PHARMACEUTICAL ORAL SOLID DOSAGE FORMS COMPRISING ISOCLONIN SALTS AND LEvothyroxIN SALTS AND

Abstract

Disclosed herein are pharmaceutical oral solid dosage forms comprising a salt of liothyronin and a salt of levothyroxine, and methods of making and using the pharmaceutical oral solid dosage forms.

Description

Technical Field

[0001] The published text relates to oral solid dosage forms of drugs, including iodine salt and levothyroxine salt, and to methods for manufacturing and using oral solid dosage forms. Background Technology

[0002] Hypothyroidism is a common endocrine disorder characterized by a deficiency of thyroid hormones. Iodine deficiency is the leading cause of hypothyroidism worldwide. In the United States and other regions with adequate iodine intake, autoimmune thyroid disease (Hashimoto's disease) is the most common cause of hypothyroidism. Hypothyroidism can also be induced by medication or caused by other iatrogenic factors.

[0003] Hypothyroidism is typically a primary process in which the thyroid gland is unable to produce sufficient amounts of thyroid hormones. Hypothyroidism can also be a secondary process, in which the thyroid gland is normal, but the thyroid gland is understimulated due to insufficient secretion of thyroid-stimulating hormone (TSH) from the pituitary gland. Furthermore, in triadic hypothyroidism, the hypothalamus releases insufficient levels of thyrotropin-releasing hormone (TRH), leading to insufficient TSH release and consequently, insufficient thyroid stimulation.

[0004] Thyroid hormone deficiency has a wide range of effects. Systemic effects are caused by disturbances in metabolic processes or directly by myxedema infiltration (i.e., the accumulation of glucosamine in tissues). Cardiac changes due to hypothyroidism result in decreased contractility, cardiomegaly, pericardial effusion, weakened pulse, and reduced cardiac output. In the gastrointestinal tract, gastric acid deficiency and prolonged intestinal transit time, accompanied by gastric retention, may occur. Delayed puberty, anovulation, menstrual irregularities, and infertility are common. Decreased thyroid hormone can also lead to increased levels of total cholesterol and low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol may change due to altered metabolic clearance. Additionally, hypothyroidism may lead to increased insulin resistance.

[0005] Third-generation TSH testing is readily available and is often the most sensitive screening tool for primary hypothyroidism. The generally accepted reference range for normal serum TSH is 0.40 mIU / L to 4.2 mIU / L. If TSH levels are above the reference range, the next step is to measure free thyroxine (T4). Subclinical hypothyroidism (also known as mild hypothyroidism) is defined as having normal serum levels of free T4 and triiodothyronine (T3), but slightly elevated serum TSH levels.

[0006] Daily administration of thyroid hormone medication is the standard treatment for hypothyroidism in humans and other mammals. Oral medications (such as levothyroxine or levothyroxine salts) can restore sufficient hormone levels to reverse the symptoms of hypothyroidism. Generally, hypothyroidism can be adequately treated with a constant daily dose of levothyroxine (LT4). The typical daily human dose of levothyroxine is low, ranging from 25 μg to 300 μg. The treatment goal for hypothyroidism is to reverse clinical progression and correct metabolic disturbances, based on normal blood levels of TSH and T4.

[0007] Cautious administration of levothyroxine is crucial to avoid overtreatment and undertreatment. Symptoms of overtreatment may include, for example, tachycardia, palpitations, atrial fibrillation, nervousness, fatigue, headache, increased excitability, insomnia, tremor, and possible angina. Doses leading to undertreatment can cause, for example, fatigue, chills, dry skin, hair loss, muscle pain, joint pain, weakness in the limbs, mental impairment, decreased sweating, paresthesia and nerve entrapment syndrome, blurred vision, and hearing impairment.

[0008] For young, otherwise healthy patients, thyroid hormone replacement therapy is typically initiated at the intended full replacement dose level. For older patients and those with a known history of ischemic heart disease, treatment usually begins at one-quarter to one-half of the intended full replacement dose, with the dose adjusted upwards in small increments after at least 4 to 6 weeks. For most cases of mild to moderate hypothyroidism, the initial levothyroxine dose is 50 to 75 μg / day.

[0009] All thyroid hormone preparations (natural or synthetic) are designed to replace a patient's natural thyroid hormone. The normal human thyroid gland primarily releases tetraiodothyronine (levothyroxine, or LT4), which is then converted to triiodothyronine (iodothyronine, or T3) in target tissues. T3 is the actual active thyroid hormone. The thyroid gland forms LT4 (containing four iodine atoms) by coupling two molecules of diiodotyrosine (DIT). T3 (containing three iodine atoms) is also formed in the thyroid gland by coupling one molecule of DIT with one molecule of monoiodotyrosine (MIT). The thyroid gland stores T4 and T3 in the thyroid colloid as thyroglobulins.

[0010] A normal thyroid gland contains approximately 200 μg of levothyroxine (T4) and 15 μg of iodothronine (T3) per gram. The ratio of these two hormones in circulation does not represent the ratio in the thyroid gland, because approximately 80% of peripheral iodothronine (T3) originates from the single deiodination of levothyroxine (T4). Peripheral single deiodination of levothyroxine (T4) at position 5 (inner ring) also results in the formation of inverse iodothronine (T3), which has no thermogenic activity.

[0011] For both T3 and T4 forms of thyroid hormone, synthetic thyroid hormone preparations are commercially available. For example, iodine sodium is a synthetic version of the T3 thyroid hormone triiodothyronine, which can be obtained through CYTOMEL... ® The tablets are obtained from King Pharmaceuticals (St. Louis, MO). Levothyroxine (T4) sodium is available from several commercial products, including LEVOXYL. ® Tablets (King Pharmaceuticals), UNITHROID ® Tablets (Jerome Stevens Pharmaceuticals, Bohemia, NY) and SYNTHROID ® Tablets (AbbVie, Chicago, IL). Levothyroxine (T4) sodium is also available in veterinary formulations sold under the trademark SOLOXINE® (King Pharmaceuticals).

[0012] Levothyroxine is relatively unstable and degrades over time. For example, levothyroxine sodium is sensitive to radiation, hydrolysis, oxidation, and heat. Degradation of the active ingredient in levothyroxine formulations can lead to loss of potency, resulting in inadequate dose delivery and undertreatment of hypothyroidism. Some drug manufacturers have adopted the practice of including excess active ingredient in levothyroxine formulations to anticipate some degree of storage degradation. This practice can complicate accurate dosing and carries the risk of overdosing. Therefore, storage stability of levothyroxine is highly desirable to ensure accurate patient dosing and to avoid complications associated with undertreatment or overtreatment.

[0013] Levothyroxine sodium tablets are available in very low microgram doses (e.g., 25 μg, 50 μg, 75 μg, 88 μg, 100 μg, 112 μg, 125 μg, 137 μg, 150 μg, 175 μg, 200 μg, and 300 μg). To facilitate accurate administration, commercially available tablets typically include a break line that allows the tablet to be divided into two substantially equal halves. The possibility that patients will utilize the break line daily and administer only half of the tablet enhances the need for even distribution of the active ingredient in the tablet to avoid incorrect dosing and associated complications.

[0014] Preparations containing natural thyroid hormones are also available. Before pure levothyroxine was available, dried animal thyroid extracts were the only available treatment for hypothyroidism. Some individuals prefer dried thyroid extracts as a more "natural" thyroid hormone. Additionally, some patients who continued to have hypothyroidism while taking levothyroxine reported improvement in these symptoms when switching to dried thyroid extracts. Thyroid powder is a natural preparation derived from porcine thyroid glands containing the thyroid hormones T3 (iothronine) and T4 (levothyroxine). Similar to synthetic thyroid hormones, naturally derived iothronine and levothyroxine can degrade over time, and natural thyroid hormone replacement preparations have a shelf life set to better ensure that a single dosage form provides the patient with the desired amount of thyroid hormone.

[0015] Therefore, there is a need for a thyroid hormone replacement formulation that includes iothronine and levothyroxine and exhibits favorable stability and improved shelf life. Summary of the Invention

[0016] It should be understood that the invention disclosed and described in this specification is not limited to the embodiments described in the content of this invention.

[0017] This article provides an oral solid dosage form of a drug comprising: about 7.5 μg to about 300 μg of levothyroxine salt; about 1.75 μg to about 75 μg of iodine salt; about 74% to about 96% by weight of microcrystalline cellulose; and at least one excipient selected from lubricants, glidants, diluents, disintegrants, and coatings.

[0018] According to one non-limiting aspect, the disclosed text provides a packaged oral solid dosage form product comprising: an oral solid dosage form comprising, by weight, about 7.5 μg to about 300 μg of levothyroxine salt, about 1.75 μg to about 75 μg of iodine salt, about 74% to about 96% of microcrystalline cellulose by weight, and at least one excipient selected from lubricants, flow aids, diluents, disintegrants, and coatings; and a container closure system comprising a container and a sealing closure; wherein a plurality of oral solid dosage forms and at least about 2 g of desiccant and / or at least 2 g of oxygen absorber are encapsulated in the container and sealed using the sealing closure; and wherein after the oral solid dosage forms have been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

[0019] According to another non-limiting aspect, the disclosed text provides a packaged oral solid dosage form product comprising: an oral solid dosage form comprising, by weight, about 7.5 μg to about 300 μg of levothyroxine salt, about 1.75 μg to about 75 μg of iodine salt, about 74% to about 96% of microcrystalline cellulose, and at least one excipient selected from lubricants, flow aids, diluents, disintegrants, and coatings; a container closure system comprising a container and a sealing closure; wherein a plurality of oral solid dosage forms and at least about 2 g of desiccant and / or at least 2 g of oxygen absorber are encapsulated in the container and sealed using the sealing closure; and wherein after the oral solid dosage forms have been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form.

[0020] According to another non-limiting aspect, the disclosed text provides a treatment method for managing hypothyroidism. The method includes administering an oral solid dosage form of a drug to a subject in need, wherein the oral solid dosage form comprises, by weight: about 7.5 μg to about 300 μg of levothyroxine salt; about 1.75 μg to about 75 μg of iodine salt; about 74% to about 95% by weight of microcrystalline cellulose; and at least one excipient selected from lubricants, flow aids, diluents, disintegrants, and coatings.

[0021] This article provides an oral solid dosage form of a drug comprising: about 7.5 μg to about 300 μg of levothyroxine salt; about 1.75 μg to about 75 μg of iodine salt; about 66% to about 90% by weight of microcrystalline cellulose; and at least one excipient selected from lubricants, flow aids, diluents, antioxidants, and colorants.

[0022] According to another non-limiting aspect, the disclosed text provides a packaged oral solid dosage form product comprising: an oral solid dosage form comprising, by weight, about 7.5 μg to about 300 μg of levothyroxine salt, about 1.75 μg to about 75 μg of iodine salt, about 66% to about 90% of microcrystalline cellulose, and at least one excipient selected from lubricants, flow aids, diluents, antioxidants, and colorants; and a container closure system comprising a container and a sealing closure; wherein a plurality of oral solid dosage forms and at least about 2 g of desiccant and / or at least 2 g of oxygen absorber are encapsulated in the container and sealed using the sealing closure; and wherein after the oral solid dosage forms have been stored for 6 months at a temperature of about 25°C to about 27°C and a relative humidity of about 55% to about 65%, each oral solid dosage form encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

[0023] According to another non-limiting aspect, the disclosed text provides a packaged oral solid dosage form product comprising: an oral solid dosage form comprising, by weight, about 7.5 μg to about 300 μg of levothyroxine salt, about 1.75 μg to about 75 μg of iodine salt, about 66% to about 90% of microcrystalline cellulose, and at least one excipient selected from lubricants, flow aids, diluents, disintegrants, and coatings; a container closure system comprising a container and a sealing closure; wherein a plurality of oral solid dosage forms and at least about 2 g of desiccant and / or at least 2 g of oxygen absorber are encapsulated in the container and sealed using the sealing closure; and wherein after the oral solid dosage forms have been stored for 6 months at a temperature of about 25°C to about 27°C and a relative humidity of about 55% to about 65%, each oral solid dosage form encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form.

[0024] According to another non-limiting aspect, the disclosed text provides a packaged oral solid dosage form product comprising: an oral solid dosage form comprising, by weight, about 7.5 μg to about 300 μg of levothyroxine salt, about 1.75 μg to about 75 μg of iodine salt, about 66% to about 90% of microcrystalline cellulose, and at least one excipient selected from lubricants, flow aids, diluents, antioxidants, and colorants; and a container closure system comprising a container and a sealing closure; wherein a plurality of oral solid dosage forms and at least about 2 g of desiccant and / or at least 2 g of oxygen absorber are encapsulated in the container and sealed using the sealing closure; and wherein after the oral solid dosage forms have been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

[0025] According to another non-limiting aspect, the disclosed text provides a packaged oral solid dosage form product comprising: an oral solid dosage form comprising, by weight, about 7.5 μg to about 300 μg of levothyroxine salt, about 1.75 μg to about 75 μg of iodine salt, about 66% to about 90% of microcrystalline cellulose, and at least one excipient selected from lubricants, flow aids, diluents, disintegrants, and coatings; a container closure system comprising a container and a sealing closure; wherein a plurality of oral solid dosage forms and at least about 2 g of desiccant and / or at least 2 g of oxygen absorber are encapsulated in the container and sealed using the sealing closure; and wherein after the oral solid dosage forms have been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form.

[0026] According to another non-limiting aspect, the disclosed text provides a treatment method for managing hypothyroidism. The method includes administering an oral solid dosage form of a drug to a subject in need, wherein the oral solid dosage form comprises, by weight: about 7.5 μg to about 300 μg of levothyroxine salt; about 1.75 μg to about 75 μg of iodine salt; about 66% to about 90% by weight of microcrystalline cellulose; and at least one excipient selected from lubricants, flow aids, diluents, antioxidants, and colorants. Attached Figure Description

[0027] By referring to the accompanying drawings, one can better understand the various features and characteristics of the non-limiting and non-exhaustive embodiments disclosed and described in this specification, wherein:

[0028] Figure 1A and Figure 1B These are, as described in this article, 30cm containers for containing oral solid dosage forms. 3 Side and cross-sectional views of an embodiment of a (1.0 oz) white high-density polyethylene (“HDPE”) bottle.

[0029] Figure 1C yes Figure 1A Side view of detail "A".

[0030] Figures 2A to 2C It is possible to be with Figure 1A , Figure 1B and Figure 1C The diagram shows an embodiment of a container closure used with containers, wherein... Figure 2A This is an external front view of a threaded closure cap with ridges. Figure 2B This is a top view of the exterior of a threaded, ribbed closure cap. Figure 2C yes Figure 2B The image shows a side sectional view of the lid.

[0031] Figure 3A and Figure 3B These are, as described in this article, 75cm for containing oral solid dosage forms. 3 Side and cross-sectional views of an embodiment of a (2.5 oz) white HDPE bottle.

[0032] Figure 3C yes Figure 3A Side view of detail "A".

[0033] Figure 4A and Figure 4B It is possible to be with Figure 3A , Figure 3B and Figure 3C The diagram shows an embodiment of a container closure used with containers, wherein... Figure 4A This is a top view of the exterior of a threaded, ribbed closure cap. Figure 4B yes Figure 4A The image shows a side sectional view of the lid.

[0034] The foregoing details, as well as others, will be understood when considering the following detailed description of various non-restrictive and non-exhaustive embodiments based on the published text. Detailed Implementation

[0035] Various embodiments are described and illustrated in this specification to provide a comprehensive understanding of the disclosed compositions and methods. It should be understood that the various embodiments described and illustrated in this specification are non-limiting and non-exhaustive. Therefore, the invention is not limited to the description of the various non-limiting and non-exhaustive embodiments disclosed in this specification. Rather, the invention is defined solely by the claims. Specific features and characteristics shown and / or described in conjunction with the various embodiments may be combined with features and characteristics of other embodiments. Such modifications and variations are intended to be included within the scope of this specification. Therefore, the claims may be modified to recite any feature or characteristic explicitly or inherently described in this specification or otherwise explicitly or inherently supported by this specification. Furthermore, the applicant reserves the right to modify the claims to explicitly waive any feature or characteristic that may be present in the prior art. The various embodiments disclosed and described in this specification may include, consist of, or substantially consist of features and characteristics as described in different aspects herein.

[0036] Unless otherwise stated, all percentages provided herein are weight percentages based on the total weight of the respective composition, tablet, mixture, etc.

[0037] Any numerical range described in this specification is intended to include all subranges with the same numerical precision contained within the described range. For example, the range “1.0 to 10.0” is intended to include all subranges between (and including) the described minimum value of 1.0 and the described maximum value of 10.0, i.e., a minimum value equal to or greater than 1.0 and a maximum value equal to or less than 10.0, for example, 2.4 to 7.6. Any maximum numerical limit described in this specification is intended to include all lower numerical limits contained therein, and any minimum numerical limit described in this specification is intended to include all higher numerical limits contained therein. The applicant reserves the right to amend this specification (including the claims) to expressly describe any subranges contained within the range expressly described herein.

[0038] As is generally used herein, the term “about” refers to the acceptable degree of error for the measured quantity, taking into account the nature or precision of the measurement. Typical exemplary degrees of error may be within 20%, 10%, or 5% of a given value or range of values.

[0039] The terms “subject” and “patient” are used interchangeably in this document and are intended to refer to, as appropriate, the recipient of a method implemented according to a published text or another method.

[0040] As used herein, the term “ready-to-use” refers to a composition suitable for administration to a patient without further preparation.

[0041] As used herein, the terms “stability” and “stable” mean that, after the oral solid dosage form of the drug has been stored under the indicated conditions for a period of time, each oral solid dosage form retains at least 90%, at least 95%, at least 99%, or at least 100% of the initial levothyroxine salt content and / or the initial iodine salt content in the oral solid dosage form of the drug.

[0042] This document discloses storage-stable oral solid dosage forms of pharmaceuticals. In specific embodiments thereof, the oral solid dosage forms of pharmaceuticals (e.g., tablets) comprise iodoxylenol salt, levothyroxine salt, microcrystalline cellulose, and at least one excipient selected from lubricants, glidants, diluents, disintegrants, and coatings. The inventors have observed that specific embodiments of the oral solid dosage forms of pharmaceuticals according to the disclosure exhibit unexpectedly favorable stability in pharmaceutical form for levothyroxine salt and iodoxylenol salt.

[0043] The oral solid dosage form of the present invention may include two active pharmaceutical ingredients: a salt of levothyroxine (also known as thyroxine and L-thyroxine) and iodoxylonine (also known as (S)-triiodothyronine), both of which are shown below.

[0044]

[0045] In a specific non-limiting embodiment, depending on the desired strength of the specific oral solid dosage form of the drug, the mass of iodoxyl salt included in the oral solid dosage form of the drug according to the disclosed text can range from about 1.75 µg to about 75 µg, for example, about 1.75 µg to about 2.75 µg, about 2.45 µg to about 3.75 µg, about 3.5 µg to about 5.5 µg, about 5 µg to about 7.5 µg, about 7 µg to about 11 µg, about 10 µg to about 15 µg, about 10 µg to about 16.5 µg, about 14 µg to about 22 µg, about 20 µg to about 30 µg, about 30 µg to about 45 µg, about 35 µg to about 55 µg, about 50 µg to about 75 µg, or about 2 µg to about 69 µg.

[0046] In certain non-limiting embodiments, iotheronine salt may be present in an oral solid dosage form of the drug according to the disclosed text at a concentration of 0.0015% to 0.055%, for example, 0.002% to 0.055%, 0.0025% to 0.055%, 0.005% to 0.055%, 0.0075% to 0.055%, 0.01% to 0.055%, 0.015% to 0.055%, 0.02% to 0.055%, 0.025% to 0.055%, 0.03% to 0.055%, 0.035% to 0.055%, 0.04% to 0.055%, 0.045% to 0.055%, 0.050% to 0.055%. 0.055%, 0.01% to 0.045%, 0.01% to 0.035%, 0.01% to 0.025%, 0.02% to 0.045%, 0.02% to 0.035%, 0.02% to 0.025%, 0.025% to 0.035%, 0.0015% to 0.01%, 0.0015% to 0.0075%, 0.0015% to 0.005%, 0.0015% to 0.003%, 0.002% to 0.01%, 0.002% to 0.0075%, 0.002% to 0.005%, 0.002% to 0.003%, all weight percentages are based on the total weight of the oral solid dosage form of the drug. In other embodiments, iodoxyl salt may be present in an oral solid dosage form at concentrations of approximately 0.0015%, 0.002%, 0.0022%, 0.0023%, 0.0024%, 0.0025%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.011%, 0.012%, 0.013%, 0.014%, 0.015%, 0.016%, 0.017%, 0.018%, 0.019%, 0.02%, 0.021%, 0.022%, 0.023%, 0.024%, 0.025%, and approximately... Concentrations of 0.026%, approximately 0.027%, approximately 0.028%, approximately 0.029%, approximately 0.03%, approximately 0.031%, approximately 0.032%, approximately 0.033%, approximately 0.034%, approximately 0.035%, approximately 0.036%, approximately 0.037%, approximately 0.038%, approximately 0.039%, approximately 0.04%, approximately 0.041%, approximately 0.042%, approximately 0.043%, approximately 0.044%, approximately 0.045%, approximately 0.046%, approximately 0.047%, approximately 0.048%, approximately 0.049%, approximately 0.05%, approximately 0.051%, approximately 0.052%, approximately 0.053%, approximately 0.054%, or approximately 0.055% are present, and all weight percentages are based on the total weight of the oral solid dosage form of the drug.

[0047] In a specific non-limiting embodiment, depending on the desired strength of the specific oral solid dosage form of the drug, the mass of levothyroxine salt included in the oral solid dosage form of the drug according to the disclosed text can range from about 7.5 µg to about 300 µg, for example, about 7.5 µg to about 11.5 µg, about 10 µg to about 15 µg, about 15 µg to about 23 µg, about 20 µg to about 30 µg, about 30 µg to about 46 µg, about 40 µg to about 60 µg, about 45 µg to about 69 µg, about 60 µg to about 92 µg, about 80 µg to about 120 µg, about 120 µg to about 180 µg, about 150 µg to about 230 µg, about 200 µg to about 300 µg, or about 8 µg to about 275 µg.

[0048] In certain non-limiting embodiments, levothyroxine salt may be present in an oral solid dosage form of the drug according to the disclosed text at a concentration of 0.005% to 0.25%, for example, 0.01% to 0.25%, 0.015% to 0.25%, 0.02% to 0.25%, 0.025% to 0.25%, 0.03% to 0.25%, 0.035% to 0.25%, 0.04% to 0.25%, 0.0 45% to 0.25%, 0.05% to 0.25%, 0.055% to 0.25%, 0.06% to 0.25%, 0.065% to 0.25%, 0.07% to 0.25%, 0.075% to 0.25%, 0.08% to 0.25%, 0.085% to 0.25%, 0.09% to 0.25%, 0.1% to 0.25%, 0.11% to 0.25%, 0.12% to 0 0.25%, 0.13% to 0.25%, 0.14% to 0.25%, 0.15% to 0.25%, 0.16% to 0.25%, 0.17% to 0.25%, 0.18% to 0.25%, 0.19% to 0.25%, 0.20% to 0.25%, 0.21% to 0.25%, 0.225% to 0.25%, 0.005% to 0.1%, 0.006% to 0.1%, 0. 0.007% to 0.1%, 0.008% to 0.1%, 0.009% to 0.1%, 0.01% to 0.1%, 0.025% to 0.1%, 0.05% to 0.1%, 0.075% to 0.1%, 0.075% to 0.125%, 0.125% to 0.2%, 0.15% to 0.2% or 0.175% to 0.2%, all weight percentages are based on the total weight of the oral solid dosage form of the drug.

[0049] In a specific non-limiting embodiment according to the published text, the weight ratio of levothyroxine salt to iodine salt in the oral solid dosage form is from about 3.5:1 to about 4.5:1, for example, from about 3.75:1 to about 4.5:1, from about 4.0:1 to about 4.5:1, or from about 4.25:1 to about 4.5:1.

[0050] Various non-limiting embodiments of the oral solid dosage form of a drug according to the disclosed text may include one or more diluents. The diluent may be included as a filler in the oral solid dosage form of a drug (e.g., tablets) to increase the dosage form weight and improve content uniformity. Non-limiting examples of suitable diluents that may be used in the oral solid dosage forms of drugs disclosed herein include at least one of the following: microcrystalline cellulose (MCC) (e.g., AVICEL). ® PH-102 MCC powder), AVICEL ® HFE-102 powder (a blend of microcrystalline cellulose and mannitol, available from FMC BioPolymer (Philadelphia, PA)), sugars from confectionery (including corn starch), croscarmellose sodium, dicalcium phosphate, inulin, carbohydrates (e.g., arabinose, sucrose, dextrose, fructose, maltose, lactose, lactose monohydrate, trehalose, isomaltitol, starch, monosaccharides, disaccharides, polysaccharides and sugar alcohols (e.g., sorbitol, mannitol, erythritol, xylitol, lactitol)), derivatives of the foregoing, and any combination thereof.

[0051] In a specific non-limiting embodiment, the diluent may be present in the oral solid dosage form of the drug according to the disclosed text at a concentration of about 74% to about 96%, for example, 74% to 93%, 74% to 90%, 74% to 87%, 74% to 84%, 74% to 81%, 74% to 78%, 78% to 93%, 78% to 90%, 78% to 87%, 78% to 86%, 78% to 84%, 80% to 93%, 80% to 90%, 80% to 87%, 80% to 84%, 81% to 93%, 81% to 90%, 81% to 87%, 81% to 84%, 82% to 93%, 82% to 90%, 82% to 87%, 82% to 84%, 83% to 93%, 83% to 90%, or 83% to 87%, all weight percentages being based on the total weight of the oral solid dosage form of the drug. In other embodiments, the diluent may be present in the oral solid dosage form of the drug according to the disclosed text at a concentration of about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, or about 96%, all weight percentages based on the total weight of the oral solid dosage form of the drug.

[0052] In a particular non-limiting embodiment, the diluent may be present in the oral solid dosage form of the drug according to the disclosed text at a concentration of about 66% to about 90%, for example, 66% to 87%, 66% to 84%, 70% to 90%, 70% to 87%, 70% to 86%, 70% to 84%, 70% to 81%, 74% to 87%, 74% to 84%, 74% to 82%, 76% to 90%, 76% to 87%, 76% to 84%, or 76% to 82%, all weight percentages being based on the total weight of the oral solid dosage form of the drug. In other embodiments, the diluent may be present in the oral solid dosage form of the drug according to the disclosed text at a concentration of about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, or about 90%, all weight percentages based on the total weight of the oral solid dosage form of the drug.

[0053] In a specific non-limiting embodiment according to the published text, the amount of diluent included in the oral solid dosage form of the drug can range from about 85 mg to about 130 mg, such as about 88 mg to about 130 mg, about 92 mg to about 130 mg, about 95 mg to about 130 mg, about 100 mg to about 130 mg, about 105 mg to about 130 mg, about 95 mg to about 115 mg, about 97.5 mg to about 115 mg, about 100 mg to about 115 mg, about 102.5 mg to about 115 mg, about 105 mg to about 115 mg, about 105 mg to about 112.5 mg, or about 105 mg to about 110 mg.

[0054] In a specific non-limiting embodiment, microcrystalline cellulose (MCC) may be present in the oral solid dosage form of the drug according to the disclosed text at a concentration of about 74% to about 96%, for example, 74% to 93%, 74% to 90%, 74% to 87%, 74% to 84%, 74% to 81%, 74% to 78%, 78% to 93%, 78% to 90%, 78% to 87%, 78% to 86%, 78% to 84%, 80% to 93%, 80% to 90%, 80% to 87%, 80% to 84%, 81% to 93%, 81% to 90%, 81% to 87%, 81% to 84%, 82% to 93%, 82% to 90%, 82% to 87%, 82% to 84%, 83% to 93%, 83% to 90%, or 83% to 87%, all weight percentages being based on the total weight of the oral solid dosage form of the drug. In other embodiments, the MCC may be present in the oral solid dosage form of the drug according to the published text at a concentration of about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, or about 96%, all weight percentages based on the total weight of the oral solid dosage form of the drug.

[0055] In a specific non-limiting embodiment, microcrystalline cellulose (MCC) may be present in the oral solid dosage form of the drug according to the disclosed text at a concentration of about 66% to about 90%, for example, 66% to 87%, 66% to 84%, 70% to 90%, 70% to 87%, 70% to 86%, 70% to 84%, 70% to 81%, 74% to 87%, 74% to 84%, 74% to 82%, 76% to 90%, 76% to 87%, 76% to 84%, or 76% to 82%, all weight percentages being based on the total weight of the oral solid dosage form of the drug. In other embodiments, the MCC may be present in the oral solid dosage form of the drug according to the published text at a concentration of about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, or about 90%, all weight percentages based on the total weight of the oral solid dosage form of the drug.

[0056] In certain non-limiting embodiments, the amount of MCC included in the oral solid dosage form of the drug can range from about 85 mg to about 130 mg, such as about 88 mg to about 130 mg, about 92 mg to about 130 mg, about 95 mg to about 130 mg, about 100 mg to about 130 mg, about 105 mg to about 130 mg, about 95 mg to about 115 mg, about 97.5 mg to about 115 mg, about 100 mg to about 115 mg, about 102.5 mg to about 115 mg, about 105 mg to about 115 mg, about 105 mg to about 112.5 mg, or about 105 mg to about 110 mg.

[0057] AVICEL ® HFE-102 powder is a pharmaceutical diluent, which is a spray-dried blend of about 90% by weight microcrystalline cellulose and about 10% by weight mannitol. In a particular non-limiting embodiment, AVICEL ®HFE-102 powder may be present in the oral solid dosage form of the drug according to the disclosed text at a concentration of about 74% to about 96%, for example, 74% to 93%, 74% to 90%, 74% to 87%, 74% to 84%, 74% to 81%, 74% to 78%, 78% to 93%, 78% to 90%, 78% to 87%, 78% to 86%, 78% to 84%, 80% to 93%, 80% to 90%, 80% to 87%, 80% to 84%, 81% to 93%, 81% to 90%, 81% to 87%, 81% to 84%, 82% to 93%, 82% to 90%, 82% to 87%, 82% to 84%, 83% to 93%, 83% to 90%, or 83% to 87%, all weight percentages are based on the total weight of the oral solid dosage form of the drug. In other embodiments, AVICEL ® HFE-102 powder may be present in oral solid dosage forms of the drug according to the published text at concentrations of approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, or approximately 96%, all weight percentages based on the total weight of the oral solid dosage form of the drug.

[0058] In a specific, non-limiting embodiment, the oral solid dosage form of the drug includes AVICEL. ® The amount of HFE-102 powder can range from about 85 mg to about 130 mg, such as about 88 mg to about 130 mg, about 92 mg to about 130 mg, about 95 mg to about 130 mg, about 100 mg to about 130 mg, about 105 mg to about 130 mg, about 95 mg to about 115 mg, about 97.5 mg to about 115 mg, about 100 mg to about 115 mg, about 102.5 mg to about 115 mg, about 105 mg to about 115 mg, about 105 mg to about 112.5 mg, or about 105 mg to about 110 mg.

[0059] AVICEL ® PH-102 is a powder form of MCC, commonly used as a pharmaceutical diluent. In a specific, non-limiting embodiment, AVICEL ®PH-102 powder may be present in the oral solid dosage form of the drug according to the disclosed text at a concentration of about 66% to about 90%, for example, 66% to 87%, 66% to 84%, 70% to 90%, 70% to 87%, 70% to 86%, 70% to 84%, 70% to 81%, 74% to 87%, 74% to 84%, 74% to 82%, 76% to 90%, 76% to 87%, 76% to 84%, or 76% to 82%, all weight percentages being based on the total weight of the oral solid dosage form of the drug. In other embodiments, AVICEL ® PH-102 powder may be present in oral solid dosage forms of the drug according to the published text at concentrations of approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, or approximately 90%, all weight percentages based on the total weight of the oral solid dosage form of the drug.

[0060] In a specific, non-limiting embodiment, AVICEL is included in the oral solid dosage form of the drug according to the published text. ® The amount of PH-102 powder can range from about 85 mg to about 130 mg, such as about 88 mg to about 130 mg, about 92 mg to about 130 mg, about 95 mg to about 130 mg, about 100 mg to about 130 mg, about 105 mg to about 130 mg, about 95 mg to about 115 mg, about 97.5 mg to about 115 mg, about 100 mg to about 115 mg, about 102.5 mg to about 115 mg, about 105 mg to about 115 mg, about 105 mg to about 112.5 mg, or about 105 mg to about 110 mg.

[0061] In a specific non-limiting embodiment, mannitol may be present in the oral solid dosage form of the drug according to the disclosed text at a concentration of about 9% to about 14%, for example, 9.25% to 14%, 9.5% to 14%, 9.75% to 14%, 10% to 14%, 10.25% to 14%, 10.5% to 14%, 11% to 14%, 9.25% to 13.75%, 9.25% to 13.5%, 9.25% to 13%, 9.25% to 12.5%, 9.25% to 12%, 9.25% to 11.75%, or 9.25% to 11.5%, all weight percentages based on the total weight of the oral solid dosage form of the drug. In other embodiments, mannitol may be present in the oral solid dosage form of the drug according to the disclosed text at concentrations of about 9%, about 9.25%, about 9.5%, about 9.75%, about 10%, about 10.25%, about 10.5%, about 10.75%, about 11%, about 11.25%, about 11.5%, about 11.75%, about 12%, about 12.25%, about 12.5%, about 13%, about 13.25%, about 13.5%, about 13.75%, or about 14%, all weight percentages based on the total weight of the oral solid dosage form of the drug.

[0062] In a specific non-limiting embodiment according to the published text, the amount of mannitol included in the oral solid dosage form of the drug can range from about 5 mg to about 20 mg, such as about 7.5 mg to about 20 mg, about 10 mg to about 20 mg, about 12.5 mg to about 20 mg, about 14 mg to about 20 mg, about 7.5 mg to about 18 mg, about 7.5 mg to about 16 mg, about 7.5 mg to about 15 mg, about 10 mg to about 16 mg, about 12 mg to about 16 mg, about 14 mg to about 16 mg, or about 13 mg to about 15 mg.

[0063] In a specific non-limiting embodiment, mannitol may be present in the oral solid dosage form of the drug according to the disclosed text at a concentration of about 16% to about 24%, for example, 16.5% to 24%, 17% to 24%, 17.5% to 24%, 18% to 24%, 18.5% to 24%, 19% to 24%, 16% to 23.5%, 16% to 23%, 16% to 22.5%, 16% to 22%, 16% to 21.5%, 16% to 21%, 17% to 23%, 17.5% to 22.5%, 18% to 22%, 19% to 22%, or 18% to 21%, all weight percentages based on the total weight of the oral solid dosage form of the drug. In other embodiments, mannitol may be present in the oral solid dosage form of the drug according to the disclosed text at concentrations of about 16%, about 16.5%, about 17%, about 17.5%, about 18%, about 18.5%, about 19%, about 19.5%, about 20%, about 20.5%, about 21%, about 21.5%, about 22%, about 22.5%, about 23%, about 23.5%, or about 24%, all weight percentages based on the total weight of the oral solid dosage form of the drug.

[0064] In a specific non-limiting embodiment according to the published text, the amount of mannitol included in the oral solid dosage form of the drug may range from about 15 mg to about 30 mg, such as about 17.5 mg to about 30 mg, about 20 mg to about 30 mg, about 22.5 mg to about 30 mg, about 24 mg to about 30 mg, about 15 mg to about 28 mg, about 18 mg to about 28 mg, about 20 mg to about 28 mg, about 22 mg to about 28 mg, or about 24 mg to about 28 mg.

[0065] In a specific non-limiting embodiment, hydroxypropyl methylcellulose may be present in the oral solid dosage form of the drug according to the disclosed text at a concentration of about 2% to about 7%, for example, 2.25% to 7%, 2.5% to 7%, 2.75% to 7%, 3% to 7%, 3.25% to 7%, 3.5% to 7%, 3.75% to 7%, 4% to 7%, 4.25% to 7%, 4.5% to 7%, 2% to 6.75%, 2% to 6.5%, 2% to 6%, 2% to 5.5%, 2% to 5%, or 2% to 4.75%, all weight percentages being based on the total weight of the oral solid dosage form of the drug. In other embodiments, hydroxypropyl methylcellulose may be present in the oral solid dosage form of the drug according to the disclosed text at concentrations of about 2%, about 2.25%, about 2.5%, about 2.75%, about 3%, about 3.25%, about 3.5%, about 3.75%, about 4%, about 4.25%, about 4.5%, about 4.75%, about 5%, about 5.25%, about 5.5%, about 5.75%, about 6%, about 6.25%, about 6.5%, about 6.75%, or about 7%, all weight percentages based on the total weight of the oral solid dosage form of the drug.

[0066] In a specific non-limiting embodiment according to the published text, the amount of hydroxypropyl methylcellulose included in the oral solid dosage form of the drug can range from about 1 mg to about 10 mg, such as about 2 mg to about 10 mg, about 3 mg to about 10 mg, about 4 mg to about 10 mg, about 5 mg to about 10 mg, about 2 mg to about 9 mg, about 2 mg to about 8 mg, about 2 mg to about 7 mg, about 3 mg to about 7 mg, about 4 mg to about 7 mg, about 2 mg to about 5 mg, or about 2 mg to about 4 mg.

[0067] In a specific, non-limiting embodiment according to the disclosed text, butylated hydroxyanisole may be present in the oral solid dosage form of the drug according to the disclosed text at a concentration of about 0.001% to about 0.009%, for example, 0.0015% to 0.009%, 0.002% to 0.009%, 0.0025% to 0.009%, 0.003% to 0.009%, 0.0035% to 0.009%, or 0.0015% to 0.0085%. 0.0015% to 0.008%, 0.0015% to 0.0075%, 0.0015% to 0.007%, 0.0015% to 0.0065%, 0.0015% to 0.006%, 0.0015% to 0.0055%, 0.0015% to 0.005%, 0.0015% to 0.0045% or 0.0015% to 0.004%, all weight percentages are based on the total weight of the oral solid dosage form of the drug. In other embodiments, butylated hydroxyanisole may be present in the oral solid dosage form of the drug according to the disclosed text at concentrations of about 0.001%, about 0.0015%, about 0.002%, about 0.0025%, about 0.003%, about 0.0035%, about 0.004%, about 0.0045%, about 0.005%, about 0.0055%, about 0.006%, about 0.0065%, about 0.007%, about 0.0075%, about 0.008%, about 0.0085%, or about 0.009%, all weight percentages based on the total weight of the oral solid dosage form of the drug.

[0068] In a specific, non-limiting embodiment according to the published text, the amount of butylated hydroxyanisole included in the oral solid dosage form of the drug can range from about 0.001 mg to about 0.01 mg, such as about 0.0015 mg to about 0.01 mg, about 0.002 mg to about 0.01 mg, about 0.0025 mg to about 0.01 mg, about 0.003 mg to about 0.01 mg, about 0.0035 mg to about 0.01 mg, about 0.004 mg to about 0.01 mg, about 0.0045 mg to about 0.01 mg, or about 0.001 mg to about 0.009 mg. 5 mg, about 0.001 mg to about 0.009 mg, about 0.001 mg to about 0.0085 mg, about 0.001 mg to about 0.008 mg, about 0.001 mg to about 0.0075 mg, about 0.001 mg to about 0.007 mg, about 0.001 mg to about 0.0065 mg, about 0.001 mg to about 0.006 mg, about 0.001 mg to about 0.0055 mg, about 0.003 mg to about 0.008 mg, about 0.003 mg to about 0.006 mg, or about 0.004 mg to about 0.006 mg.

[0069] Various non-limiting embodiments of the oral solid dosage form of a drug according to the disclosed text include one or more lubricants. Lubricants may be included in the oral solid dosage form of a drug, for example, to improve the powder processing properties of the formulation during the manufacture of the drug solid dosage form. Non-limiting examples of suitable lubricants that may be used in the oral solid dosage form of a drug according to the disclosed text include sodium stearoyl fumarate, polyethylene glycol, mineral oil, medium-chain triglycerides, sodium stearoyl sulfate, cocoa butter, sodium benzoate, stearic acid (and its derivatives or esters, such as sodium stearate, magnesium stearate, calcium stearate), and any combination thereof.

[0070] According to specific non-limiting embodiments of the disclosed text, the concentration of lubricant in the oral solid dosage form of the drug can range from about 0.6% to about 1%, about 0.65% to about 1%, about 0.6% to about 0.95%, about 0.7% to about 1%, about 0.7% to about 0.95%, about 0.75% to about 1%, about 0.75% to about 0.95%, about 0.75% to about 0.90%, about 0.7% to about 0.95%, about 0.7% to about 0.85%, or about 0.75% to about 0.85%, all weight percentages being based on the total weight of the oral solid dosage form.

[0071] In specific non-limiting embodiments, the amount of lubricant included in the oral solid dosage form of the drug according to the disclosed text may range from about 0.20 mg to about 0.32 mg, about 0.21 mg to about 0.32 mg, about 0.22 mg to about 0.32 mg, about 0.23 mg to about 0.32 mg, about 0.24 mg to about 0.32 mg, about 0.20 mg to about 0.30 mg, about 0.20 mg to about 0.28 mg, about 0.40 mg to about 0.64 mg, about 0.42 mg to about 0.64 mg, about 0.44 mg to about 0.64 mg, about 0.46 mg to... About 0.64 mg, about 0.48 mg to about 0.64 mg, about 0.4 mg to about 0.60 mg, about 0.40 mg to about 0.56 mg, about 0.48 mg to about 0.56 mg, about 0.80 mg to about 1.28 mg, about 0.84 mg to about 1.28 mg, about 0.88 mg to about 1.28 mg, about 0.92 mg to about 1.28 mg, about 0.96 mg to about 1.28 mg, about 0.8 mg to about 1.20 mg, about 0.80 mg to about 1.12 mg, about 0.96 mg to about 1.12 mg, about 1.2 mg to about 2.0 mg, About 1.2 mg to about 1.85 mg, about 1.2 mg to about 1.7 mg, about 1.2 mg to about 1.65 mg, about 1.3 mg to about 1.65 mg, about 1.4 mg to about 1.65 mg, about 1.45 mg to about 1.70 mg, about 1.5 mg to about 1.65 mg, about 1.5 mg to about 2.6 mg, about 1.6 mg to about 2.6 mg, about 1.7 mg to about 2.6 mg, about 1.8 mg to about 2.6 mg, about 1.8 mg to about 2.5 mg, about 1.8 mg to about 2.4 mg, about 1.8 mg to about 2.3 mg, about 1.8 mg to about 2. .20mg, about 2.0mg to about 2.20mg, about 2.75mg to about 4.0mg, about 2.75mg to about 3.75mg, about 2.75mg to about 3.5mg, about 3.0mg to about 3.5mg, about 3.25mg to about 3.75mg, about 3.5mg to about 5.5mg, about 3.75mg to about 5.5mg, about 4.0mg to about 5.0mg, about 4.0mg to about 4.75mg, about 4.5mg to about 6.0mg, about 5.0mg to about 6.0mg, about 5.0mg to about 5.75mg, or about 5.0mg to about 5.5mg.

[0072] Various non-limiting embodiments of the oral solid dosage form of a drug according to the disclosed text may include one or more flow aids. Flow aids may be included in the oral solid dosage form of a drug, for example, to enhance the flowability of the powder component by reducing interparticle friction, particle surface charge, and / or particle cohesion. Non-limiting examples of suitable flow aids that may be used in the oral solid dosage form according to the disclosed text include talc, silica, colloidal silica, and any combination thereof.

[0073] The concentration of the glidant in the oral solid dosage form of the drug according to a specific non-limiting embodiment of the published text may range from about 0.6% to about 1%, about 0.65% to about 1%, about 0.6% to about 0.95%, about 0.7% to about 1%, about 0.7% to about 0.95%, about 0.75% to about 1%, about 0.75% to about 0.95%, about 0.75% to about 0.90%, about 0.7% to about 0.95%, about 0.7% to about 0.85%, or about 0.75% to about 0.85%, all weight percentages being based on the total weight of the oral solid dosage form of the drug.

[0074] In specific non-limiting embodiments, the amount of the glidant included in the oral solid dosage form of the drug according to the disclosed text may range from about 0.20 mg to about 0.32 mg, about 0.21 mg to about 0.32 mg, about 0.22 mg to about 0.32 mg, about 0.23 mg to about 0.32 mg, about 0.24 mg to about 0.32 mg, about 0.20 mg to about 0.30 mg, about 0.20 mg to about 0.28 mg, about 0.40 mg to about 0.64 mg, about 0.42 mg to about 0.64 mg, about 0.44 mg to about 0.64 mg, about 0.46 mg to... About 0.64 mg, about 0.48 mg to about 0.64 mg, about 0.4 mg to about 0.60 mg, about 0.40 mg to about 0.56 mg, about 0.48 mg to about 0.56 mg, about 0.80 mg to about 1.28 mg, about 0.84 mg to about 1.28 mg, about 0.88 mg to about 1.28 mg, about 0.92 mg to about 1.28 mg, about 0.96 mg to about 1.28 mg, about 0.8 mg to about 1.20 mg, about 0.80 mg to about 1.12 mg, about 0.96 mg to about 1.12 mg, about 1.2 mg to about 2.0 mg, About 1.2 mg to about 1.85 mg, about 1.2 mg to about 1.7 mg, about 1.2 mg to about 1.65 mg, about 1.3 mg to about 1.65 mg, about 1.4 mg to about 1.65 mg, about 1.45 mg to about 1.70 mg, about 1.5 mg to about 1.65 mg, about 1.5 mg to about 2.6 mg, about 1.6 mg to about 2.6 mg, about 1.7 mg to about 2.6 mg, about 1.8 mg to about 2.6 mg, about 1.8 mg to about 2.5 mg, about 1.8 mg to about 2.4 mg, about 1.8 mg to about 2.3 mg, about 1.8 mg to about 2. .20mg, about 2.0mg to about 2.20mg, about 2.75mg to about 4.0mg, about 2.75mg to about 3.75mg, about 2.75mg to about 3.5mg, about 3.0mg to about 3.5mg, about 3.25mg to about 3.75mg, about 3.5mg to about 5.5mg, about 3.75mg to about 5.5mg, about 4.0mg to about 5.0mg, about 4.0mg to about 4.75mg, about 4.5mg to about 6.0mg, about 5.0mg to about 6.0mg, about 5.0mg to about 5.75mg, or about 5.0mg to about 5.5mg.

[0075] Various non-limiting embodiments of the oral solid dosage form of a drug according to the published text may include one or more disintegrants. Disintegrants may be included in the oral solid dosage form of a drug, for example, to facilitate disintegration after oral administration. Non-limiting examples of suitable disintegrants that may be used in the oral solid dosage form of a drug according to the published text include sodium glycolate starch and / or sodium croscarmellose.

[0076] Optionally, various non-limiting embodiments of the oral solid dosage form of the drug according to the disclosed text may include one or more antioxidants. Examples of antioxidants that may be used in the oral dosage form according to the disclosed text include, but are not limited to: butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediaminetetraacetic acid (EDTA), sodium metabisulfite, ascorbic acid, citric acid, ascorbate palmitate, sodium isoascorbate, dihydroguaiac acid, potassium sorbate, sodium bisulfate, sorbic acid, potassium ascorbate, vitamin E, 4-chloro-2,6-di-tert-butylphenol, α-tocopherol, propyl gallate, and combinations of two or more thereof.

[0077] Optionally, various non-limiting embodiments of the oral solid dosage form of the drug according to the disclosed text may include one or more colorants. Examples of colorants that may be used in oral dosage forms according to the disclosed text include, but are not limited to: FD&C Blue #1 aluminum lake pigment, D&C Yellow #10 aluminum lake pigment, FD&C Red #40 aluminum lake pigment, FD&C Yellow #6 aluminum lake pigment, D&C Red #27 aluminum lake pigment, D&C Red #30 Helendon pink aluminum lake pigment, and FD&C Blue #2 aluminum lake pigment.

[0078] Optionally, various non-limiting embodiments of the oral solid dosage form of the drug according to the disclosed text may also include one or more coatings. Coatings may be included on the oral solid dosage form of the drug to, for example, mask taste, facilitate swallowing, and / or protect the active pharmaceutical ingredient. Non-limiting examples of suitable coatings that may be applied to various non-limiting embodiments of the oral solid dosage form of the drug according to the disclosed text include OPADRY. ® white coating and OPADRY ® II 85F19316clear (transparent) coating.

[0079] In various non-limiting embodiments, the oral solid dosage form of the drug according to the published text may be provided as tablets, capsules, powders, lozenges or other suitable solid dosage forms.

[0080] In specific embodiments according to the published text, the oral solid dosage form of the drug comprises levothyroxine salt, iodoxylenine salt, microcrystalline cellulose, and at least one excipient selected from lubricants, flow aids, diluents, disintegrants, and coatings. In various embodiments, the oral solid dosage form of the drug is prepared by a method including a dry blending process. In various embodiments, the oral solid dosage form of the drug retains at least 90% of the initial levothyroxine salt content in the solid dosage form when stored under one or more of the following storage conditions: for nine months under standard test conditions (25°C ± 2°C and 60% ± 5% relative humidity); for nine months under refrigerated conditions (2°C ± 8°C); for six months under accelerated test conditions (40°C ± 2°C and 75% ± 5% relative humidity); and for 15 days under extreme test conditions (60°C ± 2°C).

[0081] In specific embodiments according to the published text, the oral solid dosage form of the drug comprises levothyroxine salt, iodoxylone salt, microcrystalline cellulose, and at least one excipient selected from lubricants, flow aids, diluents, disintegrants, and coatings. In various embodiments, the oral solid dosage form of the drug is prepared by a method including a dry blending process. In various embodiments, when the dosage form is stored under one or more of the following storage conditions, the oral solid dosage form of the drug retains at least 90% of the initial iodoxylone salt content in the solid dosage form: nine months under standard test conditions (25°C ± 2°C and 60% ± 5% relative humidity); nine months under refrigerated conditions (2°C ± 8°C); six months under accelerated test conditions (40°C ± 2°C and 75% ± 5% relative humidity); and 15 days under extreme test conditions (60°C ± 2°C).

[0082] In specific embodiments according to the published text, the oral solid dosage form of the drug comprises levothyroxine salt, iodoxylenine salt, microcrystalline cellulose, and at least one excipient selected from lubricants, flow aids, diluents, disintegrants, and coatings. In various non-limiting embodiments, the oral solid dosage form of the drug is prepared by a method including a dry blending process. In various embodiments, when the dosage form is stored under one or more of the following storage conditions, the oral solid dosage form of the drug retains at least 95% of the initial levothyroxine salt content in the solid dosage form: nine months under standard test conditions (25°C ± 2°C and 60% ± 5% relative humidity); nine months under refrigerated conditions (2°C ± 8°C); six months under accelerated test conditions (40°C ± 2°C and 75% ± 5% relative humidity); and 15 days under extreme test conditions (60°C ± 2°C).

[0083] In specific embodiments according to the published text, the oral solid dosage form of the drug comprises levothyroxine salt, iodoxylone salt, microcrystalline cellulose, and at least one excipient selected from lubricants, flow aids, diluents, disintegrants, and coatings. In various non-limiting embodiments, the oral solid dosage form of the drug is prepared by a method including a dry blending process. In various embodiments, when the dosage form is stored under one or more of the following storage conditions, the drug solid dosage form retains at least 95% of the initial iodoxylone salt content in the solid dosage form: nine months under standard test conditions (25°C ± 2°C and 60% ± 5% relative humidity); nine months under refrigerated conditions (2°C ± 8°C); six months under accelerated test conditions (40°C ± 2°C and 75% ± 5% relative humidity); and 15 days under extreme test conditions (60°C ± 2°C).

[0084] In specific embodiments according to the published text, the oral solid dosage form of the drug comprises levothyroxine salt, iodoxylenine salt, microcrystalline cellulose, and at least one excipient selected from lubricants, flow aids, diluents, disintegrants, and coatings. In various non-limiting embodiments, the oral solid dosage form of the drug is prepared by a method including a dry blending process. In various embodiments, the oral solid dosage form of the drug retains at least 99% of the initial levothyroxine content in the solid dosage form when stored under one or more of the following storage conditions: for nine months under standard test conditions (25°C ± 2°C and 60% ± 5% relative humidity); for nine months under refrigerated conditions (2°C ± 8°C); for six months under accelerated test conditions (40°C ± 2°C and 75% ± 5% relative humidity); and for 15 days under extreme test conditions (60°C ± 2°C).

[0085] In specific embodiments according to the published text, oral solid dosage forms of pharmaceuticals prepared by a dry homogeneous blending process include levothyroxine salt, iodoxylenine salt, microcrystalline cellulose, and at least one excipient selected from lubricants, flow aids, diluents, disintegrants, and coatings. In various non-limiting embodiments, oral solid dosage forms of pharmaceuticals are prepared by methods including a dry blending process. In various embodiments, when the dosage form is stored under the following storage conditions, the oral solid dosage form of pharmaceuticals retains at least 99% of the initial iodoxylenine content in the solid dosage form: storage for nine months under standard test conditions (25°C ± 2°C and 60% ± 5% relative humidity) and / or storage for nine months under refrigerated conditions (2°C ± 8°C) and / or storage for six months under accelerated test conditions (40°C ± 2°C and 75% ± 5% relative humidity) and / or storage for 15 days under extreme test conditions (60°C ± 2°C).

[0086] In specific embodiments according to the published text, the oral solid dosage form of the drug comprises levothyroxine salt, iodoxylenine salt, microcrystalline cellulose, and at least one excipient selected from lubricants, flow aids, diluents, antioxidants, and colorants. In various embodiments, the oral solid dosage form of the drug is prepared by a method including a dry blending process. In various embodiments, the oral solid dosage form of the drug retains at least 90% of the initial levothyroxine salt content in the solid dosage form when stored under one or more of the following storage conditions: storage for 6 months under standard test conditions (25°C ± 2°C and 60% ± 5% relative humidity); and storage for 6 months under accelerated test conditions (40°C ± 2°C and 75% ± 5% relative humidity).

[0087] In specific embodiments according to the published text, the oral solid dosage form of the drug comprises levothyroxine salt, iodoxylenine salt, microcrystalline cellulose, and at least one excipient selected from lubricants, flow aids, diluents, antioxidants, and colorants. In various embodiments, the oral solid dosage form of the drug is prepared by a method including a dry blending process. In various embodiments, when the dosage form is stored under one or more of the following storage conditions, the oral solid dosage form of the drug retains at least 90% of the initial iodoxylenine salt content in the solid dosage form: stored for 6 months under standard test conditions (25°C ± 2°C and 60% ± 5% relative humidity); or stored for 6 months under accelerated test conditions (40°C ± 2°C and 75% ± 5% relative humidity).

[0088] In specific embodiments according to the published text, the oral solid dosage form of the drug comprises levothyroxine salt, iodoxylenine salt, microcrystalline cellulose, and at least one excipient selected from lubricants, flow aids, diluents, antioxidants, and colorants. In various embodiments, the oral solid dosage form of the drug is prepared by a method including a dry blending process. In various embodiments, the oral solid dosage form of the drug retains at least 95% of the initial levothyroxine salt content in the solid dosage form when stored under one or more of the following storage conditions: storage for 6 months under standard test conditions (25°C ± 2°C and 60% ± 5% relative humidity); and storage for 6 months under accelerated test conditions (40°C ± 2°C and 75% ± 5% relative humidity).

[0089] In specific embodiments according to the published text, the oral solid dosage form of the drug comprises levothyroxine salt, iodoxylone salt, microcrystalline cellulose, and at least one excipient selected from lubricants, flow aids, diluents, antioxidants, and colorants. In various embodiments, the oral solid dosage form of the drug is prepared by a method including a dry blending process. In various embodiments, the oral solid dosage form of the drug retains at least 95% of the initial iodoxylone salt content in the solid dosage form when stored under one or more of the following storage conditions: storage for 6 months under standard test conditions (25°C ± 2°C and 60% ± 5% relative humidity); storage for 6 months under accelerated test conditions (40°C ± 2°C and 75% ± 5% relative humidity).

[0090] In various embodiments, oral solid dosage forms of pharmaceuticals according to the disclosure can be prepared by a dry blending process that includes providing a homogeneous blend of the components. The dry homogeneous blending of the components may include techniques known in the art, such as one or more of blending, mixing, sieving, co-grinding, milling, granulation, and high-intensity granulation.

[0091] In a specific non-limiting embodiment according to the disclosed text, a pre-packaged pharmaceutical product is provided, comprising an oral solid dosage form according to the disclosed text, the oral solid dosage form being contained in a container closure system including a container and a sealing closure. In a specific non-limiting embodiment according to the disclosed text, the container has approximately 15 cm². 3 Approximately 45cm 3 The internal volume includes approximately 10 to 20 oral solid dosage forms according to the disclosed text, and optionally includes at least one silica gel desiccant container, each containing, for example, about 2 grams of desiccant. In various embodiments, the container closure system may also include at least one oxygen absorber containing, for example, about 2 grams of oxygen-absorbing material. In a specific non-limiting embodiment according to the disclosed text, the pre-packaged pharmaceutical product according to the disclosed text includes a container closure system wherein the container has an internal volume of approximately 15 cm³. 3 Approximately 45cm 3 The internal volume contains approximately 10 to approximately 20 oral solid dosage forms according to the published text, at least one silica gel desiccant container (each container includes, for example, approximately 2 grams of desiccant), and at least one oxygen absorber (including, for example, approximately 2 grams of oxygen absorbing material).

[0092] In other non-limiting embodiments, a pre-packaged pharmaceutical product is provided, comprising an oral solid dosage form according to the disclosed text, the oral solid dosage form being contained in a container closure system including a container and a sealing closure. In a specific non-limiting embodiment according to the disclosed text, the container has approximately 60 cm². 3 Approximately 90cm 3The internal volume includes approximately 90 to approximately 110 oral solid dosage forms according to the disclosed text, and optionally includes at least one silica gel desiccant container, each containing, for example, approximately 2 grams of desiccant. In various embodiments, the container closure system may also include at least one oxygen absorber containing, for example, approximately 2 grams of oxygen-absorbing material. In a specific non-limiting embodiment according to the disclosed text, the pre-packaged pharmaceutical product according to the disclosed text includes a container closure system wherein the container has approximately 60 cm³. 3 Approximately 90cm 3 The internal volume contains approximately 90 to approximately 110 oral solid dosage forms according to the published text, at least one silica gel desiccant container (each container includes, for example, approximately 2 grams of desiccant), and at least one oxygen absorber (including, for example, approximately 2 grams of oxygen absorbing material).

[0093] The container of a container closure system for a prepackaged pharmaceutical product according to a specific non-limiting embodiment of the disclosed text may include at least one of glass, plastic, or other suitable polymer materials. For example, in a specific embodiment, the container of a container closure system for a prepackaged pharmaceutical product according to a specific non-limiting embodiment of the disclosed text may include polypropylene or high-density polyethylene. In a specific embodiment of a prepackaged pharmaceutical product according to the disclosed text, an oral solid dosage form of the drug may be stored in the container of the container closure system, and the container has been purged with an inert gas to displace at least a portion of the ambient oxygen within the container before sealing the container with a closure element. In a specific embodiment of the disclosed text, the inert gas used to purge the container may include nitrogen, argon, a mixture of nitrogen and argon, or another inert gas. In a specific embodiment of a prepackaged pharmaceutical product according to the disclosed text, an oral solid dosage form of the drug may be stored in the container of the container closure system, and the container has not been purged with an inert gas before sealing the container with a closure element. In a specific embodiment of the disclosed text, at least a portion of the air space within the container may be filled with pill packaging material, such as rayon or cotton, before sealing the container with a closure element.

[0094] The disclosed text relates to a method of administering an oral solid dosage form of a drug comprising levothyroxine and iothronine according to the disclosed text to a patient or human subject in need of such administration. According to one method, an oral solid dosage form of a drug according to the disclosed text is administered to a patient or human subject in need of such administration, such that the patient / subject receives approximately 7.5 μg to approximately 300 μg of levothyroxine and approximately 1.75 μg to approximately 75 μg of iothronine per dose.

[0095] According to a specific non-limiting embodiment, a dry stratification / mixing process typically including the following steps can be used to prepare an oral solid dosage form of a drug according to the disclosed text. A dry stratification blend is prepared by first sieving a diluent (e.g., AVICEL® HFE-102 powder or MCC) through a #30 mesh sieve, and then mixing the diluent using a high-shear mixer granulator (HSMG) to form a first layer in the HSMG. Next, a sieved blend is prepared by sieving the remaining diluent, additional diluents (e.g., butylated hydroxyanisole, mannitol, hydroxypropyl methylcellulose), a flow aid (e.g., talc), and the active pharmaceutical ingredient (levothyroxine sodium, iodide sodium) together to form a sieved blend. The sieved blend is deposited on the first layer to form a second layer in the HSMG. Next, a dry lubricant (e.g., magnesium stearate) is sieved through a #30 mesh sieve and added to the mixed and sieved dry blend. The combined components are then homogenized in HSMG to form a substantially homogeneous dry drug mixture. A predetermined amount of the dry mixture is compressed to form a tablet dosage form with a desired mass, and each tablet comprises the desired amounts of levothyroxine salt and iodine salt. Alternatively, the predetermined amount of the dry drug mixture can be arranged in capsules (e.g., hard gelatin capsules) or used to prepare other suitable oral solid dosage forms of the drug.

[0096] According to a specific non-limiting embodiment, a dry layering / mixing process typically including the following steps can be used to prepare an oral solid dosage form of the drug according to the disclosed text. This involves first adding a diluent (e.g., AVICEL) to the solution. ® A dry-layered blend is prepared by sieving PH-102MCC powder through a #30 mesh sieve and then mixing the diluent using a high-shear mixer granulator (HSMG) to form a first layer in the HSMG. Next, a sieved blend is prepared by sieving the remaining diluent, additional diluents (e.g., butylated hydroxyanisole, mannitol), gliding agents (e.g., talc), and active pharmaceutical ingredients (levothyroxine sodium, iodide sodium) together to form a sieved blend. The sieved blend is deposited on the first layer to form a second layer in the HSMG. Next, a dry lubricant (e.g., magnesium stearate) is sieved through a #30 mesh sieve and added to the mixed and sieved dry blend, and the combined components are homogenized in the HSMG to form a substantially homogeneous dry pharmaceutical mixture. A predetermined amount of the dry mixture is compressed to form a tablet dosage form with a desired quality, and each tablet comprises a desired amount of levothyroxine salt and iodide sodium. Alternatively, a predetermined amount of the dry drug mixture can be arranged in a capsule (e.g., a hard gelatin capsule) or used to prepare other suitable oral solid dosage forms of the drug.

[0097] The inventors have observed that embodiments of the oral solid dosage form comprising levothyroxine salt and iodine salt according to the disclosed text exhibit advantageous stability. For example, the inventors have observed that, under standard test conditions including a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, after storage for one month, two months, three months, six months, or nine months, specific non-limiting embodiments of the oral solid dosage form according to the disclosed text retain at least 90% of the initial levothyroxine salt amount. The inventors have also observed that, under accelerated test conditions including a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, after storage for one month, two months, three months, or six months, specific embodiments of the oral solid dosage form according to the disclosed text retain at least 90% of the initial levothyroxine salt amount. The inventors have also observed that, under refrigeration test conditions including a temperature of about 2°C to about 8°C, after storage for one month, three months, six months, or nine months, specific non-limiting embodiments of the oral solid dosage form according to the disclosed text retain at least 90% of the initial levothyroxine salt amount. The inventors also observed that, at temperatures ranging from about 58°C to about 62°C, after 15 days of storage, at least 90% of the initial levothyroxine salt content was retained according to a specific non-limiting embodiment of the oral solid dosage form of the drug according to the disclosed text.

[0098] The inventors have observed that, under standard test conditions including a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, after storage for one month, two months, three months, six months, or nine months, at least 92% of the initial levothyroxine salt content is retained according to a specific non-limiting embodiment of the oral solid dosage form of the disclosed text. The inventors have also observed that, under accelerated test conditions including a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, after storage for one month, two months, three months, or six months, at least 92% of the initial levothyroxine salt content is retained according to a specific non-limiting embodiment of the oral solid dosage form of the disclosed text. The inventors have further observed that, under refrigeration test conditions including a temperature of about 2°C to about 8°C, after storage for one month, three months, six months, or nine months, at least 92% of the initial levothyroxine salt content is retained according to a specific non-limiting embodiment of the oral solid dosage form of the disclosed text. The inventors also observed that, at temperatures ranging from about 58°C to about 62°C, after 15 days of storage, at least 92% of the initial levothyroxine salt content was retained according to a specific non-limiting embodiment of the oral solid dosage form of the drug according to the disclosed text.

[0099] The inventors have observed that, under standard test conditions including a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, after storage for one month, two months, three months, six months, or nine months, at least 95% of the initial levothyroxine salt content is retained according to a specific non-limiting embodiment of the oral solid dosage form of the disclosed text. The inventors have also observed that, under accelerated test conditions including a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, after storage for one month, two months, three months, or six months, at least 95% of the initial levothyroxine salt content is retained according to a specific non-limiting embodiment of the oral solid dosage form of the disclosed text. Furthermore, the inventors have observed that, under refrigeration test conditions including a temperature of about 2°C to about 8°C, after storage for one month, three months, six months, or nine months, at least 95% of the initial levothyroxine salt content is retained according to a specific non-limiting embodiment of the oral solid dosage form of the disclosed text. The inventors also observed that, at temperatures ranging from about 58°C to about 62°C, after 15 days of storage, at least 95% of the initial levothyroxine salt content was retained according to a specific non-limiting embodiment of the oral solid dosage form of the drug according to the disclosed text.

[0100] The inventors have observed that, under standard test conditions including a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, after storage for one month, two months, three months, six months, or nine months, at least 90% of the initial iothronine salt content is retained according to a specific non-limiting embodiment of the oral solid dosage form of the disclosed text. The inventors have also observed that, under accelerated test conditions including a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, after storage for one month, two months, three months, or six months, at least 90% of the initial iothronine salt content is retained according to a specific non-limiting embodiment of the oral solid dosage form of the disclosed text. The inventors have further observed that, under refrigeration test conditions including a temperature of about 2°C to about 8°C, after storage for one month, three months, six months, or nine months, at least 90% of the initial iothronine salt content is retained according to a specific non-limiting embodiment of the oral solid dosage form of the disclosed text. The inventors also observed that, at temperatures ranging from about 58°C to about 62°C, after 15 days of storage, at least 90% of the initial iodoxyronine salt content was retained according to a specific non-limiting embodiment of the oral solid dosage form of the drug according to the disclosed text.

[0101] The inventors have observed that, under standard test conditions including a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, after storage for one month, two months, three months, six months, or nine months, at least 92% of the initial iothronine salt content is retained according to a specific non-limiting embodiment of the oral solid dosage form of the disclosed text. The inventors have also observed that, under accelerated test conditions including a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, after storage for one month, two months, three months, or six months, at least 92% of the initial iothronine salt content is retained according to a specific non-limiting embodiment of the oral solid dosage form of the disclosed text. The inventors have further observed that, under refrigeration test conditions including a temperature of about 2°C to about 8°C, after storage for one month, three months, six months, or nine months, at least 92% of the initial iothronine salt content is retained according to a specific non-limiting embodiment of the oral solid dosage form of the disclosed text. The inventors also observed that, at temperatures ranging from about 58°C to about 62°C, after 15 days of storage, at least 92% of the initial iodoxyronine salt content was retained according to a specific non-limiting embodiment of the oral solid dosage form of the drug according to the disclosed text.

[0102] The inventors have observed that, under standard test conditions including a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, after storage for one month, two months, three months, six months, or nine months, at least 95% of the initial iotheronine salt content is retained according to a specific non-limiting embodiment of the oral solid dosage form of the disclosed text. The inventors have also observed that, under accelerated test conditions including a temperature of about 38°C to about 42°C and a relative humidity ranging from about 70% to about 80%, after storage for one month, two months, three months, or six months, at least 95% of the initial iotheronine salt content is retained according to a specific non-limiting embodiment of the oral solid dosage form of the disclosed text. The inventors have further observed that, under refrigeration test conditions including a temperature of about 2°C to about 8°C, after storage for one month, three months, six months, or nine months, at least 95% of the initial iotheronine salt content is retained according to a specific non-limiting embodiment of the oral solid dosage form of the disclosed text. The inventors also observed that, at temperatures ranging from about 58°C to about 62°C, after 15 days of storage, at least 95% of the initial iodoxyronine salt content was retained according to a specific non-limiting embodiment of the oral solid dosage form of the drug according to the disclosed text.

[0103] The following are non-limiting examples of oral dosage forms of drugs based on the published text and methods for manufacturing oral dosage forms of drugs based on the published text.

[0104] Example

[0105] Example 1

[0106] This embodiment describes a non-limiting implementation of a dry layering / mixing and tableting process, which can be used to manufacture oral solid dosage forms of pharmaceuticals according to the disclosed text.

[0107] Twenty-five percent of the required total amount of AVICEL® HFE-102 material is sieved through a #30 mesh sieve. The sieved material is then mixed for thirty seconds in a high-shear mixer pelletizer (HSMG) (Glatt VG PRO) at a power setting of 5 (500 rpm / min) and a current intensity of 3 to 4 amps. The sieved and mixed portion of the AVICEL® HFE-102 material forms the first layer in the HSMG.

[0108] Next, a sieved blend is prepared by dry sieving the remaining 75% of the required total amount of AVICEL® HFE 102 material, levothyroxine sodium (previously sieved through a #60 mesh sieve), iodine sodium (previously sieved through a #200 mesh sieve), butylated hydroxyanisole (previously sieved through a #200 mesh sieve), mannitol (previously sieved through a #60 mesh sieve), hydroxypropyl methylcellulose (HPMC) K-100 LV CR LH, and talc (previously sieved through a #30 mesh sieve) into a container. The sieved levothyroxine sodium and iodine sodium are sandwiched in an HSMG between layers of the sieved AVICEL® HFE 102. Then, the sieved butylated hydroxyanisole is added, followed by the sieved mannitol, sieved talc, and HPMC K-100 LV CR LH. The sieved blend is placed in HSMG to form a second layer adjacent to the first (AVICEL® HFE-102 material) layer.

[0109] The two layers arranged in the HSMG constitute a dry-layered blend. The HSMG is activated to homogenize the dry-layered blend for eight minutes using a power setting of 5 (500 rpm / min) and a current intensity of 3 to 4 amps. The HSMG is operated at a low purge air pressure of 0.02 psi. The mixed dry-layered blend is removed from the HSMG and sieved through a #30 mesh sieve, then returned to the HSMG and further homogenized for eight minutes using a power setting of 5 (500 rpm / min) and a current intensity of 3 to 4 amps.

[0110] Magnesium stearate was sieved through a #30 mesh sieve and added to the double-mixed and sieved dry-layered blend. The material was then uniformly mixed for 30 seconds using an HSMG power setting of 5 (500 rpm / min) and a current intensity of 3 to 4 amperes to form the final oral dose mixture.

[0111] A portion of the final oral dose mixture is removed from the HSMG using a cradle discharge method. The cradle discharge method removes multiple small portions of the final oral dose mixture from the HSMG within a short time to prevent component segregation. Finally, the dry oral dose mixture is compressed into 130 mg tablets using a Piccola / Globe Pharma tablet press. These tablets are compressed to a hardness of 4 Kp to 8 Kp.

[0112] Then, pack the tablets in 30cm boxes. 3 Or 75cm 3 In a high-density polyethylene bottle.

[0113] Arrange approximately 10 to 20 tablets and 0, 1, or 2 silica gel desiccant containers (commercially available from, for example, Clariant International (Colton, CA)) (each container contains approximately 2g of desiccant) in a 30cm space. 3 HDPE containers (such as Figure 1A , Figure 1B and Figure 1C (As shown). In a 30-pack comprising approximately 10 to 20 tablets. 3 In specific implementations of the container, 0, 1, or 2 PHARMAKEEPs are also arranged. ® Oxygen absorbent canisters (available commercially from Clariant International) (each canister contains approximately 2g of oxygen absorbent). Use a sealing seal (in...). Figure 2A , Figure 2B and Figure 2C (Depicted in the middle) Sealed 30cm 3 Containers that provide packaged oral solid dosage form products for pharmaceuticals.

[0114] Arrange approximately 90 to 110 tablets and 0, 1, or 2 silica gel desiccant containers at a height of 75 cm. 3 Containers (such as) Figure 3A , Figure 3B and Figure 3C (As shown). In a 75cm container containing approximately 90 to 110 tablets. 3 In specific implementations of the container, 0, 1, or 2 PHARMAKEEPs are also arranged. ® Oxygen absorbent tank. Use a sealed enclosure (such as...) Figure 4A and Figure 4B (As shown) Sealed 75cm 3 Containers that provide packaged oral solid dosage form products for pharmaceuticals.

[0115] Example 2

[0116] Tablets comprising approximately 2.25 μg to approximately 62.5 μg of iotheronine sodium and approximately 9.5 μg to approximately 250 μg of levothyroxine sodium were prepared by compressing portions of several homogeneous mixtures manufactured using the method generally described in Example 1. Each of these tablets comprises iotheronine sodium, levothyroxine sodium, microcrystalline cellulose (MCC), mannitol, hydroxypropyl methylcellulose, butylated hydroxyanisole, talc, and magnesium stearate. Table 1 below provides the mass of the components in a single tablet comprising approximately 2.25 μg to approximately 62.5 μg of iotheronine sodium and approximately 9.5 μg to approximately 250 μg of levothyroxine sodium per tablet; these contents are referred to as the “strength” of a single tablet.

[0117] Table 1 Tablet composition

[0118] All tablet strength 2.25 / 9.5 3.1 / 12.5 4.5 / 19 6.25 / 25 9 / 38 12.5 / 50 13.5 / 57 18 / 76 25 / 100 37.5 / 150 62.5 / 250 Element mg / tablet mg / tablet mg / tablet mg / tablet mg / tablet mg / tablet mg / tablet mg / tablet mg / tablet mg / tablet mg / tablet Iothrone sodium, USP 0.00225 0.0031 0.0045 0.00625 0.009 0.0125 0.0135 0.018 0.025 0.0375 0.0625 Levothyroxine sodium, USP 0.0095 0.0125 0.019 0.025 0.038 0.05 0.057 0.076 0.1 0.15 0.25 Avicel® HFE 102 powder 107.203 107.039 107.261 107.114 107.178 107.132 107.094 106.941 107.090 106.937 107.032 Mannitol, USP 14.65 14.65 14.65 14.65 14.65 14.65 14.65 14.65 14.65 14.65 14.65 Hydroxypropyl methylcellulose, NF 6.00 6.00 6.00 6.00 6.00 6.00 6.00 6.00 6.00 6.00 6.00 Butylated hydroxyanisole (NF) 0.005 0.005 0.005 0.005 0.005 0.005 0.005 0.005 0.005 0.005 0.005 Talc, NF 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 Magnesium stearate, NF 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 FD&C Blue #1 Aluminum Lake Pigment - 0.160 0.06 - - - 0.09 0.16 0.05 - - D&C Yellow #10 Aluminum Lake Pigment 0.130 - - 0.05 0.06 - 0.09 0.15 0.07 0.2 - FD&C Red #40 Aluminum Lake Pigment - 0.130 - 0.15 0.06 0.15 - - 0.01 0.02 - Total 130.00 130.00 130.00 130.00 130.00 130.00 130.00 130.00 130.00 130.00 130.00

[0119] Example 3

[0120] Studies were conducted to evaluate the stability of specific implementation schemes of oral solid dosage forms of drugs based on publicly available texts.

[0121] Tablets comprising about 3.1 μg of iotheronine sodium and about 12.5 μg of levothyroxine sodium were prepared by compressing portions of several homogeneous mixtures manufactured using the method generally described in Example 1. Each of these mixtures comprises iotheronine sodium, levothyroxine sodium, MCC, mannitol, hydroxypropyl methylcellulose, butylated hydroxyanisole, talc, and magnesium stearate. MCC is included as an Avicel... ® The composition of HFE 102 powder. Table 2 below provides the mass and weight / weight concentration of the ingredients in a single tablet produced in batch NB543-050, which includes approximately 3.1 µg of iodine sodium and approximately 12.5 µg of levothyroxine sodium per tablet.

[0122] Table 2 Composition of tablets in batch NB543-050

[0123] Element % weight / weight mg / unit Iothrone sodium, USP 0.00238 0.00310 Levothyroxine sodium, USP 0.00961 0.0125 Avicel® HFE 102 powder 84.65 110.039 Mannitol, USP 11.27 14.65 Hydroxypropyl methylcellulose, NF 2.31 3.00 Butylated hydroxyanisole (NF) 0.00384 0.005 Talc, NF 0.77 1.00 Magnesium stearate, NF 0.77 1.00 FD&C Blue #1 Aluminum Lake Pigment 0.12 0.160 D&C Yellow #10 Aluminum Lake Pigment - - FD&C Red #40 Aluminum Lake Pigment 0.10 0.130 Total 100.00 130

[0124] By adjusting the amounts of active and inactive ingredients to maintain the same dosage form quality, solid dosage forms containing different amounts of active agents (levothyroxine sodium and iodine sodium) can be formed in a dosage-similar manner.

[0125] To conduct stability studies, tablets from batch NB543-050 were arranged in a container closure system, which included a container and a sealing closure. The container consisted of approximately 30 cm³ of... 3 (Including 10 to 20 tablets) or approximately 75cm3 The internal volume contains 90 to 100 tablets. Each container also includes 0, 1, or 2 silica gel desiccant canisters (containing 0, 2, or 4 g of silica gel, respectively) and 0, 1, or 2 PHARMAKEEP® oxygen absorber canisters (containing 0, 2, or 4 g of oxygen absorber, respectively). Once filled, each container is induction-sealed with a closure. Alternatively, after tablet filling and before induction sealing, the air inside the container can be displaced by arranging an inert pill packaging material (e.g., rayon or cotton) inside the container.

[0126] Four studies were conducted to evaluate the stability of levothyroxine sodium and iodine sodium in tablets manufactured in batch NB543-050. The stability studies involved the following test periods and conditions:

[0127] • Store under refrigerated conditions (2°C to 8°C) for up to nine months.

[0128] • Store for up to nine months under standard testing conditions (25℃±2℃ and 60%±5% relative humidity).

[0129] • Store for up to six months under accelerated testing conditions (40℃±2℃ and 75%±5% relative humidity).

[0130] • Store under extreme test conditions (60℃±2℃) for 7 or 15 days.

[0131] A nine-month refrigeration stability study was conducted on tablets of batch NB543-050 contained in a container-sealed system to determine the physical or chemical degradation rates of levothyroxine sodium and iodine sodium contained in the tablets when stored under refrigerated conditions.

[0132] During stability testing, samples for refrigerated stability were placed upright in an environmental chamber and maintained in an upright position. As discussed, each tablet was arranged in a sealed container containing 10 to 20 or 90 to 100 tablets from batch NB543-050, each tablet comprising approximately 3.1 μg of iodine sodium and approximately 12.5 μg of levothyroxine sodium. The sealed containers were maintained uninterruptedly at 2°C to 8°C for one month, three months, six months, or nine months (except for the addition or withdrawal of test samples). At specified time points, the tablets were removed from storage conditions, and their levothyroxine sodium and iodine sodium contents were determined using high-performance liquid chromatography (HPLC).

[0133] Considering the levothyroxine sodium content, the shelf life of batch NB543-050 tablets stored under refrigerated test conditions is estimated to be at least nine months. Table 3 provides the nine-month stability test results for batch NB543-050 tablets under refrigerated test conditions. The stability test results indicate that the tablets stored under refrigerated test conditions for nine months retained more than 95% of the original levothyroxine sodium content.

[0134] Considering the sodium iotheronine content, the shelf life of tablets in batch NB543-050 is estimated to be at least nine months when stored under refrigerated test conditions. As shown in Table 3, stability tests indicate that tablets stored under refrigerated test conditions for nine months retained more than 95% of the original sodium iotheronine content.

[0135] A nine-month standard test condition stability study was conducted on tablets of batch NB543-050 contained in a container-closed system to determine the physical or chemical degradation rates of levothyroxine sodium and iodine sodium contained in the tablets when stored under standard environmental conditions.

[0136] During stability studies, the sealed container system containing tablets (each tablet comprising approximately 3.1 μg of iothronine sodium and approximately 12.5 μg of levothyroxine sodium) prepared as described above was placed upright in a calibrated environmental chamber and maintained in an upright position. Sealed containers containing 10 to 20 or 90 to 100 tablets were maintained uninterruptedly at 25°C ± 2°C and 60% ± 5% relative humidity for one month, two months, three months, six months, or nine months (except for the addition or withdrawal of test samples). At specified time points, the tablets were removed from storage conditions, and their levothyroxine sodium and iothronine sodium contents were determined using high-performance liquid chromatography (HPLC).

[0137] Considering the levothyroxine sodium content, the shelf life of batch NB543-050 tablets stored under standard testing conditions is estimated to be at least nine months. Table 3 provides the nine-month stability test results for batch NB543-050 tablets. The stability test results indicate that the tablets stored under standard testing conditions for nine months retained more than 95% of the original levothyroxine sodium content.

[0138] Considering the sodium iotheronine content, the shelf life of tablets in batch NB543-050 is estimated to be at least nine months when stored under standard testing conditions. As shown in Table 3, stability assays indicate that tablets stored for nine months under standard testing conditions retained more than 95% of the original sodium iotheronine content.

[0139] During stability testing, accelerated-condition stability samples were placed upright in an environmental chamber and maintained in an upright position. As discussed, each tablet was arranged in a sealed container containing 10 to 20 or 90 to 100 tablets from batch NB543-050, each tablet comprising approximately 3.1 μg of iodine sodium and approximately 12.5 μg of levothyroxine sodium. The sealed containers were maintained uninterruptedly at 40°C ± 2°C and 75% ± 5% relative humidity for one month, two months, three months, or six months (except for the addition or withdrawal of test samples). At specified time points, the tablets were removed from storage conditions, and their levothyroxine sodium and iodine sodium contents were determined using high-performance liquid chromatography (HPLC).

[0140] Considering the levothyroxine sodium content, the shelf life of batch NB543-050 tablets stored under accelerated testing conditions is estimated to be at least six months. Table 3 provides the results of the six-month stability test for batch NB543-050 tablets under accelerated testing conditions. The stability test results indicate that the tablets stored for six months under accelerated testing conditions retained more than 95% of the original levothyroxine sodium content.

[0141] Considering the sodium iotheronine content, the shelf life of tablets in batch NB543-050 is estimated to be at least six months when stored under accelerated testing conditions. As shown in Table 3, stability assays indicate that tablets stored for six months under accelerated testing conditions retained more than 95% of the original sodium iotheronine content.

[0142] Stability studies under extreme test conditions were conducted, in which tablets of batch NB543-050 were stored under extreme test conditions for 7 or 15 days to determine the physical or chemical degradation rates of the original content of approximately 3.1 μg of iodine sodium and approximately 12.5 μg of levothyroxine sodium in the tablets. During the stability studies, all extreme test condition stability samples (each sample consisting of a closed container system containing 10 to 20 or 90 to 100 tablets of batch NB543-050) were placed upright in an environmental chamber and maintained in an upright position. All containers were maintained at 60°C ± 2°C without interruption (except for the addition or withdrawal of test samples) for 7 or 15 days. At the specified time points, the tablets were removed from the storage conditions, and their levothyroxine sodium and iodine sodium contents were determined using high-performance liquid chromatography (HPLC).

[0143] Considering the levothyroxine sodium content, the shelf life of batch NB543-050 tablets stored under extreme test conditions is estimated to be at least fifteen days. Table 3 provides the fifteen-day stability test results for batch NB543-050 tablets. The stability test results indicate that the tablets stored under extreme test conditions for fifteen days retained more than 95% of the original levothyroxine sodium content.

[0144] Considering the sodium iotheronine content, the shelf life of tablets in batch NB543-050 is estimated to be at least fifteen days when stored under extreme test conditions. As shown in Table 3, stability assays indicate that tablets stored for fifteen days under extreme test conditions retained more than 95% of the original sodium iotheronine content.

[0145] Table 3 reports stability data for the oral solid dosage form sample (batch NB543-050) under refrigerated, standard, accelerated, and extreme conditions. The percentages determined in Table 2 are based on the expected (“label claim” content per tablet of batch NB543-050: approximately 3.1 μg of iodine sodium and approximately 12.5 μg of levothyroxine sodium.

[0146] Table 3 Stability test results of tablets in batch NB543-050

[0147]

[0148] Referring to the results shown in Table 3, the inventors surprisingly observed that when stored for nine months under refrigeration test conditions of 2°C to 8°C, the oral solid dosage form of the drug produced in batch NB543-050 retained 100% of the original levothyroxine sodium content, and when stored for nine months under standard test conditions of 25°C ± 2°C and 60% ± 5% relative humidity, the oral solid dosage form of the drug produced in the batch also retained approximately 99% of the original levothyroxine sodium content. Even when the tablets were stored for six months under accelerated conditions (40°C ± 2°C and 75% ± 5% relative humidity), the tablets produced in batch NB543-050 retained approximately 98% of the original levothyroxine sodium content (the levothyroxine sodium content of the tablets decreased by approximately two percent). When the tablets were stored for 15 days under extreme conditions (60°C ± 2°C), the tablets produced in batch NB543-050 retained approximately 95% of the original levothyroxine sodium content.

[0149] Referring to the results shown in Table 3, the inventors also surprisingly observed that when stored for nine months under refrigeration test conditions of 2°C to 8°C, the oral solid dosage form of the drug produced in batch NB543-050 retained 100% of the original iodoxylonine sodium content. Furthermore, when stored for nine months under standard test conditions of 25°C ± 2°C and 60% ± 5% relative humidity, the oral solid dosage form of the drug produced in this batch also retained 100% of the original iodoxylonine sodium content. Even when the tablets were stored for six months under accelerated conditions (40°C ± 2°C and 75% ± 5% relative humidity), the tablets produced in batch NB543-050 retained 100% of the original iodoxylonine sodium content. When the tablets were stored for 15 days under extreme conditions (60°C ± 2°C), the tablets produced in batch NB543-050 retained approximately 99.5% of the original iodoxylonine sodium content.

[0150] Example 4

[0151] A study was conducted to evaluate the stability of the implementation plan for the oral solid dosage form of the drug based on the published text.

[0152] Tablets comprising approximately 37.5 μg of iotheronine sodium and approximately 150 μg of levothyroxine sodium were prepared by compressing portions of several homogeneous mixtures manufactured using the method generally described in Example 1. Each of these mixtures comprises iotheronine sodium, levothyroxine sodium, MCC, mannitol, hydroxypropyl methylcellulose, butylated hydroxyanisole, talc, and magnesium stearate. MCC is included as an Avicel... ® The composition of HFE 102 powder. Table 4 below provides the mass and weight / weight concentration of the ingredients in a single tablet produced in batch NB543-051, which includes approximately 37.5 µg of iodine sodium and approximately 150 µg of levothyroxine sodium per tablet.

[0153] Table 4 Composition of tablets in batch NB543-051

[0154] Element % weight / weight mg / unit Iothrone sodium, USP 0.0288 0.0375 Levothyroxine sodium, USP 0.115 0.15 Avicel® HFE 102 powder 84.57 109.938 Mannitol, USP 11.27 14.65 Hydroxypropyl methylcellulose, NF 2.31 3.00 Butylated hydroxyanisole (NF) 0.00384 0.005 Talc, NF 0.77 1.00 Magnesium stearate, NF 0.77 1.00 FD&C Blue #1 Aluminum Lake Pigment - - D&C Yellow #10 Aluminum Lake Pigment 0.15 0.2 FD&C Red #40 Aluminum Lake Pigment 0.015 0.02 Total 100.00 130

[0155] By adjusting the amounts of active and inactive ingredients to maintain the same dosage form quality, solid dosage forms containing different amounts of active agents (levothyroxine sodium and iodine sodium) can be formed in a dosage-similar manner.

[0156] To conduct stability studies, tablets from batch NB543-051 were arranged in a container closure system, which includes a container and a sealing closure. The container comprises approximately 30 cm³ of... 3 (Including 10 to 20 tablets) or approximately 75cm 3The internal volume contains 90 to 100 tablets. Each container also includes 0, 1, or 2 silica gel desiccant canisters (containing 0, 2, or 4 g of silica gel, respectively) and 0, 1, or 2 PHARMAKEEP® oxygen absorber canisters (containing 0, 2, or 4 g of oxygen absorber, respectively). Once filled, each container is induction-sealed with a closure. Alternatively, after tablet filling and before induction sealing, the air inside the container can be displaced by arranging an inert pill packaging material (e.g., rayon or cotton) inside the container.

[0157] Four studies were conducted to evaluate the stability of levothyroxine sodium and iodine sodium in tablets manufactured in batch NB543-051. The stability studies involved the following test periods and conditions:

[0158] • Store under refrigerated conditions (2°C to 8°C) for up to nine months.

[0159] • Store for up to nine months under standard testing conditions (25℃±2℃ and 60%±5% relative humidity).

[0160] • Store for up to six months under accelerated testing conditions (40℃±2℃ and 75%±5% relative humidity).

[0161] • Store under extreme test conditions (60℃±2℃) for 7 or 15 days.

[0162] A nine-month refrigeration stability study was conducted on tablets of batch NB543-051 contained in a container-sealed system to determine the physical or chemical degradation rates of levothyroxine sodium and iodine sodium contained in the tablets when stored under refrigerated conditions.

[0163] During stability testing, samples for refrigerated stability were placed upright in an ambient chamber and maintained in an upright position. As discussed, each tablet was arranged in a sealed container containing 10 to 20 or 90 to 100 tablets from batch NB543-051, each tablet comprising approximately 37.5 μg of iodine sodium and approximately 150 μg of levothyroxine sodium. The sealed containers were maintained uninterruptedly at 2°C to 8°C for one month, three months, six months, or nine months (except for the addition or withdrawal of test samples). At specified time points, the tablets were removed from storage conditions, and their levothyroxine and iodine content was determined using high-performance liquid chromatography (HPLC).

[0164] Considering the levothyroxine sodium content, the shelf life of tablets in batch NB543-051 is estimated to be at least nine months when stored under refrigerated test conditions. Table 5 provides the nine-month stability test results for tablets in batch NB543-051 under refrigerated test conditions. The stability test results indicate that tablets stored under refrigerated test conditions for nine months retained more than 95% of the original levothyroxine sodium content.

[0165] Considering the sodium iotheronine content, the shelf life of tablets in batch NB543-051 is estimated to be at least nine months when stored under refrigerated test conditions. As shown in Table 5, stability tests indicate that tablets stored under refrigerated test conditions for nine months retained more than 95% of the original sodium iotheronine content.

[0166] A nine-month standard test condition stability study was conducted on tablets of batch NB543-051 contained in a container-closed system to determine the physical or chemical degradation rates of levothyroxine sodium and iodine sodium contained in the tablets when stored under standard environmental conditions.

[0167] During stability studies, the sealed container system containing tablets (each tablet comprising approximately 37.5 μg of iothronine sodium and approximately 150 μg of levothyroxine sodium), prepared as described above, was placed upright in a calibrated environmental chamber and maintained in an upright position. Sealed containers containing 10 to 20 or 90 to 100 tablets were maintained uninterruptedly at 25°C ± 2°C and 60% ± 5% relative humidity for one month, two months, three months, six months, or nine months (except for the addition or withdrawal of test samples). At specified time points, the tablets were removed from storage conditions, and their levothyroxine sodium and iothronine sodium contents were determined using high-performance liquid chromatography (HPLC).

[0168] Considering the levothyroxine sodium content, the shelf life of batch NB543-051 tablets stored under standard testing conditions is estimated to be at least nine months. Table 5 provides the nine-month stability test results for batch NB543-051 tablets. The stability test results indicate that the tablets stored under standard testing conditions for nine months retained more than 95% of the original levothyroxine sodium content.

[0169] Considering the sodium iotheronine content, the shelf life of tablets in batch NB543-051 is estimated to be at least nine months when stored under standard testing conditions. As shown in Table 5, stability tests indicate that tablets stored for nine months under standard testing conditions retained more than 95% of the original sodium iotheronine content.

[0170] During stability testing, accelerated-condition stability samples were placed upright in an environmental chamber and maintained in an upright position. As discussed, each tablet was arranged in a sealed container containing 10 to 20 or 90 to 100 tablets from batch NB543-051, each tablet comprising approximately 37.5 μg of iodine sodium and approximately 150 μg of levothyroxine sodium. The sealed containers were maintained uninterruptedly at 40°C ± 2°C and 75% ± 5% relative humidity for one month, two months, three months, or six months (except for the addition or withdrawal of test samples). At specified time points, the tablets were removed from storage conditions, and their levothyroxine sodium and iodine sodium contents were determined using high-performance liquid chromatography (HPLC).

[0171] Considering the levothyroxine sodium content, the shelf life of batch NB543-051 tablets stored under accelerated testing conditions is estimated to be at least six months. Table 5 provides the results of the six-month stability test of batch NB543-051 tablets under accelerated testing conditions. The stability test results show that the tablets stored for six months under accelerated testing conditions retained more than 95% of the original levothyroxine sodium content.

[0172] Considering the sodium iotheronine content, the shelf life of tablets in batch NB543-051 is estimated to be at least six months when stored under accelerated testing conditions. As shown in Table 5, stability assays indicate that tablets stored for six months under accelerated testing conditions retained more than 95% of the original sodium iotheronine content.

[0173] Stability studies under extreme test conditions were conducted, in which tablets of batch NB543-051 were stored under extreme test conditions for 7 or 15 days to determine the physical or chemical degradation rates of the original content of approximately 37.5 μg of iodine sodium and approximately 150 μg of levothyroxine sodium in the tablets. During the stability studies, all extreme test condition stability samples (each sample consisting of a closed container system containing 10 to 20 or 90 to 100 tablets of batch NB543-051) were placed upright in an environmental chamber and maintained in an upright position. All containers were maintained uninterruptedly at 60°C ± 2°C for 7 or 15 days (except for the addition or withdrawal of test samples). At the specified time points, the tablets were removed from the storage conditions, and their levothyroxine sodium and iodine sodium contents were determined using high-performance liquid chromatography (HPLC).

[0174] Considering the levothyroxine sodium content, the shelf life of batch NB543-051 tablets stored under extreme test conditions is estimated to be at least fifteen days. Table 5 provides the fifteen-day stability test results for batch NB543-051 tablets. The stability test results indicate that the tablets stored under extreme test conditions for fifteen days retained more than 95% of the original levothyroxine sodium content.

[0175] Considering the sodium iotheronine content, the shelf life of tablets in batch NB543-051 is estimated to be at least fifteen days when stored under extreme test conditions. As shown in Table 5, stability assays indicate that tablets stored for fifteen days under extreme test conditions retained more than 95% of the original sodium iotheronine content.

[0176] Table 5 reports the stability data of the oral solid dosage form sample (batch NB543-051) under refrigeration, standard, accelerated, and extreme conditions. The percentages of determination listed in Table 4 are based on the expected (“label claim” content per tablet of batch NB543-051: approximately 37.5 μg of iodine sodium and approximately 150 μg of levothyroxine sodium.

[0177] Table 5 Stability test results of tablets in batch NB543-051

[0178]

[0179] Referring to the results shown in Table 5, the inventors surprisingly observed that when stored for nine months under refrigeration test conditions of 2°C to 8°C, the oral solid dosage form of the drug produced in batch NB543-051 retained 100% of the original levothyroxine sodium content. Furthermore, when stored for nine months under standard test conditions of 25°C ± 2°C and 60% ± 5% relative humidity, the oral solid dosage form of the drug produced in this batch also retained approximately 100% of the original levothyroxine sodium content. Even when the tablets were stored for six months under accelerated conditions (40°C ± 2°C and 75% ± 5% relative humidity), the tablets produced in batch NB543-051 retained approximately 100% of the original levothyroxine sodium content (the levothyroxine content of the tablets decreased by approximately two percent). When the tablets were stored for 15 days under extreme conditions (60°C ± 2°C), the tablets produced in batch NB543-051 retained approximately 97% of the original levothyroxine sodium content.

[0180] Referring to the results shown in Table 5, the inventors also surprisingly observed that when stored for nine months under refrigeration test conditions ranging from 2°C to 8°C, the oral solid dosage form of the drug produced in batch NB543-051 retained 99% of the original iodoxyronine sodium content. Furthermore, when stored for nine months under standard test conditions of 25°C ± 2°C and 60% ± 5% relative humidity, the oral solid dosage form of the drug produced in this batch also retained 99% of the original iodoxyronine sodium content. Even when the tablets were stored for six months under accelerated conditions (40°C ± 2°C and 75% ± 5% relative humidity), the tablets produced in batch NB543-051 retained 100% of the original iodoxyronine content. When the tablets were stored for 15 days under extreme conditions (60°C ± 2°C), the tablets produced in batch NB543-051 retained approximately 97% of the original iodoxyronine content.

[0181] Example 5

[0182] A study was conducted to evaluate the stability of the implementation plan for the oral solid dosage form of the drug based on the published text.

[0183] Tablets comprising approximately 62.5 μg of iotheronine sodium and approximately 250 μg of levothyroxine sodium were prepared by compressing portions of several homogeneous mixtures manufactured using the method generally described in Example 1. Each of these mixtures comprises iotheronine sodium, levothyroxine sodium, MCC, mannitol, hydroxypropyl methylcellulose, butylated hydroxyanisole, talc, and magnesium stearate. MCC is included in the mixtures as an Avicel... ® The composition of HFE 102 powder. Table 6 below provides the mass and weight / weight concentration of the ingredients in a single tablet produced in batch NB543-098, which comprises approximately 62.5 µg of iodine sodium and approximately 250 µg of levothyroxine sodium per tablet.

[0184] Table 6 Composition of tablets in batch NB543-098

[0185] Element % weight / weight mg / unit Iothrone sodium, USP 0.048 0.0625 Levothyroxine sodium, USP 0.192 0.250 Avicel® HFE 102 powder 82.33 107.032 Mannitol, USP 11.27 14.65 Hydroxypropyl methylcellulose, NF 4.62 6.00 Butylated hydroxyanisole (NF) 0.00384 0.005 Talc, NF 0.77 1.00 Magnesium stearate, NF 0.77 1.00 FD&C Blue #1 Aluminum Lake Pigment - - D&C Yellow #10 Aluminum Lake Pigment - - FD&C Red #40 Aluminum Lake Pigment - - Total 100.00 130

[0186] By adjusting the amounts of active and inactive ingredients to maintain the same dosage form quality, solid dosage forms containing different amounts of active agents (levothyroxine sodium and iodine sodium) can be formed in a dosage-similar manner.

[0187] To conduct stability studies, tablets from batch NB543-098 were arranged in a container closure system, which includes a container and a sealing closure. The container comprises approximately 30 cm³ of... 3 (Including 10 to 20 tablets) or approximately 75cm 3The internal volume contains 90 to 100 tablets. Each container also includes 0, 1, or 2 silica gel desiccant canisters (containing 0, 2, or 4 g of silica gel, respectively) and 0, 1, or 2 PHARMAKEEP® oxygen absorber canisters (containing 0, 2, or 4 g of oxygen absorber, respectively). Once filled, each container is induction-sealed with a closure. Alternatively, after tablet filling and before induction sealing, the air inside the container can be displaced by arranging an inert pill packaging material (e.g., rayon or cotton) inside the container.

[0188] A study was conducted to evaluate the stability of levothyroxine sodium and iodine sodium in tablets manufactured in batch NB543-098. The stability study involved the following test periods and conditions:

[0189] • Stored for up to two months under accelerated testing conditions (40℃±2℃ and 75%±5% relative humidity).

[0190] A two-month accelerated testing condition stability study was conducted on tablets of batch NB543-098 contained in a container-closed system to determine the physical or chemical degradation rates of levothyroxine sodium and iodine sodium contained in the tablets when stored under accelerated environmental conditions.

[0191] During the stability studies, the sealed container system containing tablets (each tablet comprising approximately 62.5 μg of iodine sodium and approximately 250 μg of levothyroxine sodium) prepared as described above was placed upright in a calibrated environmental chamber and maintained in an upright position. The sealed containers, containing 10 to 20 or 90 to 100 tablets, were maintained uninterruptedly at 40 °C ± 2 °C and 75% ± 5% relative humidity for one or two months (except for the addition or withdrawal of test samples). At specified time points, the tablets were removed from the storage conditions, and their levothyroxine sodium and iodine sodium contents were determined using high-performance liquid chromatography (HPLC).

[0192] Considering the levothyroxine sodium content, the shelf life of batch NB543-098 tablets stored under accelerated testing conditions is estimated to be at least two months. Table 7 provides the stability test results for batch NB543-098 tablets under accelerated testing conditions for two months. The stability test results indicate that the tablets stored under accelerated testing conditions for two months retained more than 95% of the original levothyroxine sodium content.

[0193] Considering the sodium iotheronine content, the shelf life of tablets in batch NB543-098 is estimated to be at least two months when stored under accelerated testing conditions. As shown in Table 7, stability assays indicate that tablets stored for two months under accelerated testing conditions retained more than 95% of the original sodium iotheronine content.

[0194] Table 7 reports the stability data of the oral solid dosage form sample (batch NB543-098) under accelerated conditions. The percentages determined in Table 7 are based on the expected (“label claim” content per tablet of batch NB543-098: approximately 62.5 μg of iodine sodium and approximately 250 μg of levothyroxine sodium.

[0195] Table 7 Stability test results of tablets in batch NB543-098

[0196]

[0197] Referring to the results shown in Table 7, the inventors were surprised to observe that when stored for two months under accelerated conditions (40°C ± 2°C and 75% ± 5% relative humidity), the oral solid dosage form of the drug produced in batch NB543-098 retained approximately 96% to approximately 99% of the original levothyroxine sodium content.

[0198] Referring to the results shown in Table 7, the inventors also surprisingly observed that when stored for two months under accelerated conditions (40°C ± 2°C and 75% ± 5% relative humidity), the oral solid dosage form of the drug produced in batch NB543-098 retained approximately 96% to approximately 99% of the original sodium iodide.

[0199] Example 6

[0200] This embodiment describes a non-limiting implementation of a dry layering / mixing and tableting process, which can be used to manufacture oral solid dosage forms of pharmaceuticals according to the disclosed text.

[0201] The required total amount of AVICEL ® Thirty-three percent of the PH-102 MCC powder is sieved through a #30 mesh sieve, and then the sieved material is mixed for thirty seconds in a high-shear mixer granulator (HSMG) (Glatt VG PRO) at 250 rpm / min and a current intensity of 3 to 4 amps. AVICEL ® The sieved and mixed portion of PH-102 powder forms the first layer in HSMG.

[0202] Next, by using the required total amount of AVICEL ®The remaining 75% of PH-102 powder, levothyroxine sodium (previously sieved through a #60 mesh sieve), iodine sodium (previously sieved through a #200 mesh sieve), butylated hydroxyanisole (previously sieved through a #200 mesh sieve), mannitol (previously sieved through a #60 mesh sieve), colorant (previously sieved through a #60 mesh sieve), and talc (previously sieved through a #30 mesh sieve) were dry-sieved through a #30 mesh sieve into a container to prepare a sieved blend. The sieved levothyroxine sodium and iodine sodium were sandwiched in an HSMG, located in a sieved AVICEL. ® Between the PH-102 powder layers. Then, sieved butylated hydroxyanisole (BHA), followed by sieved mannitol, sieved colorant, and sieved talc. The sieved blend is placed in HSMG to form with the first (AVICEL) ® The second layer adjacent to the PH-102 powder layer.

[0203] The two layers arranged in the HSMG constitute a dry-layered blend. Using the HSMG, activate it at 250 rpm / min and a current intensity of 3 to 4 amps to homogenize the dry-layered blend for five minutes. The HSMG is operated at a low purge air pressure of 0.02 psi. The mixed dry-layered blend is removed from the HSMG, sieved through a #30 mesh sieve, and then returned to the HSMG for further homogenization at 250 rpm / min and a current intensity of 3 to 4 amps for 4 minutes.

[0204] Magnesium stearate was sieved through a #30 mesh sieve and added to the double-mixed and sieved dry-layered blend. The material was then uniformly mixed for 60 seconds using HSMG at 460 rpm / min and a current intensity of 3 to 4 amps to form the final oral dose mixture.

[0205] A portion of the final oral dose mixture is removed from the HSMG using a cradle discharge method. The cradle discharge method removes multiple small portions of the final oral dose mixture from the HSMG within a short time to prevent component segregation. Finally, the dry oral dose mixture is compressed into 130 mg tablets using a Piccola / Globe Pharma tablet press. These tablets are compressed to a hardness of 4 Kp to 8 Kp.

[0206] Then, pack the tablets in 30cm boxes. 3 Or 75cm 3 In a high-density polyethylene bottle.

[0207] Arrange approximately 10 to 20 tablets and 0, 1, or 2 silica gel desiccant containers (commercially available from, for example, Clariant International (Colton, CA)) (each container contains approximately 2g of desiccant) in a 30cm space.3 HDPE containers (such as Figure 1A , Figure 1B and Figure 1C (As shown). In a 30-pack comprising approximately 10 to 20 tablets. 3 In specific implementations of the container, 0, 1, or 2 PHARMAKEEPs are also arranged. ® Oxygen absorbent canisters (available commercially from Clariant International) (each canister contains approximately 2g of oxygen absorbent). Use a sealing seal (in...). Figure 2A , Figure 2B and Figure 2C (Depicted in the middle) Sealed 30cm 3 Containers that provide packaged oral solid dosage form products for pharmaceuticals.

[0208] Arrange approximately 90 to 110 tablets and 0, 1, or 2 silica gel desiccant containers at a height of 75 cm. 3 Containers (such as) Figure 3A , Figure 3B and Figure 3C (As shown). In a 75cm container containing approximately 90 to 110 tablets. 3 In specific implementations of the container, 0, 1, or 2 PHARMAKEEPs are also arranged. ® Oxygen absorbent tank. Use a sealed enclosure (such as...) Figure 4A and Figure 4B (As shown) Sealed 75cm 3 Containers that provide packaged oral solid dosage form products for pharmaceuticals.

[0209] Example 7

[0210] Tablets comprising approximately 2.25 μg to approximately 62.5 μg of iotheronine sodium and approximately 9.5 μg to approximately 250 μg of levothyroxine sodium were prepared by compressing portions of several homogeneous mixtures manufactured using the method generally described in Example 6. Each of these tablets comprises iotheronine sodium, levothyroxine sodium, microcrystalline cellulose (MCC), mannitol, butylated hydroxyanisole, talc, colorant, and magnesium stearate. Table 8 below provides the mass of the components in a single tablet comprising approximately 2.25 μg to approximately 62.5 μg of iotheronine sodium and approximately 9.5 μg to approximately 250 μg of levothyroxine sodium per tablet; these contents are referred to as the “strength” of a single tablet.

[0211] Table 8 Tablet composition

[0212]

[0213] Example 8

[0214] Studies were conducted to evaluate the stability of specific implementation schemes of oral solid dosage forms of drugs based on publicly available texts.

[0215] Tablets comprising about 25 μg of iotheronine sodium and about 100 μg of levothyroxine sodium were prepared by compressing portions of several homogeneous mixtures manufactured using the method generally described in Example 6. Each of these mixtures comprises iotheronine sodium, levothyroxine sodium, MCC, mannitol, butylated hydroxyanisole, talc, colorant, and magnesium stearate. Table 9 below provides the mass and weight / weight concentration of the components in a single tablet comprising about 25 µg of iotheronine sodium and about 100 µg of levothyroxine sodium per tablet produced in batch NB543-134.

[0216] Table 9 Composition of tablets in batch NB543-134

[0217] Element % weight / weight mg / unit Iothrone sodium, USP 0.0192 0.025 Levothyroxine sodium, USP 0.0769 0.1 <![CDATA[MCC,NF(Avicel ® PH-102 powder) 78.29 101.781 Mannitol, USP 19.97 25.959 Butylated hydroxyanisole (NF) 0.00384 0.005 Talc, NF 0.77 1.00 Magnesium stearate, NF 0.77 1.00 FD&C Blue #1 Aluminum Lake Pigment 0.038 0.05 D&C Yellow #10 Aluminum Lake Pigment 0.054 0.07 FD&C Red #40 Aluminum Lake Pigment 0.007 0.01 Total 100.00 130

[0218] By adjusting the amounts of active and inactive ingredients to maintain the same dosage form quality, solid dosage forms containing different amounts of active agents (levothyroxine sodium and iodine sodium) can be formed in a dosage-similar manner.

[0219] To conduct stability studies, tablets from batch NB543-134 were arranged in a container closure system, which included a container and a sealing closure. The container consisted of approximately 30 cm³ of... 3 (Including 10 to 20 tablets) or approximately 75cm 3 The internal volume contains 90 to 110 tablets. Each container also includes 0, 1, or 2 silica gel desiccant canisters (containing 0, 2, or 4 g of silica gel, respectively) and 0, 1, or 2 PHARMAKEEP® oxygen absorber canisters (containing 0, 2, or 4 g of oxygen absorber, respectively). Once filled, each container is induction-sealed with a closure. Alternatively, after tablet filling and before induction sealing, the air inside the container can be displaced by arranging an inert pill packaging material (e.g., rayon or cotton) inside the container.

[0220] Two studies were conducted to evaluate the stability of levothyroxine sodium and iodine sodium in tablets produced in batch NB543-134. The stability studies involved the following test periods and conditions:

[0221] • Store for up to six months under standard testing conditions (25℃±2℃ and 60%±5% relative humidity).

[0222] • Store for up to six months under accelerated testing conditions (40℃±2℃ and 75%±5% relative humidity).

[0223] A six-month standard test condition stability study was conducted on batches of NB543-134 tablets contained in a container-closed system to determine the physical or chemical degradation rates of levothyroxine sodium and iodine sodium contained in the tablets when stored under standard environmental conditions.

[0224] During the stability studies, the sealed container system containing tablets (each tablet comprising approximately 25 μg of iodine sodium and approximately 100 μg of levothyroxine sodium), prepared as described above, was placed upright in a calibrated environmental chamber and maintained in an upright position. The sealed containers, containing 10 to 20 or 90 to 110 tablets, were maintained uninterruptedly at 25°C ± 2°C and 60% ± 5% relative humidity for three to six months (except for the addition or withdrawal of test samples). At specified time points, the tablets were removed from the storage conditions, and their levothyroxine sodium and iodine sodium contents were determined using high-performance liquid chromatography (HPLC).

[0225] Considering the levothyroxine sodium content, the shelf life of batch NB543-134 tablets stored under standard testing conditions is estimated to be at least six months. Table 10 provides the six-month stability test results for batch NB543-134 tablets. The stability test results indicate that the tablets stored for six months under standard testing conditions retained at least 98% of the original levothyroxine sodium content.

[0226] Considering the sodium iotheronine content, the shelf life of tablets in batch NB543-134 is estimated to be at least six months when stored under standard test conditions. As shown in Table 10, stability assays indicate that tablets stored for six months under standard test conditions retained at least 99% of the original sodium iotheronine content.

[0227] During stability testing, accelerated-condition stability samples were placed upright in an environmental chamber and maintained in an upright position. As discussed, each tablet was arranged in a sealed container containing 10 to 20 or 90 to 110 tablets from batch NB543-134, each tablet comprising approximately 25 μg of iodine sodium and approximately 100 μg of levothyroxine sodium. The sealed containers were maintained uninterruptedly at 40°C ± 2°C and 75% ± 5% relative humidity for one month, two months, three months, or six months (except for the addition or withdrawal of test samples). At specified time points, the tablets were removed from storage conditions, and their levothyroxine sodium and iodine sodium contents were determined using high-performance liquid chromatography (HPLC).

[0228] Considering the levothyroxine sodium content, the shelf life of batch NB543-134 tablets stored under accelerated testing conditions is estimated to be at least six months. Table 10 provides the results of the six-month stability test for batch NB543-134 tablets under accelerated testing conditions. The stability test results indicate that the tablets stored for six months under accelerated testing conditions retained at least 95% of the original levothyroxine sodium content.

[0229] Considering the sodium iotheronine content, the shelf life of tablets in batch NB543-134 is estimated to be at least six months when stored under accelerated testing conditions. As shown in Table 10, stability assays indicate that tablets stored for six months under accelerated testing conditions retained at least 97% of the original sodium iotheronine content.

[0230] Table 10 reports stability data for the oral solid dosage form sample (batch NB543-134) under standard and accelerated conditions. The percentages of determination listed in Table 10 are based on the expected (“label claim” content per tablet of batch NB543-134: approximately 25 μg of iodine sodium and approximately 100 μg of levothyroxine sodium.

[0231] Table 10 Stability test results of tablets in batch NB543-134

[0232]

[0233] Referring to the results shown in Table 10, the inventors surprisingly observed that when stored for six months under standard test conditions of 25°C ± 2°C and 60% ± 5% relative humidity, the oral solid dosage form of the drug produced in batch NB543-134 retained at least about 98% of the original levothyroxine sodium content. Even when the tablets were stored for six months under accelerated conditions (40°C ± 2°C and 75% ± 5% relative humidity), the tablets produced in batch NB543-134 retained at least about 95% of the original levothyroxine sodium content (the levothyroxine sodium content in the tablets decreased by about five percent).

[0234] Referring to the results shown in Table 10, the inventors also surprisingly observed that when stored for six months under standard test conditions of 25°C ± 2°C and 60% ± 5% relative humidity, the oral solid dosage form of the drug produced in batch NB543-134 retained at least about 99% of the original iothronine sodium content. Even when the tablets were stored for six months under accelerated conditions (40°C ± 2°C and 75% ± 5% relative humidity), the tablets produced in batch NB543-134 retained at least about 97% of the original iothronine sodium content.

[0235] The following numbered clauses relate to various non-limiting embodiments of the invention based on the published text:

[0236] 1. An oral solid dosage form of a drug, comprising:

[0237] Approximately 7.5 μg to approximately 300 μg of levothyroxine salt;

[0238] Approximately 1.75 μg to approximately 75 μg of iodized thorium salt;

[0239] Microcrystalline cellulose, by weight, comprises approximately 74% to approximately 96%; and

[0240] At least one excipient selected from lubricants, gliding agents, diluents, disintegrants, and coatings.

[0241] 2. The oral solid dosage form of the drug according to Clause 1, comprising about 7.5 µg to about 11.5 µg of levothyroxine salt and about 1.75 µg to about 2.75 µg of iodine salt.

[0242] 3. Oral solid dosage forms of the drug according to Clause 1, comprising about 10 µg to about 15 µg of levothyroxine salt and about 2.45 µg to about 3.75 µg of iodine salt.

[0243] 4. Oral solid dosage forms of the drug according to Clause 1, comprising about 15 µg to about 23 µg of levothyroxine salt and about 3.5 µg to about 5.5 µg of iodine salt.

[0244] 5. Oral solid dosage forms of drugs according to Clause 1, comprising about 20 µg to about 30 µg of levothyroxine salt and about 5 µg to about 7.5 µg of iodine salt.

[0245] 6. Oral solid dosage forms of drugs according to Clause 1, comprising about 30 µg to about 46 µg of levothyroxine salt and about 7 µg to about 11 µg of iodine salt.

[0246] 7. Oral solid dosage forms of drugs according to Clause 1, comprising about 40 µg to about 60 µg of levothyroxine salt and about 10 µg to about 15 µg of iodine salt.

[0247] 8. Oral solid dosage forms of drugs according to Clause 1, comprising about 45 µg to about 69 µg of levothyroxine salt and about 10 µg to about 16.5 µg of iodine salt.

[0248] 9. Oral solid dosage forms of drugs according to Clause 1, comprising about 60 µg to about 92 µg of levothyroxine salt and about 14 µg to about 22 µg of iodine salt.

[0249] 10. Oral solid dosage forms of drugs according to Clause 1, comprising about 80 µg to about 120 µg of levothyroxine salt and about 20 µg to about 30 µg of iodine salt.

[0250] 11. Oral solid dosage forms of drugs according to Clause 1, comprising about 120 µg to about 180 µg of levothyroxine salt and about 30 µg to about 45 µg of iodine salt.

[0251] 12. Oral solid dosage forms of drugs according to Clause 1, comprising about 150 µg to about 230 µg of levothyroxine salt and about 35 µg to about 55 µg of iodine salt.

[0252] 13. Oral solid dosage forms of drugs according to Clause 1, comprising about 200 µg to about 300 µg of levothyroxine salt and about 50 µg to about 75 µg of iodine salt.

[0253] 14. An oral solid dosage form of a drug according to any one of clauses 1 to 13, wherein the weight ratio of levothyroxine salt to iodine salt is about 3.5:1 to about 4.5:1.

[0254] 15. An oral solid dosage form of a drug according to any one of Clauses 1 to 14, comprising about 78% to about 86% by weight of microcrystalline cellulose.

[0255] 16. Oral solid dosage forms of drugs according to any one of clauses 1 to 15 also include mannitol.

[0256] 17. The oral solid dosage form of the drug according to any one of clauses 1 to 16 also includes mannitol in the form of about 9% to about 14% by weight.

[0257] 18. Oral solid dosage forms of medicines according to any one of clauses 1 to 17 also include hydroxypropyl methylcellulose.

[0258] 19. The oral solid dosage form of the drug according to any one of clauses 1 to 17 further comprises about 2% to about 7% by weight of hydroxypropyl methylcellulose.

[0259] 20. Oral solid dosage forms of medicines according to any one of clauses 1 to 19 also include butylated hydroxyanisole.

[0260] 21. The oral solid dosage form of the drug according to any one of clauses 1 to 20 further includes at least one lubricant selected from calcium stearate and magnesium stearate.

[0261] 22. Oral solid dosage forms of medicines according to Clause 1 include:

[0262] Approximately 7.5 μg to approximately 300 μg of levothyroxine salt;

[0263] Approximately 1.75 μg to approximately 75 μg of iodized thorium salt;

[0264] Microcrystalline cellulose, by weight, comprises approximately 74% to approximately 96%; and

[0265] Mannitol.

[0266] 23. Oral solid dosage forms of medicines pursuant to Clause 22 also include hydroxypropyl methylcellulose.

[0267] 24. Oral solid dosage forms of drugs pursuant to any of clauses 22 or 23 also include butylated hydroxyanisole.

[0268] 25. The oral solid dosage form of the drug according to any one of clauses 22 to 24 further includes at least one lubricant selected from calcium stearate and magnesium stearate.

[0269] 26. Oral solid dosage forms of medicines according to Clause 1 include:

[0270] Approximately 10 μg to approximately 15 μg of levothyroxine salt;

[0271] Approximately 2.45 μg to approximately 3.75 μg of iodized thorium salt;

[0272] Microcrystalline cellulose, by weight, comprises approximately 74% to approximately 96%; and

[0273] Mannitol.

[0274] 27. Oral solid dosage forms of medicines according to Clause 1 include:

[0275] Approximately 120 μg to approximately 180 μg of levothyroxine salt;

[0276] Approximately 30 μg to approximately 45 μg of iodized thionine salt;

[0277] Microcrystalline cellulose, by weight, comprises approximately 74% to approximately 96%; and

[0278] Mannitol.

[0279] 28. Oral solid dosage forms of medicines according to Clause 1 include:

[0280] Approximately 200 μg to approximately 300 μg of levothyroxine salt;

[0281] Approximately 50 μg to approximately 75 μg of iodized thorium salt;

[0282] Microcrystalline cellulose, by weight, comprises approximately 74% to approximately 96%; and

[0283] Mannitol.

[0284] 29. Oral solid dosage forms of medicines under any of clauses 26 to 28 also include hydroxypropyl methylcellulose.

[0285] 30. Oral solid dosage forms of medicines under any of clauses 26 to 29 also include butylated hydroxyanisole.

[0286] 31. The oral solid dosage form of the drug according to any one of clauses 26 to 30 further includes at least one lubricant selected from calcium stearate and magnesium stearate.

[0287] 32. An oral solid dosage form of a drug according to any one of Clauses 1 to 31, wherein after the oral solid dosage form has been stored for 3 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

[0288] 33. An oral solid dosage form of a drug according to any one of Clauses 1 to 31, wherein after the oral solid dosage form has been stored for 6 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

[0289] 34. An oral solid dosage form of a drug according to any one of Clauses 1 to 31, wherein after the oral solid dosage form has been stored for 9 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

[0290] 35. An oral solid dosage form of a drug according to any one of Clauses 1 to 31, wherein after the oral solid dosage form has been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

[0291] 36. An oral solid dosage form of a drug according to any one of Clauses 1 to 31, wherein after the oral solid dosage form has been stored for 3 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

[0292] 37. An oral solid dosage form of a drug according to any one of Clauses 1 to 31, wherein after the oral solid dosage form has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

[0293] 38. An oral solid dosage form of a drug according to any one of clauses 1 to 31, wherein after the oral solid dosage form has been stored at a temperature of about 2°C to about 8°C for 6 months, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92% or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

[0294] 39. An oral solid dosage form of a drug according to any one of Clauses 1 to 31, wherein after the oral solid dosage form has been stored at a temperature of about 2°C to about 8°C for 9 months, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

[0295] 40. An oral solid dosage form of a drug according to any one of Clauses 1 to 31, wherein after the oral solid dosage form has been stored at a temperature of about 58°C to about 62°C for 15 days, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

[0296] 41. An oral solid dosage form of a drug according to any one of clauses 1 to 40, wherein after the oral solid dosage form has been stored for 3 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, the content of iodoxyronine salt in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form.

[0297] 42. An oral solid dosage form of a drug according to any one of clauses 1 to 40, wherein after the oral solid dosage form has been stored for 6 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, the content of iodoxyronine salt in the oral solid dosage form is at least 90%, at least 92% or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form.

[0298] 43. An oral solid dosage form of a drug according to any one of clauses 1 to 40, wherein after the oral solid dosage form has been stored for 9 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, the content of iodoxyronine salt in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form.

[0299] 44. An oral solid dosage form of a drug according to any one of clauses 1 to 40, wherein after the oral solid dosage form has been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the iodine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form.

[0300] 45. An oral solid dosage form of a drug according to any one of clauses 1 to 40, wherein after the oral solid dosage form has been stored for 3 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the iodine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form.

[0301] 46. ​​An oral solid dosage form of a drug according to any one of clauses 1 to 40, wherein after the oral solid dosage form has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the iodine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form.

[0302] 47. An oral solid dosage form of a drug according to any one of clauses 1 to 40, wherein after the oral solid dosage form has been stored at a temperature of about 2°C to about 8°C for 6 months, the content of iodoxyronine salt in the oral solid dosage form is at least 90%, at least 92% or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form.

[0303] 48. An oral solid dosage form of a drug according to any one of clauses 1 to 40, wherein after the oral solid dosage form has been stored at a temperature of about 2°C to about 8°C for 9 months, the content of iodoxyronine salt in the oral solid dosage form is at least 90%, at least 92% or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form.

[0304] 49. An oral solid dosage form of a drug according to any one of clauses 1 to 40, wherein after the oral solid dosage form has been stored at a temperature of about 58°C to about 62°C for 15 days, the content of iodoxyronine salt in the oral solid dosage form is at least 90%, at least 92% or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form.

[0305] 50. An oral solid dosage form of a drug according to any one of Clauses 1 to 31, wherein when multiple oral solid dosage forms of a drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of a drug have been stored for 1 month at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

[0306] 51. An oral solid dosage form of a drug according to any one of Clauses 1 to 31, wherein when multiple oral solid dosage forms of a drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of a drug have been stored at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80% for 2 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

[0307] 52. An oral solid dosage form of a drug according to any one of Clauses 1 to 31, wherein when multiple oral solid dosage forms of a drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of a drug have been stored for 1 month at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of the drug.

[0308] 53. An oral solid dosage form of a drug according to any one of Clauses 1 to 31, wherein when multiple oral solid dosage forms of a drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of a drug have been stored at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80% for 2 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of the drug.

[0309] 54. An oral solid dosage form of medicine according to any one of clauses 50 to 53, wherein the container comprises approximately 15 cm 3Approximately 45cm 3 The internal volume.

[0310] 55. Oral solid dosage forms of medicines pursuant to Clause 54, wherein about 10 to about 20 oral solid dosage forms of medicines are arranged in a container.

[0311] 56. An oral solid dosage form of a drug according to any one of clauses 50 to 53, wherein the container comprises approximately 60 cm³. 3 Approximately 90cm 3 The internal volume.

[0312] 57. Oral solid dosage forms of medicines pursuant to Clause 56, wherein approximately 90 to approximately 110 oral solid dosage forms of medicines are arranged in a container.

[0313] 58. A packaged oral solid dosage form of medicine, comprising:

[0314] Oral solid dosage forms of medicines, by weight, include:

[0315] Approximately 7.5 μg to approximately 300 μg of levothyroxine salt;

[0316] Approximately 1.75 μg to approximately 75 μg of iodized thorium salt;

[0317] Microcrystalline cellulose, by weight, comprises approximately 74% to approximately 96%, and

[0318] At least one excipient selected from lubricants, gliding agents, diluents, disintegrants, and coatings; and

[0319] A container closure system, comprising a container and a sealing closure;

[0320] The container encapsulates multiple oral solid dosage forms of the drug and at least approximately 2 grams of desiccant and / or at least 2 grams of oxygen absorber and seals it with a sealing closure; and

[0321] Wherein, after the oral solid dosage form of the drug has been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

[0322] 59. A packaged oral solid dosage form of medicine pursuant to Clause 58, wherein the oral solid dosage form of medicine has the composition pursuant to any one of Clauses 2 to 31.

[0323] 60. Packaged oral solid dosage forms of medicines in accordance with Clause 58 or 59, wherein after the oral solid dosage form of medicine has been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form of medicine encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of medicine.

[0324] 61. A packaged oral solid dosage form of medicine, comprising:

[0325] Oral solid dosage forms of medicines, by weight, include:

[0326] Approximately 7.5 μg to approximately 300 μg of levothyroxine salt;

[0327] Approximately 1.75 μg to approximately 75 μg of iodized thorium salt;

[0328] Microcrystalline cellulose, by weight, comprises approximately 74% to approximately 96%, and

[0329] At least one excipient selected from lubricants, gliding agents, diluents, disintegrants, and coatings;

[0330] A container closure system, comprising a container and a sealing closure;

[0331] The container encapsulates multiple oral solid dosage forms of the drug and at least approximately 2 grams of desiccant and / or at least 2 grams of oxygen absorber and seals it with a sealing closure; and

[0332] Wherein, after the oral solid dosage form of the drug has been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of the drug.

[0333] 62. A packaged oral solid dosage form of medicine pursuant to Clause 61, wherein the oral solid dosage form of medicine has the composition pursuant to any one of Clauses 2 to 31.

[0334] 63. Packaged oral solid dosage forms of medicines in accordance with Clause 61 or 62, wherein after the oral solid dosage form of medicine has been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form of medicine encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of medicine.

[0335] 64. A treatment method for hypothyroidism, comprising administering an oral solid dosage form of a drug to a subject in need, wherein the oral solid dosage form comprises, by weight:

[0336] Approximately 7.5 μg to approximately 300 μg of levothyroxine salt;

[0337] Approximately 1.75 μg to approximately 75 μg of iodized thorium salt;

[0338] Microcrystalline cellulose, by weight, comprises approximately 74% to approximately 95%; and

[0339] At least one excipient selected from lubricants, gliding agents, diluents, disintegrants, and coatings.

[0340] 65. A treatment for hypothyroidism, comprising administering to a subject in need of the drug an oral solid dosage form according to any one of clauses 1 to 57.

[0341] 66. An oral solid dosage form of a drug, comprising:

[0342] Approximately 7.5 μg to approximately 300 μg of levothyroxine salt;

[0343] Approximately 1.75 μg to approximately 75 μg of iodized thorium salt;

[0344] Microcrystalline cellulose, by weight, comprises approximately 66% to approximately 90%; and

[0345] At least one excipient selected from lubricants, flow aids, diluents, antioxidants and colorants.

[0346] 67. Oral solid dosage forms of medicines pursuant to Clause 66, comprising about 7.5 µg to about 11.5 µg of levothyroxine salt and about 1.75 µg to about 2.75 µg of iodine salt.

[0347] 68. Oral solid dosage forms of medicines pursuant to Clause 66, comprising about 10 µg to about 15 µg of levothyroxine salt and about 2.45 µg to about 3.75 µg of iodine salt.

[0348] 69. Oral solid dosage forms of medicines pursuant to Clause 66, comprising about 15 µg to about 23 µg of levothyroxine salt and about 3.5 µg to about 5.5 µg of iodine salt.

[0349] 70. Oral solid dosage forms of medicines pursuant to Clause 66, comprising about 20 µg to about 30 µg of levothyroxine salt and about 5 µg to about 7.5 µg of iodine salt.

[0350] 71. Oral solid dosage forms of medicines pursuant to Clause 66, comprising about 30 µg to about 46 µg of levothyroxine salt and about 7 µg to about 11 µg of iodine salt.

[0351] 72. Oral solid dosage forms of drugs pursuant to Clause 66, comprising about 40 µg to about 60 µg of levothyroxine salt and about 10 µg to about 15 µg of iodine salt.

[0352] 73. Oral solid dosage forms of medicines pursuant to Clause 66, comprising about 45 µg to about 69 µg of levothyroxine salt and about 10 µg to about 16.5 µg of iodine salt.

[0353] 74. Oral solid dosage forms of drugs pursuant to Clause 66, comprising about 60 µg to about 92 µg of levothyroxine salt and about 14 µg to about 22 µg of iodine salt.

[0354] 75. Oral solid dosage forms of medicines pursuant to Clause 66, comprising about 80 µg to about 120 µg of levothyroxine salt and about 20 µg to about 30 µg of iodine salt.

[0355] 76. Oral solid dosage forms of drugs pursuant to Clause 66, comprising about 120 µg to about 180 µg of levothyroxine salt and about 30 µg to about 45 µg of iodine salt.

[0356] 77. Oral solid dosage forms of medicines pursuant to Clause 66, comprising about 150 µg to about 230 µg of levothyroxine salt and about 35 µg to about 55 µg of iodine salt.

[0357] 78. Oral solid dosage forms of medicines pursuant to Clause 66, comprising about 200 µg to about 300 µg of levothyroxine salt and about 50 µg to about 75 µg of iodine salt.

[0358] 79. An oral solid dosage form of a drug according to any one of clauses 66 to 78, wherein the weight ratio of levothyroxine salt to iodine salt is about 3.5:1 to about 4.5:1.

[0359] 80. An oral solid dosage form of a drug under any of clauses 66 to 79, comprising about 70% to about 86% by weight of microcrystalline cellulose.

[0360] 81. An oral solid dosage form of a drug under any of clauses 66 to 79, comprising about 74% to about 82% by weight of microcrystalline cellulose.

[0361] 82. Oral solid dosage forms of drugs pursuant to any of clauses 66 to 81 also include mannitol.

[0362] 83. The oral solid dosage form of the drug pursuant to any of clauses 66 to 81 further comprises, by weight, about 16% to about 24% mannitol.

[0363] 84. The oral solid dosage form of the drug pursuant to any of clauses 66 to 81 further comprises about 18% to about 22% by weight of mannitol.

[0364] 85. Oral solid dosage forms of medicines under any of clauses 66 to 84 also include butylated hydroxyanisole.

[0365] 86. The oral solid dosage form of the drug according to any one of clauses 66 to 85 further includes at least one lubricant selected from calcium stearate and magnesium stearate.

[0366] 87. Oral solid dosage forms of medicines as defined in Clause 66 include:

[0367] Approximately 7.5 μg to approximately 300 μg of levothyroxine salt;

[0368] Approximately 1.75 μg to approximately 75 μg of iodized thorium salt;

[0369] Microcrystalline cellulose, by weight, comprises approximately 66% to approximately 90%; and

[0370] Mannitol.

[0371] 88. Oral solid dosage forms of medicines pursuant to Clause 87 also include butylated hydroxyanisole.

[0372] 89. The oral solid dosage form of the drug according to any one of clauses 87 and 88 further includes at least one lubricant selected from calcium stearate and magnesium stearate.

[0373] 90. Oral solid dosage forms of medicines as defined in Clause 66 include:

[0374] Approximately 80 μg to approximately 120 μg of levothyroxine salt;

[0375] Approximately 20 μg to approximately 30 μg of iodized thionine salt;

[0376] Microcrystalline cellulose, by weight, comprises approximately 66% to approximately 90%; and

[0377] Mannitol.

[0378] 91. Oral solid dosage forms of medicines pursuant to Clause 90 also include butylated hydroxyanisole.

[0379] 92. The oral solid dosage form of the drug according to any one of clauses 90 and 91 further includes at least one lubricant selected from calcium stearate and magnesium stearate.

[0380] 93. An oral solid dosage form of a drug according to any one of clauses 66 to 92, wherein after the oral solid dosage form has been stored for 3 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

[0381] 94. An oral solid dosage form of a drug according to any one of clauses 66 to 92, wherein after the oral solid dosage form has been stored for 6 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

[0382] 95. An oral solid dosage form of a drug according to any one of clauses 66 to 92, wherein after the oral solid dosage form has been stored for one month at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

[0383] 96. An oral solid dosage form of a drug according to any one of clauses 66 to 92, wherein after the oral solid dosage form has been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

[0384] 97. An oral solid dosage form of a drug according to any one of clauses 66 to 92, wherein after the oral solid dosage form has been stored for 3 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

[0385] 98. An oral solid dosage form of a drug according to any one of clauses 66 to 92, wherein after the oral solid dosage form has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

[0386] 99. An oral solid dosage form of a drug according to any one of clauses 66 to 98, wherein after the oral solid dosage form has been stored for 3 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, the iodine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form.

[0387] 100. An oral solid dosage form of a drug according to any one of clauses 66 to 98, wherein after the oral solid dosage form has been stored for 6 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, the content of iodoxyronine salt in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form.

[0388] 101. An oral solid dosage form of a drug according to any one of clauses 66 to 98, wherein after the oral solid dosage form has been stored for one month at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the iodine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form.

[0389] 102. An oral solid dosage form of a drug according to any one of clauses 66 to 98, wherein after the oral solid dosage form has been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the iodine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form.

[0390] 103. An oral solid dosage form of a drug according to any one of clauses 66 to 98, wherein after the oral solid dosage form has been stored for 3 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the content of iodoxyronine salt in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form.

[0391] 104. An oral solid dosage form of a drug according to any one of clauses 66 to 98, wherein after the oral solid dosage form has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the iodine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form.

[0392] 105. An oral solid dosage form of a drug according to any one of Clauses 66 to 92, wherein when multiple oral solid dosage forms of a drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of a drug have been stored at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65% for 3 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

[0393] 106. An oral solid dosage form of a drug according to any one of Clauses 66 to 92, wherein when multiple oral solid dosage forms of a drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of a drug have been stored at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65% for 6 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

[0394] 107. An oral solid dosage form of a drug according to any one of Clauses 66 to 92, wherein when multiple oral solid dosage forms of a drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of a drug have been stored at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65% for 3 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of the drug.

[0395] 108. An oral solid dosage form of a drug according to any one of Clauses 66 to 92, wherein when multiple oral solid dosage forms of a drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of a drug have been stored at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65% for 6 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of the drug.

[0396] 109. An oral solid dosage form of a drug according to any one of Clauses 66 to 92, wherein when multiple oral solid dosage forms of a drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of a drug have been stored for 1 month at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

[0397] 110. An oral solid dosage form of a drug according to any one of Clauses 66 to 92, wherein when multiple oral solid dosage forms of a drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of a drug have been stored at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80% for 2 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

[0398] 111. An oral solid dosage form of a drug according to any one of Clauses 66 to 92, wherein when multiple oral solid dosage forms of a drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of a drug have been stored at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80% for 3 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

[0399] 112. An oral solid dosage form of a drug according to any one of Clauses 66 to 92, wherein when multiple oral solid dosage forms of a drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of the drug have been stored at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80% for 6 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

[0400] 113. An oral solid dosage form of a drug according to any one of Clauses 66 to 92, wherein when multiple oral solid dosage forms of a drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of a drug have been stored for 1 month at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of the drug.

[0401] 114. An oral solid dosage form of a drug according to any one of Clauses 66 to 92, wherein when multiple oral solid dosage forms of a drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of the drug have been stored at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80% for 2 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of the drug.

[0402] 115. An oral solid dosage form of a drug according to any one of clauses 66 to 92, wherein when multiple oral solid dosage forms of a drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of the drug have been stored at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80% for 3 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of the drug.

[0403] 116. An oral solid dosage form of a drug according to any one of clauses 66 to 92, wherein when multiple oral solid dosage forms of a drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of a drug have been stored at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80% for 6 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of the drug.

[0404] 117. An oral solid dosage form of medicine according to any one of clauses 105 to 116, wherein the container comprises approximately 15 cm 3 Approximately 45cm 3 The internal volume.

[0405] 118. Oral solid dosage forms of medicines in accordance with Clause 117, wherein about 10 to about 20 oral solid dosage forms of medicines are arranged in a container.

[0406] 119. An oral solid dosage form of medicine according to any one of clauses 105 to 116, wherein the container comprises approximately 60 cm³ 3 Approximately 90cm 3 The internal volume.

[0407] 120. Oral solid dosage forms of medicines pursuant to Clause 119, wherein approximately 90 to approximately 110 oral solid dosage forms of medicines are arranged in a container.

[0408] 121. A packaged oral solid dosage form of medicine, comprising:

[0409] Oral solid dosage forms of medicines, by weight, include:

[0410] Approximately 7.5 μg to approximately 300 μg of levothyroxine salt;

[0411] Approximately 1.75 μg to approximately 75 μg of iodized thorium salt;

[0412] Microcrystalline cellulose, by weight, comprises approximately 66% to approximately 90%, and

[0413] At least one excipient selected from lubricants, flow aids, diluents, antioxidants, and colorants; and

[0414] A container closure system, comprising a container and a sealing closure;

[0415] The container encapsulates multiple oral solid dosage forms of the drug and at least approximately 2 grams of desiccant and / or at least 2 grams of oxygen absorber and seals it with a sealing closure; and

[0416] Wherein, after the oral solid dosage form of the drug has been stored for 6 months at a temperature of about 25°C to about 27°C and a relative humidity of about 55% to about 65%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

[0417] 122. A packaged oral solid dosage form of medicine pursuant to Clause 56, wherein the oral solid dosage form of medicine has a composition pursuant to any one of Clauses 67 to 92.

[0418] 123. Packaged oral solid dosage forms of medicines in accordance with Clause 121 or 122, wherein after the oral solid dosage form of medicine has been stored for 6 months at a temperature of about 25°C to about 27°C and a relative humidity of about 55% to about 65%, each oral solid dosage form of medicine encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of medicine.

[0419] 124. A packaged oral solid dosage form of medicine, comprising:

[0420] Oral solid dosage forms of medicines, by weight, include:

[0421] Approximately 7.5 μg to approximately 300 μg of levothyroxine salt;

[0422] Approximately 1.75 μg to approximately 75 μg of iodized thorium salt;

[0423] Microcrystalline cellulose, by weight, comprises approximately 66% to approximately 90%, and

[0424] At least one excipient selected from lubricants, gliding agents, diluents, disintegrants, and coatings;

[0425] A container closure system, comprising a container and a sealing closure;

[0426] The container encapsulates multiple oral solid dosage forms of the drug and at least approximately 2 grams of desiccant and / or at least 2 grams of oxygen absorber and seals it with a sealing closure; and

[0427] Wherein, after the oral solid dosage form of the drug has been stored for 6 months at a temperature of about 25°C to about 27°C and a relative humidity of about 55% to about 65%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of the drug.

[0428] 125. A packaged oral solid dosage form of medicine pursuant to Clause 59, wherein the oral solid dosage form of medicine has the composition pursuant to any one of Clauses 67 to 92.

[0429] 126. Packaged oral solid dosage forms of medicines in accordance with Clause 124 or 125, wherein after the oral solid dosage form of medicine has been stored for 6 months at a temperature of about 25°C to about 27°C and a relative humidity of about 55% to about 65%, each oral solid dosage form of medicine encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of medicine.

[0430] 127. A packaged oral solid dosage form of medicine, comprising:

[0431] Oral solid dosage forms of medicines, by weight, include:

[0432] Approximately 7.5 μg to approximately 300 μg of levothyroxine salt;

[0433] Approximately 1.75 μg to approximately 75 μg of iodized thorium salt;

[0434] Microcrystalline cellulose, by weight, comprises approximately 66% to approximately 90%, and

[0435] At least one excipient selected from lubricants, flow aids, diluents, antioxidants, and colorants; and

[0436] A container closure system, comprising a container and a sealing closure;

[0437] The container encapsulates multiple oral solid dosage forms of the drug and at least approximately 2 grams of desiccant and / or at least 2 grams of oxygen absorber and seals it with a sealing closure; and

[0438] Wherein, after the oral solid dosage form of the drug has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

[0439] 128. A packaged oral solid dosage form of medicine pursuant to Clause 127, wherein the oral solid dosage form of medicine has a composition pursuant to any one of Clauses 67 to 92.

[0440] 129. Packaged oral solid dosage forms of medicines in accordance with Clause 127 or 128, wherein after the oral solid dosage form of medicine has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form of medicine encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of medicine.

[0441] 130. A packaged oral solid dosage form of medicine, comprising:

[0442] Oral solid dosage forms of medicines, by weight, include:

[0443] Approximately 7.5 μg to approximately 300 μg of levothyroxine salt;

[0444] Approximately 1.75 μg to approximately 75 μg of iodized thorium salt;

[0445] Microcrystalline cellulose, by weight, comprises approximately 66% to approximately 90%, and

[0446] At least one excipient selected from lubricants, gliding agents, diluents, disintegrants, and coatings;

[0447] A container closure system, comprising a container and a sealing closure;

[0448] The container encapsulates multiple oral solid dosage forms of the drug and at least approximately 2 grams of desiccant and / or at least 2 grams of oxygen absorber and seals it with a sealing closure; and

[0449] Wherein, after the oral solid dosage form of the drug has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of the drug.

[0450] 131. A packaged oral solid dosage form of medicine pursuant to Clause 65, wherein the oral solid dosage form of medicine has a composition pursuant to any one of Clauses 67 to 92.

[0451] 132. Packaged oral solid dosage forms of medicines in accordance with Clause 130 or 131, wherein after the oral solid dosage form of medicine has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form of medicine encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of medicine.

[0452] 133. A treatment for hypothyroidism, comprising administering an oral solid dosage form of a drug to a subject in need, wherein the oral solid dosage form comprises, by weight:

[0453] Approximately 7.5 μg to approximately 300 μg of levothyroxine salt;

[0454] Approximately 1.75 μg to approximately 75 μg of iodized thorium salt;

[0455] Microcrystalline cellulose, by weight, comprises approximately 66% to approximately 90%; and

[0456] At least one excipient selected from lubricants, flow aids, diluents, antioxidants and colorants.

[0457] 134. A treatment for hypothyroidism, comprising administering to a subject in need an oral solid dosage form of a drug according to any one of clauses 66 to 120.

Claims

1. An oral solid dosage form of a drug, comprising: Approximately 7.5 μg to approximately 300 μg of levothyroxine salt; Approximately 1.75 μg to approximately 75 μg of iodized thorium salt; Microcrystalline cellulose, by weight, comprises approximately 74% to approximately 96%; and At least one excipient selected from lubricants, gliding agents, diluents, disintegrants, and coatings.

2. The oral solid dosage form of the drug according to claim 1, comprising about 7.5 µg to about 11.5 µg of levothyroxine salt and about 1.75 µg to about 2.75 µg of iodine salt.

3. The oral solid dosage form of the drug according to claim 1, comprising about 10 µg to about 15 µg of levothyroxine salt and about 2.45 µg to about 3.75 µg of iodine salt.

4. The oral solid dosage form of the drug according to claim 1, comprising about 15 µg to about 23 µg of levothyroxine salt and about 3.5 µg to about 5.5 µg of iodine salt.

5. The oral solid dosage form of the drug according to claim 1, comprising about 20 µg to about 30 µg of levothyroxine salt and about 5 µg to about 7.5 µg of iodine salt.

6. The oral solid dosage form of the drug according to claim 1, comprising about 30 µg to about 46 µg of levothyroxine salt and about 7 µg to about 11 µg of iodine salt.

7. The oral solid dosage form of the drug according to claim 1, comprising about 40 µg to about 60 µg of levothyroxine salt and about 10 µg to about 15 µg of iodine salt.

8. The oral solid dosage form of the drug according to claim 1, comprising about 45 µg to about 69 µg of levothyroxine salt and about 10 µg to about 16.5 µg of iodine salt.

9. The oral solid dosage form of the drug according to claim 1, comprising about 60 µg to about 92 µg of levothyroxine salt and about 14 µg to about 22 µg of iodine salt.

10. The oral solid dosage form of the drug according to claim 1, comprising about 80 µg to about 120 µg of levothyroxine salt and about 20 µg to about 30 µg of iodine salt.

11. The oral solid dosage form of the drug according to claim 1, comprising about 120 µg to about 180 µg of levothyroxine salt and about 30 µg to about 45 µg of iodine salt.

12. The oral solid dosage form of the drug according to claim 1, comprising about 150 µg to about 230 µg of levothyroxine salt and about 35 µg to about 55 µg of iodine salt.

13. The oral solid dosage form of the drug according to claim 1, comprising about 200 µg to about 300 µg of levothyroxine salt and about 50 µg to about 75 µg of iodine salt.

14. The oral solid dosage form of the drug according to any one of claims 1 to 13, wherein the weight ratio of levothyroxine salt to iodine salt is about 3.5:1 to about 4.5:

1.

15. The oral solid dosage form of the drug according to any one of claims 1 to 14, comprising about 78% to about 86% by weight of microcrystalline cellulose.

16. The oral solid dosage form of the drug according to any one of claims 1 to 15 further comprises mannitol.

17. The oral solid dosage form of the drug according to any one of claims 1 to 16 further comprises about 9% to about 14% by weight of mannitol.

18. The oral solid dosage form of the drug according to any one of claims 1 to 17 further comprises hydroxypropyl methylcellulose.

19. The oral solid dosage form of the drug according to any one of claims 1 to 17 further comprises about 2% to about 7% by weight of hydroxypropyl methylcellulose.

20. The oral solid dosage form of the drug according to any one of claims 1 to 19 further comprises butylated hydroxyanisole.

21. The oral solid dosage form of the drug according to any one of claims 1 to 20 further comprises at least one lubricant selected from calcium stearate and magnesium stearate.

22. The oral solid dosage form of the drug according to claim 1, comprising: Approximately 7.5 μg to approximately 300 μg of levothyroxine salt; Approximately 1.75 μg to approximately 75 μg of iodized thorium salt; Microcrystalline cellulose, by weight, comprises approximately 74% to approximately 96%; and Mannitol.

23. The oral solid dosage form of the drug according to claim 22 further comprises hydroxypropyl methylcellulose.

24. The oral solid dosage form of the drug according to claim 22 or 23 further comprises butylated hydroxyanisole.

25. The oral solid dosage form of the drug according to any one of claims 22 to 24 further comprises at least one lubricant selected from calcium stearate and magnesium stearate.

26. The oral solid dosage form of the drug according to claim 1, comprising: Approximately 10 μg to approximately 15 μg of levothyroxine salt; Approximately 2.45 μg to approximately 3.75 μg of iodized thorium salt; Microcrystalline cellulose, by weight, comprises approximately 74% to approximately 96%; and Mannitol.

27. The oral solid dosage form of the drug according to claim 1, comprising: Approximately 120 μg to approximately 180 μg of levothyroxine salt; Approximately 30 μg to approximately 45 μg of iodized thionine salt; Microcrystalline cellulose, by weight, comprises approximately 74% to approximately 96%; and Mannitol.

28. The oral solid dosage form of the drug according to claim 1, comprising: Approximately 200 μg to approximately 300 μg of levothyroxine salt; Approximately 50 μg to approximately 75 μg of iodized thorium salt; Microcrystalline cellulose, by weight, comprises approximately 74% to approximately 96%; and Mannitol.

29. The oral solid dosage form of the drug according to any one of claims 26 to 28 further comprises hydroxypropyl methylcellulose.

30. The oral solid dosage form of the drug according to any one of claims 26 to 29 further comprises butylated hydroxyanisole.

31. The oral solid dosage form of the drug according to any one of claims 26 to 30 further comprises at least one lubricant selected from calcium stearate and magnesium stearate.

32. The oral solid dosage form of a drug according to any one of claims 1 to 31, wherein after the oral solid dosage form of the drug has been stored for 3 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, the levothyroxine salt content in the oral solid dosage form of the drug is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

33. The oral solid dosage form of a drug according to any one of claims 1 to 31, wherein after the oral solid dosage form has been stored for 6 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

34. The oral solid dosage form of a drug according to any one of claims 1 to 31, wherein after the oral solid dosage form of the drug has been stored for 9 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, the levothyroxine salt content in the oral solid dosage form of the drug is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

35. The oral solid dosage form of a drug according to any one of claims 1 to 31, wherein after the oral solid dosage form has been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

36. The oral solid dosage form of a drug according to any one of claims 1 to 31, wherein after the oral solid dosage form has been stored for 3 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

37. The oral solid dosage form of a drug according to any one of claims 1 to 31, wherein after the oral solid dosage form has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

38. The oral solid dosage form of a drug according to any one of claims 1 to 31, wherein after the oral solid dosage form has been stored at a temperature of about 2°C to about 8°C for 6 months, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

39. The oral solid dosage form of a drug according to any one of claims 1 to 31, wherein after the oral solid dosage form has been stored at a temperature of about 2°C to about 8°C for 9 months, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

40. The oral solid dosage form of a drug according to any one of claims 1 to 31, wherein after the oral solid dosage form has been stored at a temperature of about 58°C to about 62°C for 15 days, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

41. The oral solid dosage form of a drug according to any one of claims 1 to 40, wherein after the oral solid dosage form of the drug has been stored for 3 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, the iodine salt content in the oral solid dosage form of the drug is at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form of the drug.

42. The oral solid dosage form of a drug according to any one of claims 1 to 40, wherein after the oral solid dosage form of the drug has been stored for 6 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, the iodine salt content in the oral solid dosage form of the drug is at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form of the drug.

43. The oral solid dosage form of a drug according to any one of claims 1 to 40, wherein after the oral solid dosage form of the drug has been stored for 9 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, the iodine salt content in the oral solid dosage form of the drug is at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form of the drug.

44. The oral solid dosage form of a drug according to any one of claims 1 to 40, wherein after the oral solid dosage form has been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the iodine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form.

45. The oral solid dosage form of a drug according to any one of claims 1 to 40, wherein after the oral solid dosage form has been stored for 3 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the iodine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form.

46. ​​The oral solid dosage form of a drug according to any one of claims 1 to 40, wherein after the oral solid dosage form has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the iodine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form.

47. The oral solid dosage form of a drug according to any one of claims 1 to 40, wherein after the oral solid dosage form has been stored at a temperature of about 2°C to about 8°C for 6 months, the iodine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form.

48. The oral solid dosage form of a drug according to any one of claims 1 to 40, wherein after the oral solid dosage form has been stored at a temperature of about 2°C to about 8°C for 9 months, the iodine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form.

49. The oral solid dosage form of a drug according to any one of claims 1 to 40, wherein after the oral solid dosage form has been stored at a temperature of about 58°C to about 62°C for 15 days, the iodine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form.

50. The oral solid dosage form of a drug according to any one of claims 1 to 31, wherein when a plurality of the oral solid dosage forms of the drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of the drug have been stored for one month at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

51. The oral solid dosage form of a drug according to any one of claims 1 to 31, wherein when a plurality of the oral solid dosage forms of the drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of the drug have been stored at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80% for 2 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

52. The oral solid dosage form of a drug according to any one of claims 1 to 31, wherein when a plurality of the oral solid dosage forms of the drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of the drug have been stored at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80% for one month, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of the drug.

53. The oral solid dosage form of a drug according to any one of claims 1 to 31, wherein when a plurality of the oral solid dosage forms of the drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of the drug have been stored at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80% for 2 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of the drug.

54. The oral solid dosage form of a drug according to any one of claims 50 to 53, wherein the container comprises about 15 cm 3 Approximately 45cm 3 The internal volume.

55. The oral solid dosage form of the drug according to claim 54, wherein about 10 to about 20 of the oral solid dosage forms of the drug are arranged in the container.

56. The oral solid dosage form of a drug according to any one of claims 50 to 53, wherein the container comprises about 60 cm³. 3 Approximately 90cm 3 The internal volume.

57. The oral solid dosage form of the drug according to claim 56, wherein about 90 to about 110 of the oral solid dosage forms of the drug are arranged in the container.

58. A packaged oral solid dosage form of medicine, comprising: Oral solid dosage forms of medicines, wherein the oral solid dosage forms of medicines comprise, by weight: Approximately 7.5 μg to approximately 300 μg of levothyroxine salt; Approximately 1.75 μg to approximately 75 μg of iodized thorium salt; Microcrystalline cellulose, by weight, comprises approximately 74% to approximately 96%, and At least one excipient selected from lubricants, gliding agents, diluents, disintegrants, and coatings; and A container closure system, comprising a container and a sealing closure; The container contains multiple oral solid dosage forms of the aforementioned drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber, and is sealed using the aforementioned sealing closure; and Wherein, after the oral solid dosage form of the drug has been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

59. The packaged oral solid dosage form of a drug according to claim 58, wherein the oral solid dosage form of the drug has the composition of any one of claims 2 to 31.

60. The packaged oral solid dosage form of a drug according to claim 58 or 59, wherein after the oral solid dosage form has been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form.

61. A packaged oral solid dosage form of medicine, comprising: Oral solid dosage forms of medicines, wherein the oral solid dosage forms of medicines comprise, by weight: Approximately 7.5 μg to approximately 300 μg of levothyroxine salt; Approximately 1.75 μg to approximately 75 μg of iodized thorium salt; Microcrystalline cellulose, by weight, comprises approximately 74% to approximately 96%, and At least one excipient selected from lubricants, gliding agents, diluents, disintegrants, and coatings; A container closure system, comprising a container and a sealing closure; The container contains multiple oral solid dosage forms of the aforementioned drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber, and is sealed using the aforementioned sealing closure; and Wherein, after the oral solid dosage form of the drug has been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of the drug.

62. The packaged oral solid dosage form of a drug according to claim 61, wherein the oral solid dosage form of the drug has the composition of any one of claims 2 to 31.

63. The packaged oral solid dosage form of a drug according to claim 61 or 62, wherein after the oral solid dosage form has been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

64. A treatment method for hypothyroidism, the method comprising administering an oral solid dosage form of a drug to a subject in need, wherein the oral solid dosage form of the drug comprises, by weight: Approximately 7.5 μg to approximately 300 μg of levothyroxine salt; Approximately 1.75 μg to approximately 75 μg of iodized thorium salt; Microcrystalline cellulose, by weight, comprises approximately 74% to approximately 95%; and At least one excipient selected from lubricants, gliding agents, diluents, disintegrants, and coatings.

65. A treatment method for hypothyroidism, the method comprising administering to a subject in need of the oral solid dosage form of any one of claims 1 to 57.

66. An oral solid dosage form of a drug, comprising: Approximately 7.5 μg to approximately 300 μg of levothyroxine salt; Approximately 1.75 μg to approximately 75 μg of iodized thorium salt; Microcrystalline cellulose, by weight, comprises approximately 66% to approximately 90%; and At least one excipient selected from lubricants, flow aids, diluents, antioxidants and colorants.

67. The oral solid dosage form of the drug according to claim 66, comprising about 7.5 µg to about 11.5 µg of levothyroxine salt and about 1.75 µg to about 2.75 µg of iodine salt.

68. The oral solid dosage form of the drug according to claim 66, comprising about 10 µg to about 15 µg of levothyroxine salt and about 2.45 µg to about 3.75 µg of iodine salt.

69. The oral solid dosage form of the drug according to claim 66, comprising about 15 µg to about 23 µg of levothyroxine salt and about 3.5 µg to about 5.5 µg of iodine salt.

70. The oral solid dosage form of the drug according to claim 66, comprising about 20 µg to about 30 µg of levothyroxine salt and about 5 µg to about 7.5 µg of iodine salt.

71. The oral solid dosage form of the drug according to claim 66, comprising about 30 µg to about 46 µg of levothyroxine salt and about 7 µg to about 11 µg of iodine salt.

72. The oral solid dosage form of the drug according to claim 66, comprising about 40 µg to about 60 µg of levothyroxine salt and about 10 µg to about 15 µg of iodine salt.

73. The oral solid dosage form of the drug according to claim 66, comprising about 45 µg to about 69 µg of levothyroxine salt and about 10 µg to about 16.5 µg of iodine salt.

74. The oral solid dosage form of the drug according to claim 66, comprising about 60 µg to about 92 µg of levothyroxine salt and about 14 µg to about 22 µg of iodine salt.

75. The oral solid dosage form of the drug according to claim 66, comprising about 80 µg to about 120 µg of levothyroxine salt and about 20 µg to about 30 µg of iodine salt.

76. The oral solid dosage form of the drug according to claim 66, comprising about 120 µg to about 180 µg of levothyroxine salt and about 30 µg to about 45 µg of iodine salt.

77. The oral solid dosage form of the drug according to claim 66, comprising about 150 µg to about 230 µg of levothyroxine salt and about 35 µg to about 55 µg of iodine salt.

78. The oral solid dosage form of the drug according to claim 66, comprising about 200 µg to about 300 µg of levothyroxine salt and about 50 µg to about 75 µg of iodine salt.

79. The oral solid dosage form of the drug according to any one of claims 66 to 78, wherein the weight ratio of levothyroxine salt to iodine salt is about 3.5:1 to about 4.5:

1.

80. The oral solid dosage form of the drug according to any one of claims 66 to 79, comprising about 70% to about 86% by weight of microcrystalline cellulose.

81. The oral solid dosage form of the drug according to any one of claims 66 to 79, comprising about 74% to about 82% by weight of microcrystalline cellulose.

82. The oral solid dosage form of the drug according to any one of claims 66 to 81 further comprises mannitol.

83. The oral solid dosage form of the drug according to any one of claims 66 to 81 further comprises about 16% to about 24% by weight of mannitol.

84. The oral solid dosage form of the drug according to any one of claims 66 to 81 further comprises about 18% to about 22% by weight of mannitol.

85. The oral solid dosage form of the drug according to any one of claims 66 to 84 further comprises butylated hydroxyanisole.

86. The oral solid dosage form of the drug according to any one of claims 66 to 85 further comprises at least one lubricant selected from calcium stearate and magnesium stearate.

87. The oral solid dosage form of the drug according to claim 66, comprising: Approximately 7.5 μg to approximately 300 μg of levothyroxine salt; Approximately 1.75 μg to approximately 75 μg of iodized thorium salt; Microcrystalline cellulose, by weight, comprises approximately 66% to approximately 90%; and Mannitol.

88. The oral solid dosage form of the drug according to claim 87 further comprises butylated hydroxyanisole.

89. The oral solid dosage form of the drug according to any one of claims 87 and 88 further comprises at least one lubricant selected from calcium stearate and magnesium stearate.

90. The oral solid dosage form of the drug according to claim 66, comprising: Approximately 80 μg to approximately 120 μg of levothyroxine salt; Approximately 20 μg to approximately 30 μg of iodized thionine salt; Microcrystalline cellulose, by weight, comprises approximately 66% to approximately 90%; and Mannitol.

91. The oral solid dosage form of the drug according to claim 90 further includes butylated hydroxyanisole.

92. The oral solid dosage form of the drug according to any one of claims 90 and 91 further comprises at least one lubricant selected from calcium stearate and magnesium stearate.

93. The oral solid dosage form of a drug according to any one of claims 66 to 92, wherein after the oral solid dosage form has been stored for 3 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

94. The oral solid dosage form of a drug according to any one of claims 66 to 92, wherein after the oral solid dosage form has been stored for 6 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

95. The oral solid dosage form of a drug according to any one of claims 66 to 92, wherein after the oral solid dosage form of the drug has been stored for one month at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the levothyroxine salt content in the oral solid dosage form of the drug is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

96. The oral solid dosage form of a drug according to any one of claims 66 to 92, wherein after the oral solid dosage form has been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the levothyroxine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

97. The oral solid dosage form of a drug according to any one of claims 66 to 92, wherein after the oral solid dosage form of the drug has been stored for 3 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the levothyroxine salt content in the oral solid dosage form of the drug is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

98. The oral solid dosage form of a drug according to any one of claims 66 to 92, wherein after the oral solid dosage form of the drug has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the levothyroxine salt content in the oral solid dosage form of the drug is at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

99. The oral solid dosage form of a drug according to any one of claims 66 to 98, wherein after the oral solid dosage form has been stored for 3 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, the iodine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form.

100. The oral solid dosage form of a drug according to any one of claims 66 to 98, wherein after the oral solid dosage form has been stored for 6 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, the iodine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form.

101. The oral solid dosage form of a drug according to any one of claims 66 to 98, wherein after the oral solid dosage form has been stored for one month at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the iodine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form.

102. The oral solid dosage form of a drug according to any one of claims 66 to 98, wherein after the oral solid dosage form has been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the iodine salt content in the oral solid dosage form is at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form.

103. The oral solid dosage form of a drug according to any one of claims 66 to 98, wherein after the oral solid dosage form of the drug has been stored for 3 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the iodine salt content in the oral solid dosage form of the drug is at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form of the drug.

104. The oral solid dosage form of a drug according to any one of claims 66 to 98, wherein after the oral solid dosage form of the drug has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, the iodine salt content in the oral solid dosage form of the drug is at least 90%, at least 92%, or at least 95% of the initial iodine salt content in the oral solid dosage form of the drug.

105. The oral solid dosage form of a drug according to any one of claims 66 to 92, wherein when a plurality of the oral solid dosage forms of the drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of the drug have been stored at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65% for 3 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

106. The oral solid dosage form of a drug according to any one of claims 66 to 92, wherein when a plurality of the oral solid dosage forms of the drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of the drug have been stored at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65% for 6 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

107. The oral solid dosage form of a drug according to any one of claims 66 to 92, wherein when a plurality of the oral solid dosage forms of the drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of the drug have been stored at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65% for 3 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of the drug.

108. The oral solid dosage form of a drug according to any one of claims 66 to 92, wherein when a plurality of the oral solid dosage forms of the drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of the drug have been stored at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65% for 6 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of the drug.

109. The oral solid dosage form of a drug according to any one of claims 66 to 92, wherein when a plurality of the oral solid dosage forms of the drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of the drug have been stored for one month at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

110. The oral solid dosage form of a drug according to any one of claims 66 to 92, wherein when a plurality of the oral solid dosage forms of the drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of the drug have been stored at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80% for 2 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

111. The oral solid dosage form of a drug according to any one of claims 66 to 92, wherein when a plurality of the oral solid dosage forms of the drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of the drug have been stored at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80% for 3 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

112. The oral solid dosage form of a drug according to any one of claims 66 to 92, wherein when a plurality of the oral solid dosage forms of the drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of the drug have been stored at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80% for 6 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

113. The oral solid dosage form of a drug according to any one of claims 66 to 92, wherein when a plurality of the oral solid dosage forms of the drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of the drug have been stored for one month at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of the drug.

114. The oral solid dosage form of a drug according to any one of claims 66 to 92, wherein when a plurality of the oral solid dosage forms of the drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of the drug have been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of the drug.

115. The oral solid dosage form of a drug according to any one of claims 66 to 92, wherein when a plurality of the oral solid dosage forms of the drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of the drug have been stored at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80% for 3 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of the drug.

116. The oral solid dosage form of a drug according to any one of claims 66 to 92, wherein when a plurality of the oral solid dosage forms of the drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber are placed in a container sealed with a closure, after the oral solid dosage forms of the drug have been stored at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80% for 6 months, each oral solid dosage form retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of the drug.

117. The oral solid dosage form of a drug according to any one of claims 105 to 116, wherein the container comprises about 15 cm 3 Approximately 45cm 3 The internal volume.

118. The oral solid dosage form of the drug according to claim 117, wherein about 10 to about 20 of the oral solid dosage forms of the drug are arranged in the container.

119. The oral solid dosage form of a drug according to any one of claims 105 to 116, wherein the container comprises about 60 cm³. 3 Approximately 90cm 3 The internal volume.

120. The oral solid dosage form of the drug according to claim 119, wherein about 90 to about 110 of the oral solid dosage forms of the drug are arranged in the container.

121. A packaged oral solid dosage form of medicine, comprising: Oral solid dosage forms of medicines, wherein the oral solid dosage forms of medicines comprise, by weight: Approximately 7.5 μg to approximately 300 μg of levothyroxine salt; Approximately 1.75 μg to approximately 75 μg of iodized thorium salt; Microcrystalline cellulose, by weight, comprises approximately 66% to approximately 90%, and At least one excipient selected from lubricants, flow aids, diluents, antioxidants, and colorants; and A container closure system, comprising a container and a sealing closure; The container contains multiple oral solid dosage forms of the aforementioned drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber, and is sealed using the aforementioned sealing closure; and Wherein, after the oral solid dosage form of the drug has been stored for 6 months at a temperature of about 25°C to about 27°C and a relative humidity of about 55% to about 65%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

122. The packaged oral solid dosage form of a drug according to claim 56, wherein the oral solid dosage form of the drug has the composition of any one of claims 67 to 92.

123. The packaged oral solid dosage form of a drug according to claim 121 or 122, wherein after the oral solid dosage form has been stored for 6 months at a temperature of about 25°C to about 27°C and a relative humidity of about 55% to about 65%, each oral solid dosage form encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form.

124. A packaged oral solid dosage form of medicine, comprising: Oral solid dosage forms of medicines, wherein the oral solid dosage forms of medicines comprise, by weight: Approximately 7.5 μg to approximately 300 μg of levothyroxine salt; Approximately 1.75 μg to approximately 75 μg of iodized thorium salt; Microcrystalline cellulose, by weight, comprises approximately 66% to approximately 90%, and At least one excipient selected from lubricants, gliding agents, diluents, disintegrants, and coatings; A container closure system, comprising a container and a sealing closure; The container contains multiple oral solid dosage forms of the aforementioned drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber, and is sealed using the aforementioned sealing closure; and Wherein, after the oral solid dosage form of the drug has been stored for 6 months at a temperature of about 25°C to about 27°C and a relative humidity of about 55% to about 65%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of the drug.

125. The packaged oral solid dosage form of a drug according to claim 59, wherein the oral solid dosage form of the drug has the composition of any one of claims 67 to 92.

126. The packaged oral solid dosage form of claim 124 or 125, wherein after the oral solid dosage form has been stored for 6 months at a temperature of about 25°C to about 27°C and a relative humidity of about 55% to about 65%, each oral solid dosage form encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

127. A packaged oral solid dosage form of medicine, comprising: Oral solid dosage forms of medicines, wherein the oral solid dosage forms of medicines comprise, by weight: Approximately 7.5 μg to approximately 300 μg of levothyroxine salt; Approximately 1.75 μg to approximately 75 μg of iodized thorium salt; Microcrystalline cellulose, by weight, comprises approximately 66% to approximately 90%, and At least one excipient selected from lubricants, flow aids, diluents, antioxidants, and colorants; and A container closure system, comprising a container and a sealing closure; The container contains multiple oral solid dosage forms of the aforementioned drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber, and is sealed using the aforementioned sealing closure; and Wherein, after the oral solid dosage form of the drug has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form of the drug.

128. The packaged oral solid dosage form of a pharmaceutical product according to claim 127, wherein the oral solid dosage form of the pharmaceutical product has the composition of any one of claims 67 to 92.

129. The packaged oral solid dosage form of a drug according to claim 127 or 128, wherein after the oral solid dosage form has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form.

130. A packaged oral solid dosage form of medicine, comprising: Oral solid dosage forms of medicines, wherein the oral solid dosage forms of medicines comprise, by weight: Approximately 7.5 μg to approximately 300 μg of levothyroxine salt; Approximately 1.75 μg to approximately 75 μg of iodized thorium salt; Microcrystalline cellulose, by weight, comprises approximately 66% to approximately 90%, and At least one excipient selected from lubricants, gliding agents, diluents, disintegrants, and coatings; A container closure system, comprising a container and a sealing closure; The container contains multiple oral solid dosage forms of the aforementioned drug and at least about 2 grams of desiccant and / or at least 2 grams of oxygen absorber, and is sealed using the aforementioned sealing closure; and Wherein, after the oral solid dosage form of the drug has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial iodoxyronine salt content in the oral solid dosage form of the drug.

131. The packaged oral solid dosage form of a pharmaceutical product according to claim 65, wherein the oral solid dosage form of the pharmaceutical product has the composition of any one of claims 67 to 92.

132. The packaged oral solid dosage form of a drug according to claim 130 or 131, wherein after the oral solid dosage form has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, each oral solid dosage form encapsulated in the container retains at least 90%, at least 92%, or at least 95% of the initial levothyroxine salt content in the oral solid dosage form.

133. A treatment method for hypothyroidism, the method comprising administering an oral solid dosage form of a drug to a subject in need, wherein the oral solid dosage form of the drug comprises, by weight: Approximately 7.5 μg to approximately 300 μg of levothyroxine salt; Approximately 1.75 μg to approximately 75 μg of iodized thorium salt; Microcrystalline cellulose, by weight, comprises approximately 66% to approximately 90%; and At least one excipient selected from lubricants, flow aids, diluents, antioxidants and colorants.

134. A treatment for hypothyroidism, the method comprising administering to a subject in need of the oral solid dosage form of any one of claims 66 to 120.

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