of claim 17, wherein the composition exhibits, in the Example 3 LT4-Na Dissolution Assay, an extent and rate of input levothyroxine sodium dissolution of at least 80% in five minutes.

19. The unit-dose, orodispersible composition of claim 17, wherein the composition exhibits, in the Example 3 LT4-Na Dissolution Assay, an extent and rate of input levothyroxine sodium dissolution of at least 90% in five minutes.

20. The unit-dose, orodispersible composition of claim 17, wherein the composition exhibits, in the Example 3 LT4-Na Dissolution Assay, an extent and rate of input levothyroxine sodium dissolution of at least 95% in five minutes.

27