JP2005517720A - Levothyroxine composition and method - Google Patents

Abstract

The present invention relates generally to stable pharmaceutical compositions and methods for making and administering such compositions. In one aspect, the invention provides a stabilized pharmaceutical composition comprising pharmaceutically active ingredients, such as levothyroxine (T4) sodium and liothyronine (T3) sodium (thyroid hormone drug), preferably in a fast acting solid dosage form. Features. Also provided are methods for making and using such fast-acting and stabilized compositions.

Description

(US patent application)
This application for US patents is filed as an application under 35 USC 111 (a).

(Related US patent application)
This application for a US patent was filed on February 15, 2001 and assigned US Provisional Application No. 60 / 269,009, “Stabilized Pharmaceutical and Tyroid Hormone Composition and -Relates to a US provisional application entitled "Stabilized Pharmaceutical and Thyroid Hormone Compositions and Method of Preparation". This application for US patents was also filed on Feb. 15, 2001 and assigned US provisional application 60 / 268,998, “Manufacturer of Tyroid Hormone Tablets Hubbing Consistent. Related to a US provisional application entitled “Manufacture of Thyroid Hormone Tablets Having Consistent Active Moiety Amounts”.

  The present invention relates to generally stable pharmaceutical compositions and methods for making and administering such compositions. In one aspect, the present invention comprises a stabilized pharmaceutical composition comprising pharmaceutically active ingredients, such as levothyroxine (T4) sodium and liothyronine (T3) sodium (thyroid hormone drug), preferably in a fast acting solid dosage form. Features. Also provided are methods for making and using such fast acting and stabilized compositions.

  Levothyroxine sodium and liothyronine sodium thyroid hormone preparations are useful pharmaceutical preparations for the treatment of hypothyroidism and thyroid hormone replacement therapy in mammals such as humans and dogs.

  Thyroid hormone preparations are used to treat reduced or absent thyroid function due to any cause, including human or animal diseases such as myxedema, cretinism and obesity.

  Hypothyroidism is a common symptom. The US Gazette reports that the prevalence of hypothyroidism is between 0.5 percent and 1.3 percent in adults. In people over the age of 60, the prevalence of primary hypothyroidism increases to 2.7 percent for men and 7.1 percent for women. Congenital hypothyroidism can result in irreversible mental retardation, which can be avoided with early diagnosis and treatment, so in North America, Europe and Japan, neonatal screening for this disease is mandatory. It has become.

  Thyroid hormone replacement therapy can be a chronic lifetime effort. The dose is determined individually for each patient. Generally, the initial amount is a small amount. The amount is increased in stages until clinical evaluation and laboratory tests indicate that an optimal response has been achieved. The dosage required to maintain this response is then continued. The patient's age and systemic symptoms, as well as the severity and duration of the hypothyroidism, will determine the rate of change that can increase the dose to the initial dose and the final maintenance level. It has been reported that dose escalation should be very gradual to prevent angina, myocardial infarction, or stroke promotion in patients with myxedema or cardiovascular disease.

  It is important that thyroid hormone treatment is at a reasonable dose. Both undertreatment and overtreatment can have detrimental effects on health. Insufficient treatment results in suboptimal responses and hypothyroidism. Undertreatment has also been reported to be a possible factor in reduced cardiac contractility and increased risk of coronary artery disease. On the other hand, overtreatment can lead to toxic symptoms of hyperthyroidism such as heart pain, palpitations, or cardiac arrhythmias. In particular, in patients suffering from coronary heart disease, even small dose increases of levothyroxine sodium can be dangerous.

  Hyperthyroidism is a well-known risk factor for osteoporosis. Several studies suggest that asymptomatic hyperthyroidism is associated with bone loss in premenopausal women taking thyroid hormone drugs for replacement or suppression therapy. In order to minimize the risk of osteoporosis, it is preferable to maintain the dosage at the lowest effective dosage.

  Because of the risks associated with over- or under-treatment with levothyroxine sodium, thyroid hormone formulations with consistent potency and bioavailability are needed. Such consistency is best achieved by manufacturing techniques that maintain a consistent amount of active moiety during tablet manufacture.

Thyroid hormone drugs are natural or synthetic containing tetraiodothyronine (T ₄ , levothyroxine) or triiodothyronine (T ₃ , liothyronine) or both, usually as their pharmaceutically acceptable salts (eg, sodium salts). It is a formulation. T ₄ and T ₃ are produced in the human thyroid by the iodination and coupling of the amino acid tyrosine. T ₄ contains four iodine atoms and is formed by the coupling of two molecules of diiodotyrosine (DIT). T ₃ contains three iodine atoms and is formed by the coupling of one molecule of DIT and one molecule of monoiodotyrosine (MIT). Both hormones are stored in thyroid colloids as thyroglobulin. Thyroid hormone preparations belong to two categories: (1) natural hormone preparations derived from animal thyroid gland, and (2) synthetic preparations. Natural preparations include dry thyroid and thyroglobulin.

  Dry thyroid is derived from livestock (either bovine or boar) used for food by humans, and thyroglobulin is derived from bovine thyroid. The United States Pharmacopeia (USP) has standardized the total iodine content of natural formulations. Thyroid USP contains more than 0.17 percent and contains no more than 0.23 percent iodine, and thyroglobulin contains more than 0.7 percent organically bound iodine. The iodine content is only an indirect indicator of the biological activity of true hormones.

T ₄ and T ₃ thyroid hormone both synthetic are available from several manufacturers. For example, liothyronine sodium (T ₃ ) tablets are available from King Pharmaceuticals, Inc. (St. Louis, MO) under the trade name Cytomel®. Levothyroxine sodium (T ₄ ) is available from King Pharmaceuticals, Inc. under the trade name Levoxil (registered trademark), and Knor Pharmaceutical (Knoll Pharmaceutical) under the trade name Scintiloid (registered trademark). (Mount Olive, New Jersey) and under the trade name Unithroid® from Jerome Stevens Pharmaceuticals (Bohemia, New York). Furthermore, a veterinary pharmaceutical formulation of levothyroxine sodium is available from King Pharmaceuticals, Inc. under the trade name Soroxin®.

Levoxil® (levothyroxine sodium tablet, USP) contains synthetic crystals L-3,3 ′, 5,5′-tetraiodothyronine sodium salt [levothyroxine (T ₄ ) sodium]. As described above, the synthetic T ₄ in Rebokishiru (TM) is the same as that produced in human thyroid. Levothyroxine (T ₄ ) sodium in Levoxil® has an empirical formula C ₁₅ H ₁₀ I ₄ NNaO ₄ .H ₂ O, a molecular weight of 798.86 g / mol (anhydrous), and a structural formula as shown below: Have:

  It is well known that thyroid hormone drugs are extremely unstable. They are hygroscopic and decompose in the presence of moisture or light and under high temperature conditions. This instability is particularly pronounced in the presence of pharmaceutical excipients such as carbohydrates including lactose, sucrose, dextrose and starch, and certain pigments. The critical nature of the required dosage in common pharmaceutical formulations, and the lack of stability of the active ingredient, poses a crisis that adversely affects most formulated thyroid pharmaceutical formulations. See, for example, 62 Gazette 43535 (August 14, 1997).

  Accordingly, it is desirable to produce a stabilized dosage of levothyroxine and liothyronine that has a longer shelf life that can be used to treat human or animal thyroid hormone deficiency. Patent Document 1 is directed to improving the stability of levothyroxine sodium. In one embodiment disclosed by US Pat. No. 6,057,049, stabilized levothyroxine sodium is mixed with levothyroxine sodium in a dry state using geometrical dilution with a cellulose tableting agent, and then the mixture is microcrystalline cellulose. By mixing with the same or a second cellulose tableting agent. Other tableting aids or excipients may be used in this formulation. The entire '204 patent is incorporated herein by reference.

  The microcrystalline cellulose disclosed in Patent Document 1 includes AVICEL101, AVICEL102, AVICEL103, and AVICEL105 which are registered trademarks of FMC (New Work, DE), and microcrystalline cellulose NF or Penwest Pharmaceuticals (Patterson). , NY) is a registered trademark of EMCOCEL. These microcrystalline cellulose products are made by resuspending cellulose and spray drying the product. This gives an α helix spherical microcrystalline cellulose product.

  Patent Documents 2 and 3 disclose pharmaceutical preparations comprising levothyroxine and microcrystalline cellulose, and other excipients. The microcrystalline cellulose products used in Patent Document 2 and Patent Document 3 were also α-type AVICEL microcrystalline cellulose products. The entirety of Patent Document 2 and Patent Document 3 is incorporated herein by reference.

  Another microcrystalline cellulose product is a flat needle-shaped β-sheet type microcrystalline cellulose, which is marketed by FMC (Newwork, Delaware) under the registered trademark CEOLUS KG801. The CEOLUS® product has a different form and different performance characteristics than that of the AVICEL product. The β-sheet microcrystalline cellulose of the present invention is disclosed in Patent Document 4, which is incorporated herein by reference. Further disclosure regarding β-sheet microcrystalline cellulose is found in Non-Patent Document 1. This is incorporated herein by reference.

  CEOLUS® product (beta sheet microcrystalline cellulose) is disclosed by FMC in a product bulletin dated October 1997 as being suitable for “smaller size tablets” and “excellent drug delivery performance” . CEOLUS (R) products were said to provide excellent compressibility and drug compounding performance and showed more effective flowability. The example shown in the CEOLUS (R) bulletin was of vitamin C mixed with CEOLUS (R) microcrystalline cellulose at a CEOLUS (R) product level of 30-45% by weight in tablet form.

  However, there was a problem in using CEOLUS (registered trademark) products. For example, higher levels of CEOLUS® product concentrations cause flow problems in the tableting process, and CEOLUS® products are not suitable for tableting at concentrations greater than about 45% by weight. It was thought.

  There is definitely a need for a solid levothyroxine (T4) and / or liothyronine (T3) (thyroid hormone drug) pharmaceutical composition comprising T4 and T3 in the form of a relatively stable sodium salt, preferably in a fast acting solid dosage form. is there. There is also a need for a process for the preparation of such a fast acting and stabilized solid levothyroxine (T4) and / or liothyronine (T3) (thyroid hormone drug) pharmaceutical composition.

US Pat. No. 5,225,204 US Pat. No. 5,955,105 ('105) US Pat. No. 6,056,975 (continuation of '105) US Pat. No. 5,574,150 International Journal of Pharmaceutics, 182 (199) 155

  The present invention overcomes and alleviates the aforementioned shortcomings and disadvantages in thyroid drug technology through the discovery of novel oral levothyroxine (T4) and / or liothyronine (T3) (thyroid hormone drugs) pharmaceutical compositions and methods.

  In general, the present invention relates to solids stabilized as levothyroxine (T4) sodium and / or liothyronine (T3) sodium (thyroid hormone drug) pharmaceutical composition, especially levothyroxine (T4) sodium and / or liothyronine. (T3) It relates to a fast-acting stabilized pharmaceutical composition comprising a pharmaceutically active ingredient such as sodium (thyroid hormone drug). Although not necessarily so, the novel pharmaceutical composition is preferably provided in a solid dosage form such as a tablet.

  The pharmaceutical compositions of the present invention are particularly hypothyroid due to some other cause, except transient hypothyroidism during the recovery phase of subacute thyroiditis in warm-blooded animals, particularly humans including children. To suppress pituitary TSH secretion in the treatment or prevention of various types of normal thyroid goiter, including replacement or replacement therapy, thyroid nodules, Hashimoto thyroiditis, multinodular goiter, and It is useful as an adjunct therapy in the management of thyrotropin-dependent differentiated thyroid cancer.

  The present invention also provides a method for producing such a fast-acting and stabilized levothyroxine (T4) sodium and / or liothyronine (T3) sodium (thyroid hormone drug) pharmaceutical composition.

  Also, according to the present invention, because of the surprising release characteristics of the preferred composition, a solid composition containing an appropriate dosage for children and infants who are difficult to take tablets is simply a liquid, for example An administration method has also become practical here in which the juice dissolves in approximately 1 to 3 minutes and then the patient can ingest the liquid to obtain an appropriate dosage.

  The present invention has a wide range of important applications, including providing pharmaceutically active levothyroxine compositions with enhanced bioavailability, improved expiration dates, and more reliable potency.

  The inventors have found an immediate-acting pharmaceutical composition comprising at least one levothyroxine and liothyronine as pharmaceutically active ingredients, preferably at least one levothyroxine salt as the main active ingredient. Such preferred immediate release compositions desirably exhibit at least about 85% (w / v) dissolution of the levothyroxine salt in less than about 20 minutes as required by the standard assays disclosed herein. Surprisingly, by mixing the pharmaceutically active ingredient with the specific additive of the present invention, the composition is formulated almost immediately after ingestion or contact with an aqueous solution, eg, released in a few minutes. I found out that it is possible. Preferred compositions of the present invention are stable and provide better shelf life and potency characteristics than conventional pharmaceutical compositions.

  The immediate-acting pharmaceutical composition of the present invention provides important uses and advantages. The main advantage is the stability of the active ingredient in the composition. For example, as noted above, conventional formulations containing various types of cellulose, including microporous cellulose, such as sugar, starch, and AVICEL products, have undergone substantial degradation of the active ingredient, such as T4 sodium. It was. To address this problem, pharmaceutical manufacturers have over-prescribed T4-containing pharmaceutical compositions containing such active ingredients, so patients obtain at least the prescribed dose regardless of carbohydrate-induced active ingredient instability be able to. However, patients who receive a medicinal product immediately after manufacture will receive an overdose of the active compound, while those who receive a drug that has been on the pharmacy shelf for a long time will receive an underdose active ingredient. become. In either case, the patient may receive the wrong dose and have serious consequences.

  In striking contrast, surprisingly, the use of β-sheet microcrystalline cellulose in the compositions of the present invention substantially increases the stability of thyroid hormone drugs, resulting in patients being more than conventional thyroid hormone drug products. We have found that consistent titers can be obtained over a long shelf life. In this application, “stabilized” as applied to levothyroxine and / or liothyronine means a titer loss of about 0.7% per month for a period of at least about 18 months over the lifetime of the product. Means less than. Preferred composition titer loss is less than about 0.5% per month during such period, and more preferred composition titer loss is less than about 0.3% per month during such period. .

  Furthermore, the compositions of the present invention provide advantageous pharmacokinetic properties when compared to conventional formulations. In particular, fast-acting pharmaceutical compositions comprising levothyroxine salts are more rapidly available and more fully absorbed due to faster digestion (GI) tract absorption than was previously possible. The present invention is characterized by substantially increasing levothyroxine bioavailability, thereby improving the effectiveness and reliability of a number of standard thyroid hormone replacement methods.

  Furthermore, the desired immediate effect of the present invention facilitates patient dosing that can be disadvantageous for thyroid hormone replacement methods, which generally include solid dosing. More particularly, the immediate release pharmaceutical compositions disclosed herein are suitable aqueous solutions (eg, water, saline, juice) or colloidal suspensions (eg, water) for convenient administration to such patients. Powdered milk or milk) may be rapidly dissolved. Examples of such patients include infants, children, and adults who can cause dysphagia. Thus, the present invention makes standard thyroid hormone replacement methods more adaptive and reliable for such patients.

  Thus, in one embodiment, the invention features a fast acting pharmaceutical composition comprising at least one levothyroxine salt, preferably one of such salts. At least about 80% of levothyroxine dissolves in the aqueous solution in less than about 20 minutes as required by the standard assay disclosed herein. Preferably, at least about 80% of levothyroxine dissolves in the aqueous solution from the time the tableted composition is placed in the aqueous solution up to about 15 minutes. More preferably, after exposure of the composition to an aqueous solution, at least about 85% levothyroxine is released into the aqueous solution by about 10 minutes, most preferably up to about 5 minutes. As shown below, the compositions of the present invention may be formulated to release 85% levothyroxine within 2-3 minutes after exposure to an aqueous solution.

  It has been found that a composition having a preferred immediate effect can be produced by combining one or more pharmaceutically effective drugs with β-type microcrystalline cellulose. Without wishing to be bound by theory, it is believed that this drug does not bind well to certain grades of beta sheet microcrystalline cellulose. Thus, more of the drug is available for immediate effect. In contrast, many conventional formulations contain an effective agent that binds to the cellulose additive, which is believed to be less available. The release characteristics of the compositions of the present invention are also improved by the use of other drugs, as discussed further below.

  Accordingly, in certain embodiments, the present invention relates to a stabilized pharmaceutical composition comprising a pharmaceutically active ingredient, such as levothyroxine, and beta sheet microcrystalline cellulose in solid dosage form. More particularly, the present invention relates to solid dosage forms of pharmaceutically active ingredients such as levothyroxine sodium and / or liothyronine sodium into beta sheet type microcrystalline cellulose and optionally further excipients. In contrast, it relates to a stabilized pharmaceutical composition comprising a dosage weight of at least about 50% by weight.

  In another aspect, the invention provides an aqueous solution or colloid comprising at least one composition of the invention, preferably between about 1 and about 5 of the same composition, more preferably about 1 such composition. Provide a suspension.

  It has also been found that β-sheet microcrystalline cellulose grades with a preferred volume density provide a denser process than using other celluloses. That is, the use of β-sheet microcrystalline cellulose having the volume density of the present invention helps to provide a higher compressibility (initial volume / final volume). As discussed below, other inventive aspects help to reduce or avoid the generation of deleterious heat of compression that has been damaging to conventional formulations made at high compressibility. Also, the compositions of the present invention generally require less compression to form tablets.

Accordingly, the present invention also provides a process for the preparation of a fast acting pharmaceutical composition comprising at least one levothyroxine salt, preferably one such salt. In certain embodiments, the method comprises at least one and preferably all of the following steps:
a) A levothyroxine salt is mixed with microcrystalline β cellulose and preferably croscarmellose salt to make a blend; and b) the blend has an initial volume to final volume ratio of about 2: 1 to about 5: 1. Compression, preferably about 4: 1.

  In certain embodiments, the method comprises producing an oral dosage form of the pharmaceutically active ingredient, which is a dry blend of the pharmaceutically active ingredient and at least about 50 wt% beta sheet type microcrystalline cellulose; The method further comprises compressing the blend to form a solid dosage.

  These and other objects, features and advantages of the present invention will be better understood and appreciated from the following detailed description of embodiments thereof, which is selected for purposes of illustration and shown in conjunction with the figures and examples. Accordingly, it is to be understood that the specific embodiments that illustrate the invention are exemplary only and should not be considered limiting of the invention.

  To illustrate and provide a more complete application of the invention and a number of attendant advantages, novel oral levothyroxine (T4) and / or liothyronine (T3) (thyroid hormone drug) pharmaceutical compositions and warm-blooded animals, particularly The following detailed description is given regarding usage in humans and children.

  As described above, the present invention provides a stabilized pharmaceutical composition comprising pharmaceutically active ingredients, such as levothyroxine (T4) sodium and liothyronine (T3) sodium (thyroid hormone drug), preferably in solid dosage forms, etc. The present invention relates to a rapid-acting solid pharmaceutical composition. Also provided is a method for producing such an immediate and stabilized composition.

  An embodiment of the present invention, entitled Stabilized Pharmaceutical and Thyroid Hormone Compositions and Method of Preparation, is described in Flanz, G.A. (Franz, GA) et al., U.S. Provisional Application No. 60 / 269,089, filed Feb. 15, 2001. The disclosure of the provisional application is incorporated herein by reference.

“Immediate effect” refers to at least about 80% (w / v) dissolution, preferably about 90% (w / v) of one or more active agents in 15-20 minutes as determined by standard dissolution testing. / V) to about 95% (w / v), more preferably about 95% (w / v) to about 99% (w / v) or more. Suitable standard dissolution tests are well known in the art [www. fda. gov / cder / guidance / index. FDA, Drug Research Center, Guidance for Industry , In Vivo Pharmacokinetics and Bioavailability Studies and In Vitro Dissolution Testing for Levothyroxine・ Sodium Tablets (see Guidance for Industry , In Vivo Pharmacokinetics and Bioavailability Studies and In Vitro Dissolution Testing for Levothyroxine Sodium Tablets)]. A particularly preferred dissolution test is provided in Example 2 below.

  A pharmaceutical composition of the invention is “stable” or “stabilized” if one or more of the active agents therein shows good stability when the results obtained by standard titer tests show good stability. It is said. More particularly, such compositions exhibit a potency loss of less than about 15%, preferably less than about 10%, more preferably less than about 1% to less than about 5% as determined by testing. The titer may be assessed by one method or combination of methods well known in the art (see USP). A preferred titer test compares the loss or conversion of the active agent in the presence (test sample) or absence (control) of a carrier or excipient. Particularly preferred titer tests are provided in Examples 1 and 3 below.

  In a preferred embodiment, the pharmaceutical composition of the invention comprises levothyroxine (T4) as an active agent, preferably a salt thereof such as levothyroxine sodium USP. Such compositions typically exhibit levothyroxine (T4) plasma Cmax, preferably between about 12 μg / dl and about 16 μg / dl as determined by a standard Cmax test. Preferably, the levothyroxine (T4) plasma level ln (Cmax) is in the range of about 1 to about 3.

  The standard Cmax test may be performed by one method or combination of methods well known in the art (see USP). Preferred Cmax tests are disclosed in Examples 8 and 9 below.

  More preferred compositions of the present invention have a triiodothyronine (T3) plasma Cmax of between about 0.1 ng / ml and about 10 ng / ml, preferably between 0.5 ng / ml and about 2 ng / ml as determined by a standard Cmax test. I will provide a. Typically, ln (Cmax) is in the range of about 0.01 to about 5. See Examples 8 and 9 for more information.

  More preferred compositions preferably exhibit a levothyroxine (T4) plasma Tmax of between about 0.5 hours and about 5 hours as determined by a standard Tmax test. Standard Tmax testing may be performed by procedures well known in the art (see, eg, USP). Preferred Tmax tests are disclosed in Examples 8 and 9 below.

  Even more preferred compositions of the invention exhibit a triiodothyronine (T3) plasma Tmax of between about 10 hours to about 20 hours, preferably about 12 to about 16 hours, as determined by a standard Tmax test.

  Further preferred compositions of the invention are between about 450 μg-hr / dl to about 600 μg-hr / dl, preferably between 500 μg-hr / dl to about 550 μg-hr / dl as determined by standard AUC (0-t) tests. Characterized by levothyroxine (T4) plasma AUC (0-t). Preferably, ln [AUC (0-t)] is in the range of about 1 to about 10.

  Standard methods for performing AUC (0-t) test measurements are widely known in the art (see, eg, USP). Examples 8 and 9 below provide a method for measuring particularly preferred AUC (0-t).

  Further preferred compositions of the invention are between about 10 ng-hr / ml to about 100 ng-hr / ml, preferably between 20 ng-hr / ml to about 60 ng-hr / ml as determined by standard AUC (0-t) tests. It is characterized by triiodothyronine (T3) AUC (0-t). Preferably, ln [AUC (0-t)] is in the range of about 1 to about 5.

  As will be appreciated, many conventional pharmaceutical formulations contain lactose or other sugars as pharmaceutically acceptable carriers. However, it has been found that sugars such as lactose can react with active agents including the levothyroxine (T4) composition of the present invention. For example, without wishing to be theorized, it is believed that lactose specifically damages T4 and T3 molecules via a Schiff reaction. The present invention addresses this problem by providing a composition that is substantially sugar free. Certain inventive compositions are substantially free of lactose.

  Further provided are preferred pharmaceutical compositions of the invention wherein the active substance is a non-granular substance. Conventional levothyroxine compositions have been granulated, for example, into granules having an average particle size of less than 5-20 microns with various grinders so that they can be efficiently incorporated into an administrable pharmaceutical composition. This granulation process exposes the active substance to heat of decomposition, which can adversely affect the active substance and reduce the activity level. Conventional manufacturers are DMF No. Micronized levothyroxine manufactured at 4789 is purchased and then granulated and then incorporated into the levothyroxine drug product.

  In a preferred method of the invention, the raw material is not granulated prior to incorporation into the pharmaceutical composition. Rather, the preferred pharmaceutical ingredients are mixed and the mixture is directly compressed to form the appropriate dosage pharmaceutical tablet. As a result, the activity of the active ingredient is not degraded prior to the direct tableting process. The native levothyroxine is preferably obtained in fine powder form from Biochemie GmbH (A-6250 Kundle, Austria). More importantly, by using a preferred process, a product can be obtained that can be readily dispersed in an aqueous solution, yielding an active ingredient that can be absorbed in the body. In the present application, “non-granular” means that the active USP compound is used without mixing with other pharmaceutical ingredients to form a suitable tablet without subjecting to a crusher or similar high energy mill. Preferably, the active ingredient is mixed with an appropriate amount of other ingredients and compressed directly into a tablet form. Since it is not necessary to granulate the substance, it is not necessary to be exposed to the decomposition temperature in the process of forming a pharmaceutical composition comprising the active substance. In this process, we only need to start with the finely divided active material, blend it with B and other materials, and then tablet. Others must be granulated and then dried, this process hindering the elution of the active substance. The drying temperature used in preparing other active ingredients can cause degradation of levothyroxine, just as it is with other available thyroxines. Providing a non-granular composition of the present invention reduces or eliminates the degradation of the active drug, possibly by facilitating the reduction of friction and thus the heat of degradation when the composition is compressed into tablets. I found it useful.

The practice of the present invention is compatible with several β-type microcrystalline cellulose grades. Preferably, the volume density of the β-type microcrystalline cellulose is between about 0.10 g / cm ³ to about 0.35 g / cm ³ , more preferably between about 0.15 g / cm ³ to about 0.25 g / cm ³ . , even more preferably between about 0.17 g / cm ³ ~ about 0.23 g / cm ^3, and most preferably from about 0.19 g / cm ³ ~ about 0.21 g / cm ^3.

  A further preferred grade of β-type microcrystalline cellulose is substantially non-conductive. Preferably, the conductivity of the β-type microcrystalline cellulose is less than about 200 μS / cm, more preferably less than about 75 μS / cm, even more preferably between about 0.5 μS / cm and 50 μS / cm, most preferably about 15 μS / cm. It is in the range of cm to 30 μS / cm.

  Particularly preferred β-type microcrystalline cellulose is sold as Asola (KG-801 and / or KG-802 type) by Asahi Kasei Kogyo Co., Ltd. (Tokyo, Japan).

  More preferred compositions of the present invention have post-packaging titer values determined by standard titer tests in the range of about 95% to about 120%, preferably 98% to about 110%.

  The present invention is a pharmaceutical in the form of a solid dosage such as a sublingual lozenge, buccal tablet, oral troche, suppository or compressed tablet. The pharmaceutically active ingredient is β-type microcrystalline cellulose, optionally dry mixed with further excipients to form a suitable solid dosage.

  The total hardness value determined by the standard hardness test of the preferred tablets of the present invention is between about 1 and about 30 KP, preferably about 6 to about 14 KP. Methods for measuring tablet hardness are generally known in the art (see, eg, USP). A preferred standard hardness test is disclosed in Example 4 below.

  More preferred pharmaceutical compositions, including those in tablet form, preferably contain less than about 10% total impurities, more preferably less than about 5%, as determined by standard impurity testing.

  As used herein, “standard impurity test” means a USP-approved analytical method for detecting and preferably quantifying active drug degradation products. In embodiments where destruction of levothyroxine or liothyronine is observed, such products include, but are not limited to, diiodothyronine (T2), triiodothyronine (T3), levothyroxine, triiodothyroacetamide, triiodo It includes at least one of tyroethylamine, triiodothyroacetic acid, triiodotyroethyl alcohol, tetraiodothyroacetamide, tetraiodotyroacetic acid, triiodothyroethane, and tetraiodothyroethane. Of particular interest are diiodothyronine (T2), triiodothyronine (T3), triiodothyroacetic acid, and tetraiodothyroacetic acid impurities.

  Preferred impurity tests for testing levothyroxine and liothyronine disruption products include liquid chromatography (LC) separation and detection, more preferably HPLC. Particularly preferred impurity tests are provided in Examples 5 and 6 below.

  Further preferred compositions of the present invention comprise one or more standard disintegrants, preferably croscarmellose, more preferably a salt thereof. Even more preferred compositions include pharmaceutically acceptable additives or excipients such as magnesium salts.

  The present invention may or may not be accompanied by pre-blending of the drug, but is preferably produced by a direct tableting format, pre-blending format, dry granulation format, or wet granulation format.

  The pharmaceutically active ingredient may be any type of drug that acts locally or systemically in the mouth, in which case the active drug is placed in the gastrointestinal tract and the human blood, body fluids and It can be given orally for delivery to the tissue. Apart from this, the drug acts through the oral tissues in the mouth to carry the active ingredient directly into the bloodstream, resulting in ineffective or destructive effects on the initial liver metabolism and many active ingredients. It may be a type of drug that can avoid metabolism by gastric juice or intestinal fluid (except where it is particularly protected against such bodily fluid by enteric coating). The active ingredient may also be a type of drug that can be carried into the blood circulation through rectal tissue.

  Examples of typical active drugs include antacids, antibacterial agents, coronary vasodilators, peripheral vasodilators, antipsychotics, antiepileptics, stimulants, antihistamines, laxatives, decongestants Drugs, vitamins, gastrointestinal sedatives, antidiarrheal drugs, vasodilators, antiarrhythmic drugs, vasoconstrictors and migraine drugs, anticoagulants and antithrombotics, analgesics, stimulants, sedatives, anticonvulsants , Neuromuscular drugs, hyperglycemic and hypoglycemic drugs, thyroid and antithyroid preparations, diuretics, antispasmodic drugs, uterine relaxants, minerals and nutrient additives, anti-obesity drugs, anabolic agents, erythropoiesis drugs, bronchial asthma treatment Drugs, expectorants, cough suppressants, mucolytics, antiuricemias, and drugs or substances that act locally in the mouth.

Typical active drugs include gastrointestinal sedatives such as metoclopramide and propanthel bromide, antacids such as aluminum trisilicate, aluminum hydroxide and cimetidine, phenylbutazone, indomethacin, and naproxen, ibuprofen, flubiprofen , Aspirin-like drugs such as diclofenac, dexamethasone, prednisone and prednisolone, coronary vasodilators such as nitroglycerin, isosorbide nitrate and pentaerythritol tetranitrate, soloctidilum, vincamamine, naftidrofuryl oxalate, comesylate, Peripheral and cerebral vasodilators such as cyclandrate, papaverine and nicotinic acid, erythromycin stearate, cephalexin, nalidixic acid, tetracycline hydrochloride, ampicill Antibacterial agents such as phosphorus, flucolaxacillin sodium, hexamine mandelate and hippurate hexamine, fluazepam, diazepam, temazepam, amitriptyline, doxepin, lithium carbonate, lithium sulfate, chlorpromazine, thioridazine, trifluperazine (trifluperazine), neuroblockers such as fluphenazine, piperothiazine, haloperidol, maprotiline hydrochloride, imipramine, desmethylimipramine, central nervous system stimulants such as methylphenidate, ephedrine, epinephrine, isoproterenol, amphetamine sulfate and amphetamine hydrochloride, diphenyl Anitidrugs such as hydramine (diphenilhydramine), diphenylpyramine, chlorpheniramine and brompheniramine, bisacodyl and hydroxylated Antidiarrheal drugs such as nesium, laxatives, dioctyl sodium sulfosuccinate, ascorbic acid, alpha tocopherol, thiamine and pyridoxine, antispasmodic drugs such as dicyclomine and diphenoxylate, verapamil, nifedepine, diltiazem, procainamide, disopyramide, tosyl For the treatment of hypertension such as bretylate, quinidine sulfate and quinidine gluconate, which affect the heart rhythm, propranolol hydrochloride, guanethidine monosulfate, methyldopa, oxprenolol hydrochloride, captopril, Actace and hydralazine Drugs used, drugs used for the treatment of migraine such as ergotamine, drugs that affect blood coagulation properties such as epsilon aminocaproic acid and protamine sulfate, acetylsalicylic acid Acetaminophen, codeine phosphate, codeine sulfate, oxycodone, dihydrocodeine tartrate, oxydodeinone, morphine, heroin, nalbuphine, butorphanol tartrate, pentazocine hydrochloride, cyclazacine, pethidine, buprenorphine, scopolamine and mefenamic acid Triiodo, a substance used for the treatment of diabetes, such as analgesics, antldrugs such as sodium phenytoin and sodium valproate, neuromuscular drugs such as dantrolene sodium, tolbutamide, diabenase glucagon and insulin Drugs used in the treatment of thyroid dysfunction such as thyronine, liothyronine sodium, levothyrokinin sodium and related compounds and propylthiouracil, furosem , Diuretics such as chlorthalidone, hydrochlorthiazide, spironolactone and triampterene, uterine relaxants, ritodrine, fenfluramine hydrochloride, phentermine and diethylproprion hydrochloride, aminophylline, theophylline, salbutamol Antidrugs stimulants such as orciprenaline sulfate and terbutaline sulfate, expectorants such as guaifenesin, cough suppressants such as dextromethorphan and mescaline, mucolytic agents such as carbocysteine, cetylpyridinium chloride, thyrotricine and chlorhexidine Antiseptics, decongestants such as phenylpropanolamine and pseudoephedrine, hypnotics such as dichlorfenazone and nitrazepam, promethazine theosate (theocia antidrug H ₁ blockers such as te), hematopoietic drugs such as ferrous sulfate, folic acid and calcium gluconate, and uric acid excretion drugs such as sulphinpyrazine, allopurinol and probenecid. It will be understood that the present invention is not limited to the aforementioned drugs.

  The amount of pharmaceutically active ingredient in the composition may vary over a very wide range if desired. Preferably the active ingredient is present in an effective dosage in the composition of the present invention. A typical range in which active ingredients may be present in the compositions of the present invention is from about 0.000001 to about 10% by weight. More preferably, the amount of active ingredient is present in the range of about 0.001 to 5% by weight.

  It will be appreciated that any suitable pharmaceutically acceptable form of the active ingredient, i.e. the free base, as well as its pharmaceutically acceptable salt, such as levothyroxine sodium salt, etc. in the composition of the present invention. It should be understood that it may be used.

  When the pharmaceutically active ingredient is levothyroxine sodium, the preferred amount of active ingredient in the composition is present in the range of about 0.00005 to about 5% by weight. A more preferred range is about 0.001 to about 1.0% by weight, and the most preferred range is about 0.002 to about 0.6% by weight levothyroxine. The minimum amount of levothyroxine can vary as long as an effective amount is used to cause the desired pharmaceutical effect. Typically, dosage forms range from about 25 to 300 micrograms per 145 milligram tablet when applied to humans, and about 100 to 800 micrograms per 145 mg tablet for veterinary application. Including quantity.

  According to the present invention, the goal of levothyroxine replacement therapy is to achieve and maintain normal clinical and biochemical thyroid function, while the goal of suppressive therapy is the growth and / or function of abnormal thyroid tissue. Is to inhibit. The appropriate dose of levothyroxine to achieve these goals will determine the specific nature of the patient's age, weight, cardiovascular condition, accompanying medical symptoms, accompanying medications, and the condition being treated. Naturally, it depends on various factors including the beginning. Therefore, the following recommendations serve only as medication guidelines. Those skilled in the art should understand that the medication should be individualized and adjusted based on the patient's clinical response and periodic assessment of laboratory parameters.

  Preferably, although not required, if treated with levothyroxine, it should be taken at least 30 minutes before eating any food on an empty morning. Furthermore, levothyroxine is preferably taken at least about 4 hours apart from drugs known to interfere with its absorption.

  Due to the long half-life of levothyroxine, peak therapeutic effects may not be reached for a given dose of levothyroxine sodium for about 4 to about 6 weeks.

  In humans over the age of 50 who have recently been treated for hyperthyroidism or who have declined thyroid function for only a short period (such as several months), the average complete replacement dose of levothyroxine sodium is about 1.7 mcg / kg / day (eg, about 100 to about 125 mcg / day for a 70 kg adult). Older patients may require less than 1 mcg / kg / day. A levothyroxine sodium dose greater than about 200 mcg / day may or may not be required.

  An initial dose of levothyroxine sodium of about 25 to about 50 mcg / day is recommended for most patients over the age of 50 or suffering from heart disease under the age of 50, optionally about 6 to about 8 weeks Increase the dose step by step. The recommended initial dose of levothyroxine sodium for older adults with heart disease is about 12.5 to about 25 mcg / day, with doses being increased in steps of about 4 to about 6 weeks. The levothyroxine sodium dose is generally adjusted by increasing the dose by about 12.5 to about 25 mcg until the patient suffering from primary hypothyroidism becomes clinically normal thyroid function and serum TSH is normalized.

  For patients with severe hypothyroidism, the recommended initial levothyroxine sodium dose is about 12.5 to about 25 mcg / day, and TSH levels are considered while taking into account clinical and laboratory evaluations. Increase by about 25 mcg / day about every 2-4 weeks until normalized.

  In patients with secondary (pituitary) or tertiary (hypothalamic) hypothyroidism, levothyroxine sodium dose is clinically normal for thyroid function and serum free T4 levels in the upper half of the normal range The dosage should be gradually increased until recovery.

  In children, levothyroxine treatment may be performed as soon as possible with a full replacement dose. The levothyroxine composition of the present invention is suitable for infants and children who cannot swallow a complete tablet by crushing the tablet and suspending the freshly crushed tablet in a small amount (5-10 mL or 1-2 teaspoons) of water. It may be administered. This suspension may be administered with a spoon or a spoid. Foods that reduce absorption of levothyroxine, such as soy special formula, should not be used to administer levothyroxine sodium tablets.

  The recommended initial dose of levothyroxine sodium in neonates is about 10-15 mcg / kg / day. Lower initial doses (eg, about 25 mcg / day) may be considered in infants at risk for heart failure, and doses may vary from 4-6 weeks as needed based on clinical and laboratory response to treatment Should be increased. For infants with very low serum T4 concentrations (<about 5 mcg / dL) or not detectable, the recommended initial dose is about 50 mcg / day levothyroxine sodium.

  As mentioned above, levothyroxine treatment usually starts with a fully substituted dose, and the recommended dose per body weight decreases with age (see dose table below). However, in children with chronic or severe hypothyroidism, an initial amount of levothyroxine sodium of about 25 mcg / day is recommended and increased by 25 mcg every 2-4 weeks until the desired effect is achieved. In older children, the initial dose should be 1/4 of the recommended full replacement dose, and then the dose should be 1/4 of the fully recommended replacement dose on a weekly basis until the full recommended replacement dose is reached. Increasing by an amount equal to 1 minimizes hyperactivity.

  The levothyroxine sodium tablet (USP) of the present invention may be supplied as an oval or violin type, color-coded, for example, a tablet with a strength indicated at 12 strengths as shown in the strength table.

  When the pharmaceutically active ingredient is liothyronine sodium, the preferred amount of active ingredient in the composition is present in the range of about 0.000005 to 0.5% by weight. A more preferred range is from about 0.00001 to 0.1% by weight and the most preferred range is from about 0.00004 to about 0.002% by weight liothyronine. The minimum amount of liothyronine can vary as long as an effective amount is used to cause the desired pharmaceutical effect. Typically, for human application, the dosage form contains an amount of levothyroxine in the range of about 5-50 micrograms per 1 45 milligram tablet.

  As disclosed in US Pat. No. 5,574,150, the β-type microcrystalline cellulose product of the present invention forms a wet cake, which is dried in a drum dryer, and then the dried product for sizing. Produced by passing through a screen or a mill, whereby flat needle-like β-sheet microcrystalline cellulose is obtained. Such β-sheet microcrystalline products are available from Asahi Kasei in Japan and / or are sold under the registered trademark CEOLUS by FMC, New Work, Delaware. The form and performance characteristics of CEOLUS® products are different from those of α-type microcrystalline products (eg AVICEL® and Emcocel®), and the stabilized pharmaceutical composition of the present invention It is suitable for manufacturing a product.

  The amount of β-type microcrystalline product used in the composition is at least 50% by weight of the final composition. Preferably, the amount of β-type microcrystalline product ranges from about 50 to 99% by weight. Most preferably, the amount of β-type microcrystalline product ranges from about 60 to 90% by weight of the final composition.

  Other suitable excipients of the present invention include bulking agents such as starch, trisodium phosphate, tricalcium phosphate, calcium sulfate, and alkali inorganic salts such as sodium carbonate or magnesium. Bulking agents may be present in the composition in the range of about 0-50% by weight.

  Suitable disintegrants include corn starch, cross-linked sodium carboxymethylcellulose (croscarmellose) and cross-linked polyvinyl pyrrolidone (crospovidone). A more preferred disintegrant is croscarmellose. The amount of disintegrant used is in the range of about 0-50% by weight. Preferably, the disintegrant is in the range of about 5-40% by weight, more preferably about 10 to about 30% by weight. This is essentially an excess of the recommended level of such substances. For example, the recommended amount of croscarmellose is 0.5 to about 2% by weight. However, it has been found that a higher formulation of disintegrant substantially improves the dispersibility of the product in an aqueous medium.

  Suitable gildents for use in the present invention include colloidal silicon dioxide and talc. The amount of gildent in the composition is about 0-5% by weight, the preferred amount is about 0-2% by weight.

  Suitable lubricants include magnesium and zinc stearate, sodium stearate fumarate and sodium lauryl sulfate and magnesium. A preferred lubricant is magnesium stearate. The amount of lubricant is typically in the range of about 0-5% by weight, preferably in the range of about 0.1-3% by weight.

  Oral drugs are manufactured by thoroughly mixing the active ingredient and β-type microcrystalline cellulose with other excipients to form an oral dosage. Edible grade dyes may also be added. For example, it is often the case that different titer doses are identified by the color characteristics of such dyes.

As mentioned above, a preferred immediate-acting pharmaceutical composition in tablet form comprises levothyroxine sodium. In a preferred embodiment, the composition comprises at least one of the following, preferably all:
a) Levothyroxine sodium (USP) between about 0.01 mg / tablet and about 500 mg / tablet,
b) between about 100 mg / tablet and about 110 mg / tablet microcrystalline β cellulose, NF (CEOLUS), with a volume density ranging from about 0.10 g / cm ³ to about 0.35 g / cm ³ ;
c) between about 25 mg / tablet to about 50 mg / tablet of croscarmellose sodium, NF (Ac-di-sol), and d) about 0.5 mg / tablet to about 5 mg / tablet. In between magnesium stearate, NF.

  Preferably, the composition further comprises at least one pharmaceutically acceptable colorant.

  The more specific method of the present invention provides a composition comprising less than about 5% total impurities as determined by standard impurity testing. Preferably, the method further comprises forming a tablet, in particular a swollen violin shaped tablet.

  Stabilized oral doses of thyroid hormone are prepared by forming a trituration of active ingredient (ie levothyroxine sodium and / or liothyronine sodium) and β-type microcrystalline cellulose. This trituration is blended with β-type microcrystalline cellulose and additional excipients and compressed into an oral dose.

  In order to maintain consistency between oral administrations, the design of a tableting device is important. Formulation batches are blends of solid compositions of various shapes and sizes. A certain uniformity is achieved by blending. In particular, it is desired that the active thyroid portion be evenly distributed throughout the batch. In a typical 410 kg batch, the amount of active ingredient represents less than 1 kg of the total weight. For example, when manufacturing a 145 mg tablet with a 300 mcg dose, about 0.8 kg of the 410 kg batch is the active ingredient. In addition, each tablet is formulated to contain 100% label claim strength.

  For compressible pharmaceutical tablets, it is typically formed using a loading that results in a compression ratio of 2: 1. However, for pharmaceutical tablets formed using the present invention, a filling amount is required to achieve a compression ratio of 3.3: 1 to 4: 1 to obtain the desired tablet density. Compared to other excipients, the volume density of β-type microcrystalline cellulose is low.

  Higher tablet density can be achieved by adjusting the tablet press to increase the compression ratio. Tablet presses are widely known to those skilled in the art and include those available from Manesty and Stokes. It has been found that such adjustments to the compression ratio result in poor tablet surface finish and at the same time inconsistent tablet weights. Instead, the design of the tableting mold should be adjusted. When filling a tableting mold, it was determined that a minimum of 5-6 mm mold would be full. In most cases, this requires replacing the conventional tableting die with a die that is 2 to 3 mm deeper.

  Especially when using deep molds and compression ratios of 3.3: 1 to 4.0: 1, tablets with good surface finish and consistent weight were produced.

Preferably, the tablet shape is designed to enhance heat transfer from the tablet. More preferred tablets between about 0.9in ² ~ about 0.15In ² per tablet to help the movement of such heat, preferably has a surface area of about 0.115in ^2. Further tablet shapes are contemplated, such as chamfered and / or tablets with V-shaped cuts. A preferred tablet form is the swollen violin form shown in FIG.

  The following examples are given solely by way of illustration and should not be considered a limitation of the present invention, and many obvious modifications are possible without departing from the spirit or scope thereof.

Stability test A stability test was performed on a sample of a thyroid hormone drug product used in the manufacture of tablets containing levothyroxine sodium as an active ingredient. The test was performed with a direct tableting formulation with a dose strength of 25 mcg. The tablet of Example 1 comprises β-type microcrystalline cellulose, while the control 1 tablet comprises conventional microcrystalline cellulose. The composition of the tablet of Example 1 and Control 1 is shown in Table 3, and the stability test results are shown in Table 4.

  As is apparent from Table 4, the stability of the pharmaceutical preparation of the present invention is significantly improved by using β-sheet microcrystalline cellulose. The titer loss of the present invention after 15 months was 3.5%, whereas a similar formulation using α-type microcrystalline cellulose received a 16.0% titer loss. The average loss of titer per month is only about 0.2% per month for the compositions of the present invention compared to more than 1% per month for T4 formulations containing β-type microcrystalline cellulose, thus The stability was about 3 to 4 times better than the T4 product using α-type microcrystalline cellulose.

  A tableting test was performed with the formulation of Example 1. Initial results using standard mold depth showed a relative standard deviation of 2.2-3.5% tablet weight. Using the particularly deep tableting dies described herein, the relative standard deviation is 1.2%. The test was conducted on a Manestee tableting machine with a compression ratio of 3.3: 1 to 4.0: 1.

  Tablet quality also depends on storage of beta sheet microcrystalline cellulose. Best results are achieved when cellulose is received in drums or portable containers instead of bags. The bag mold is subjected to pressure while being transported from the raw material supplier. The results of tableting test are shown in Attachment A.

  Further examples of solid dosage formulations are shown in Tables 5 and 6. Additional example stability test data is shown in Table 7.

  Table 7 shows drug stability data for several such formulations.

  As such, the formulations of the present invention provide excellent stability over the long shelf life of these pharmaceuticals with respect to levothyroxine activity.

The following preferred method of testing the dissolution test titer may be referred to herein as method number: AM-004B.

Formula (elution%): sample area / standard area × 798.86 / 776.87 × injected standard solution / injected sample solution × 100% = elution%
Where 798.86 = as the sodium salt of levothyroxine
Molecular weight
776.87 = Molecular weight as base for levothyroxine

  Table 10 shows comparative dissolution data for all strengths of Levoxil® tablets.

  FIG. 3 shows a graph showing the average value of the strength of each tablet of Levoxil® tested. Each point is an average value obtained by conducting 3 dissolution tests for each of 12 types of tablets. That is, n = 36. Data are shown as percent dissolved label claim to elution time.

  The results show that the multipoint dissolution profile of Levoxil® tablets is similar over a wide range of tablet strengths. Furthermore, all strengths substantially exceed the requirements for immediate-acting oral dosage forms (ie, at least 80% dissolution within 15-20 minutes). In each dosage form, these tablets dissolved over 90% within 2.5 minutes.

  The extremely rapid dispersion rate of the tablets of the present invention allows a simple treatment method for infants or other people who have difficulty swallowing the tablets. In this approach, suitable dosages of immediate-acting tablets made according to the present invention for the patient in question are simply appropriate amounts, for example 50-200 ml of water, soft drinks, juice, milk and other liquids. Just mix. Fast-acting tablets readily elute into liquid with agitation or shaking as desired and are easily administered to patients.

Potency Test The method of testing the following tablet titers is sometimes referred to herein as method number AM-003. Alternatively, tablet titer may be tested according to method AM-021. Method number: AM-021 is the same as method number: AM-003 except that the whole tablet is eluted without first crushing the tablet into powder as in method number: AM-003.
Method Reference: USP 24 pp. 968-970

Chromatographic conditions :
Mobile phase: degassed and filtered, H ₂ O: CH ₃ CN: H ₃ PO ₄ = 65: 35: 0.05
The mobile phase composition may be varied to achieve a satisfactory resolution factor.
Column: ACN, 4.6 mm x 25-30 cm
Flow rate: 1.5 ml / min Detector: Deuterium, set at 225 nm Injection volume: 100 ml

System suitability :
Inject standard 5 times and chromatograph. Record the peak response as instructed in the “Procedure”.
1.0 Standard repeat RSD should not be more than 2.0% of T4.
1.0 Calculate resolution factor R for 1 out of 5 iterations. Next
For this purpose, the R value must be 5.0 or more. See Method QC-009.
Standard preparation :
Accurately weigh 25 mg of USP levothyroxine RS into a 250 ml brown volumetric flask. Add about 50 ml of elution mobile phase. Let stand for 20 minutes with occasional rotation. Sonicate for 30 seconds. Slowly add additional eluate and repeat sonication until no undissolved particles are observed. Dilute to volume with eluate. Mix thoroughly. The concentration of T4 is about 100 μg / ml. An accurately weighed amount of USP liothyronine RS was dissolved to about 100 mg / ml, and the same procedure was performed as for USP levothyroxine RS. This solution is labeled Storage T3-A.

Storage standard dilution :
The A-type volumetric flask 1.500ml put the saved _T 3 -A of 10.0ml in the pipette.
2. Dilute to volume with mobile phase at a concentration of about 2 μg / ml. Mix thoroughly and label this solution as standard T3-B.
3. Pipet 50.0 ml each from T4 and T3-B stock standards into a 500 ml A-type volumetric flask.
Dilute to volume with mobile phase and mix well. This standard product is indicated as T ₃ / T ₄ practical standard. Practical standard concentrations should be about 0.2 μg / ml T3 and 10.0 μg / ml T4.

Note :
The concentration of levothyroxine and liothyronine needs to be adjusted for water content.

Assay preparation :
The average tablet weight is calculated by weighing the tablet amount above the specified amount. Crush the tablets with a mortar and pestle to a uniform fine powder. Measure the tare of a polypropylene weighing boat.

  Weighing a portion of the powder accurately (up to 0.1 mg) using a pre-adjusted stainless steel scoop or spatula (either Teflon coated or uncoated) Put in the boat. Spatula or scoop is pre-adjusted by soaking in powder. The following calculation example is used to achieve 50 ml of 10 μg / ml assay solution.

Record the measured sample weight. Carefully transfer the sample to an Erlenmeyer flask, reweigh the weighing boat and subtract the remaining weight from the measured weight to obtain the actual sample weight. Pipette 50 ml of mobile phase into the flask. The flask is covered with parafilm, sonicated for about 10 seconds, and vortexed at a speed of 6 to faster for about 235 seconds. Observe the sample preparation and if aggregation is observed, repeat the sonication and / or vortexing steps. Centrifuge for 1 min or more (~ 3,000 rpm) until a clear supernatant is achieved. Transfer a portion of the supernatant to an automatic sampler vial.
For in-process granule analysis, the theoretical tablet weight (0.1455 g) is used instead of (tablet weight / number of tablets) in the following formula.

Calculation example :
(Tablet weight / number of tablets) × 10 μg / ml × (50 ml / dose (μg)) = Amount measured per assay

Operation procedure :
Individually inject 100 μl of sample onto the column. Record the analyte peak response and calculate the% label claim as follows.

Calculation :
(Sample area / standard product area) × standard product concentration (μg / ml) × 50 (ml / g) × (average tablet weight in g / actual sample weight in g) × (798.86 / 776.87 ) = [(Μg / dose) / label claim] × 100 = label claim%
Where 798.86 = molecular weight of levothyroxine as sodium salt 776.87 = molecular weight of levothyroxine reference standard

Result :
FIGS. 4 and 5 show HPLC chromatograms of a levothyroxine and liothyronine control (T3 / T4 practical standard shown in FIG. 4) and of an experimental sample (FIG. 5) prepared according to the invention described above. The peaks in both chromatograms in the 1.325-3.1 region correspond to the substance in the solvent. The peak at about 7.2 in FIG. 4 indicates the presence of T3. FIG. 5 shows the absence of T3, as well as the absence of other related products or degradation products of levothyroxine.

Hardness Test The following preferred method of testing tablet hardness may be referred to herein as Method Number: QC-005.

  Generally, the hardness of the tablet is between about 6.0 and about 14.0 kilopounds. Preferably, the tablet hardness is from about 9 to about 13 kilopounds. Typical results for formulations prepared in accordance with the present invention are about 9.3, 11.3, 9.8, 10.2, 12.3, and the like. Pharmaceutical tablets incorporating the granulated active ingredient are typically quite hard, which can make them difficult to dissolve or dissolve. In general, tablets with low hardness have more problems of tablet disintegration during handling and storage.

Impurity Test The following preferred method for testing tablet impurities may be referred to herein as Method No. SA-004.

Calculation :
Diiodothyronine :
(Sample area / standard product area) × standard product concentration (mcg / ml) × (100 ml / W simple (simpl) (g)) × (100% / 1000000 mcg / g) × 1.11 ^* =% w / w
Or sample area × standard product concentration (mcg / ml) × 0.01 × 1.11 ^* =% w / w
In the formula, 1.11 is a correction coefficient.
Triiodothyroacetic acid :
(Sample area / standard product area) × standard product concentration (mcg / ml) × (100 ml / W simple (simpl) (g)) × (100% / 1000000 mcg / g) =% w / w
Or (sample area / standard product area) × standard product concentration (mcg / ml) × (0.01 / W simple (simpl) (g)) =% w / w
Tetraiodothyroacetic acid :
(Sample area / standard product area) × standard product concentration (mcg / ml) × (100 ml / W simple (simpl) (g)) × (100% / 1000000) mcg / g × 1.16 ^* =% w / w
Or (sample area / standard product area) × standard concentration (mcg / ml) × (0.01 / W simple (simpl) (g)) × 1.16 ^* =% w / w
In the formula, 1.16 is a correction coefficient.

The theoretical area of 0.05% levothyroxine sodium is calculated based on the initial amount in mg of levothyroxine sodium in the total sample weight.
(Area of rsII) (A) (10.0) / (0.05) (T 4 standard wt.) (P) (1.0283 ) = 0.05% of the levothyroxine sodium which is based on actual weight The area of rsII is the average area of levothyroxine in the standard reference solution II.
A = initial weight of levothyroxine Na in mg as indicated by sample weight. This is calculated using the formula = (claim weight (g) × claim T _{4 in} mcg) / (0.1450 g × 1000 mcg / mg).
10.0 = theoretical initial weight of levothyroxine USP reference standard 0.500 = theoretical initial weight in mg of levothyroxine NA tested T ₄ standard wt = mg of levothyroxine USP standard Initial weight P = Purity of USP standard for Levothyroxine Na (Purity% / 100%)
1.0283 = Conversion value of levothyroxine to levothyroxine sodium

Maximum unknown impurities (individually):
(Area impurity) _{(T 4} standard wtmg) (1.0283) (P) (100) / ( the area of reference standard I) (A) (2000) = impurities (%)
In the formula: the area impurity is the area of the largest unknown impurity in the test solution, considering that the area is larger than the theoretical area of 0.05% levothyroxine Na.
1.0283 = Conversion value of levothyroxine to levothyroxine sodium P = Purity of USP standard product of levothyroxine Na (purity% / 100%)
100 is the dilution of the test solution.
The area of reference standard I is the area of levothyroxine in standard reference solution I.
A = initial weight of levothyroxine Na in mg as indicated by sample weight This is calculated using the formula = (sample weight (g) x claim T4 in mcg) / (0.1450 g x 1000 mcg / mg) .
2000 is the dilution of the reference solution.

Total of other unknown impurities:
(Total area impurities) (T4 standard product weight mg) (1.0283) (P) (100) / (Reference standard I area) (A) (2000) = Total of unknown impurities (%)
Where: total area impurity is the sum of the areas of all other unknown impurities in the test solution (considering only areas larger than the theoretical area of 0.05% levothyroxine sodium).
T4 standard weight = initial weight of levothyroxine USP standard in mg.
1.0283 = converted value of levothyroxine to levothyroxine sodium.
P = Purity of USP standard of levothyroxine Na (Purity% / 100%)
100 is the dilution of the test solution.
The area of reference standard I is the area of levothyroxine in standard reference solution I.
A = initial weight of levothyroxine Na in mg as indicated by sample weight.
This is calculated using the formula = (sample weight (g) × claim C4 at mcg) / (0.1450 g × 100 mcg / mg).
2000 is the dilution of the reference solution.

  The test results are shown in FIGS. FIG. 6 shows an example of the chromatogram of Standard Reference Solution II, about 5.4 of diiodo-1-thyronine, 8.4 of liothyronine, 12.8 of levothyroxine, 19.3 of triiodothyroacetic acid, And 21.9 with the typical peak of tetraiodothyroacetic acid. FIG. 7 shows the results of an experimental sample of levothyroxine sodium prepared according to the present invention. As can be seen, the sample contained substantially only levothyroxine and the impurities were insignificant.

Liothyronine (T3) Test The following preferred method for testing triiodothyronine may be referred to herein as method number QC-001.

Standard value S-1 for method A and method B The 10 active tablets% tested must fall within the range of 85.0% to 115.0% and the RSD of the 10 tablets is 6. Must not exceed 0%.
Note: If one unit in S-1 does not meet one of the standard values, but is not outside the range of 75% to 125%, then test another 20 units and proceed to S-2.
In the case of S-2 n = 30, 1 unit or more is not outside 85.0 to 115.0%, outside 75.0 to 125.0%, and RSD is 7.80. Not more than%.

Result :
The results for various doses using a sample size of 120 tablets are shown in Table 15.

  The above results confirm a very low amount of variability in the active substance content between the 120 tablets tested. In general, the variability of the 120 tablet samples should be between about 90 and about 110% of the claimed activity, preferably in the range of about 95% to about 105%. The RSD of 120 tablet samples should be 5% or less, preferably less than 3%.

Levothyroxine Sodium Release Standards and Analytical Methods The specification for levothyroxine sodium tablets is USP24 p. 969-970 and Appendix 1p. 2638. For individual tablet strengths, there are further requirements to ensure the physical properties that ensure a tablet appearance and high quality tablets.

Analysis method :
All test methods used to test levothyroxine sodium meet the USP system suitability requirements. All Levoxil® batches are tested for conformance to the following specifications: Table 16 below lists the test parameters, standards and test methods used.

  Additional requirements are shown in Table 17 below.

Bioavailability measurement of two levothyroxine formulations The following examples are in vivo pharmacokinetics and bioavailability studies and in vitro dissolution testing for levothyroxine • Conducted in accordance with 1999 FDA publication policy entitled So-dium Tablets (In-Vivo Pharmacokinetics and Bioavailability studies and In-Vitro Dissolution Testing for Levothyroxine Sodium Tablets). The examples include the following two tests.
Study 1 . Single-Dose Bioavailability Study The purpose of this study was to measure the bioavailability of Levoxil® compared to the baseline (oral solution) under fasting conditions.
Study 2 : Dosage Form Equivalence Study The purpose of this study was to determine the dosage form bioequivalence between three different strengths of Levoxil® tablets (low, medium and high).

Research purpose :
200 g of levothyroxine sodium from Knoll Pharmaceutical Company (JONES PHARMA compared to Sinthroid® injection) given as an oral solution according to a single 0.6 mg dose To measure the bioavailability of levothyroxine sodium (levoxil®) 0.3 mg tablets manufactured by INCORPORATED).
Research method :
Single dose, randomized, open-label, reciprocal crossover design.
Reference protocol :
Guidance for Industry: In Vivo Pharmacokinetics and Bioavailability Studies and In Vitro Dissolution Testing for Guidance for Industry: In Vivo Pharmacokinetics and Bioavailability Studies and In Vitro Dissolution Testing for Levothyroxine Sodium Tablets) (June 1999).
Number of subjects :
A total of 30 subjects participated in the study, and 27 subjects completed the study. All 30 subjects were subjected to safety analysis, and 27 subjects who completed the study were subjected to pharmacokinetic analysis.
Diagnosis and main patient criteria :
All subjects who participated in this study were judged by the investigator to be healthy volunteers who met the test patient criteria and non-target criteria.
Test formulation, dose, duration, mode of administration, and batch number :
The test formulation was a levothyroxine sodium (levoxil®) 2 × 0.3 mg tablet administered as a single oral dose. The batch number used in this study was TT26.
Reference formulation, dose, duration, mode of administration, and batch number :
The reference formulation was reconstituted and levothyroxine sodium (Synthroid®) 2 × 500 μg injection vial (Knoll Pharmaceutical Company), 600 μg administered orally. The reference formulation used was a 500 μg injection instead of 200 μg because the 200 μg injection, which is sufficient to carry out this study, was unusable. The batch number used in this study was 80130028.
Evaluation criteria :
Pharmacokinetics :
Pharmacokinetic assessment consists of measuring total (bound and free) T4 and T3 concentrations in serum at specific times after drug administration. Parameters AUC (0-t), Cmax, and Tmax are calculated from the serum data.
Safety :
Safety assessments included vital signs, clinical laboratory assessments (including TSH), physical examinations, and adverse event (AE) assessments.

Statistical method
Pharmacokinetics :
Descriptive statistics (arithmetic mean, standard deviation (SD), coefficient of variation (CV), standard mean error (SE), sample size (N), minimum and maximum) for all pharmacokinetic parameters Provided. Parametric (usually theoretical) linear model (ANCOVA) with treatment, duration, sequelae, sequelae subjects, ln (baseline), and interaction between ln (baseline) and treatment as factors ) Were used to assess baseline effects and baseline treatment interactions and applied to ln-transformed pharmacokinetic parameters and Cmax. If there is no significant ln (baseline) and no interaction between ln (baseline) and treatment, these parameters are removed from the model. The two hypothesized hypotheses were tested by constructing a 90% confidence interval for the treatment A to treatment ratio at a 5% significance level for ln [AUC (0-t)] and ln (Cmax).
Safety :
The frequency numbers of all subjects who participated in the study who completed the study and were discontinued early were tabulated. Descriptive statistics were calculated for continuous population statistical variables, and frequency numbers were tabulated for each gender and overall categorical population statistical variables.
AE was coded using the fifth edition of the COSTART dictionary. AEs were summarized by the number and percentage of subjects who experienced each coded event. A summary as a percentage of the total number of each coded event and the total AE was also provided.
The test summary table included descriptive statistics of continuous serum chemistry and hematology results at each time point. Values outside the range of each test parameter were listed by the subject.
Vital sign measurements at each time point and descriptive statistics of changes from baseline to each time point were calculated by treatment group. Changes from physical examination screening to post-study results were tabulated.
Pharmacokinetic results-T4 :
ANCOVA analysis showed that the effect of ln (baseline) and the interaction between ln (baseline) and treatment were not significant. Therefore, these factors were removed from the general linear model and applied to the Cmax and AUC (0-t) parameters of ANOVA using the treatment, duration, sequelae and sequelae subjects. A statistical comparison of the arithmetic mean and ln transformed parameters of the serum T4 pharmacokinetic parameters of treatments A and B is summarized in the table below.

Pharmacokinetic result-T3 :
ANCOVA analysis shows that the effect of In (baseline) and the interaction between In (baseline) and treatment is not significant, excluding In (baseline) for In (Cmax), which is significant and maintains the model And excluded from the ANOVA model. If treatment, duration, sequelae and sequelae subjects, and ANOVA with In (baseline) were significant, ln-transformed Cmax and AUC (0-t) parameters were applied. A statistical comparison of the arithmetic mean and In conversion parameters of the serum T3 pharmacokinetic parameters of treatments A and B is summarized in the table below.

A comparison of the total T4 and T3 pharmacokinetics after administration of Levoxil® (Treatment A, test formulation) and Synthroid (Treatment B, reference formulation) establishes that the test formulation requires a bioequivalence to the reference formulation. It was shown to meet.
The 90% confidence interval for the comparison of ln (Cmax) and ln [AUC (0-t)] for T4 and T3 was within the 80% -125% range required for bioequivalence.
Regarding subject safety, both treatments seemed equally safe and well tolerated.

Bioavailability studies to assess single dose bioequivalence of three strengths of levothyroxine The following examples are for three different strengths of levothyroxine sodium according to a single 600 mcg dose ( This was done to determine the dosage form bioequivalence between Levoxil (R) tablets.
Research method :
Single dose, random, open-label, three-way crossover design.
Reference protocol :
Guidance for Industry: In Vivo Pharmacokinetics and Bioavailability Studies and In Vitro Dissolution Testing for Guidance for Industry: In Vivo Pharmacokinetics and Bioavailability Studies and In Vitro Dissolution Testing for Levothyroxine Sodium Tablets) (June 1999). This protocol was submitted at IND 59,117.
Number of subjects :
A total of 28 subjects participated in the study, and 24 subjects completed the study. All 28 subjects were subjected to safety analysis and 24 subjects who completed the study were subjected to pharmacokinetic analysis.
Diagnosis and main patient criteria :
All subjects who participated in this study were judged by the investigator to be healthy volunteers who met the test patient criteria and non-target criteria.
Test formulation, dose, duration, mode of administration, and batch number :
Subjects randomized to Treatment A received a single oral dose of 12 × 50 mcg levothyroxine sodium (levoxil®) tablets, lot number TT24. Subjects randomized to Treatment B received 6 × 100 mcg levothyroxine sodium (levoxil®) tablets, lot number TT25. Subjects randomized to Treatment C received 2 × 300 mcg levothyroxine sodium (levoxil®) tablets, lot number TT26. The test formulations were manufactured by JMI-Daniels, a subsidiary of Jones Pharma Incorporated.
Pharmacokinetics :
Pharmacokinetic assessment consists of measuring total (bound and free) T4 and T3 concentrations in serum at specific times after drug administration. Parameters AUC (0-t), Cmax, and Tmax are calculated from the serum data.
Safety :
Safety assessments included vital sign monitoring, laboratory evaluation, thyroid stimulating hormone (TSH), physical examination, electrocardiogram (ECG) and adverse events (AE).

Statistical method
Pharmacokinetics :
Descriptive statistics (arithmetic mean, standard deviation (SD), coefficient of variation (CV), standard mean error (SEM), sample size (N), minimum, and maximum) for all pharmacokinetic parameters Provided. A parametric (usually theoretical) general linear model including treatment, duration, sequelae and sequelae subjects as factors was applied to ln transformed Cmax and AUC (0-t). The two hypothesized hypotheses are the ratio of treatment A and treatment B, treatment A and treatment C, and treatment B and treatment C at the 5% significance level for ln [AUC (0-t)] and ln (Cmax). Was verified by constructing a 90% confidence interval.
Safety :
The frequency numbers of all subjects who participated in the study who completed the study and were discontinued early were tabulated. Descriptive statistics were calculated for continuous population statistical variables, and frequency numbers were tabulated for each gender and overall categorical population statistical variables.
AE was coded using the fifth edition of the COSTART dictionary. AEs were summarized by the number and percentage of subjects who experienced each coded event. A summary as a percentage of the total number of each coded event and the total AE was also provided. The test summary table included descriptive statistics on continuous serum chemistry and hematology results at each time point. Values outside the range of each test parameter were listed by the subject. Vital sign measurements at each time point and descriptive statistics of changes from baseline to each time point were calculated by treatment group. The transition from screening to post-study results for physical diagnosis is summarized in a table.
Pharmacokinetic results-T4
A statistical comparison of the arithmetic mean and ln transformed parameters of the serum T4 pharmacokinetic parameters of treatments A and B is summarized in the table below.

  A statistical comparison of the arithmetic mean and ln transformed parameters of the serum T4 pharmacokinetic parameters of treatments A and C is summarized in the table below.

  The arithmetic mean of serum T4 pharmacokinetic parameters for treatments B and C and the statistical comparison of the ln transformed parameters are summarized in the table below.

Pharmacokinetic result-T3 :
An arithmetic mean of serum T3 pharmacokinetic parameters for treatments A and B and a statistical comparison of the ln transformed parameters are summarized in the table below.

  A statistical comparison of the arithmetic mean and In-transformed parameters of the serum T3 pharmacokinetic parameters of treatments A and C is summarized in the table below.

  An arithmetic mean of serum T3 pharmacokinetic parameters for treatments B and C and a statistical comparison of the ln transformed parameters are summarized in the table below.

Safety results:
A total of 59 treatment-related AEs were reported by 15 (54%) of 28 subjects dosed in study treatment. The incidence of AEs was similar throughout treatment. Headache was the most frequently reported event. Most AEs were moderate in strength. One subject experienced a serious adverse event of chest pain, but was determined by the investigator to be unrelated to treatment. There was no trend in ECG suggesting vital signs, laboratory test results, or treatment related differences.

  Comparison of total T4 and T3 pharmacokinetics after administration of 12 × 50 mcg levoxil® tablets (treatment A) and 6 × 100 mcg levoxil® tablets (treatment B) shows that the two formulations are bioequivalent It was shown that it meets the requirements of The 90% confidence interval for the comparison of ln (Cmax) and ln [AUC (0-t)] for T4 and T3 was within the range of 80% to 125% required for bioequivalence.

  Comparison of total T4 and T3 pharmacokinetics after administration of 12 × 50 mcg levoxil® tablets (Treatment A) and 2 × 300 mcg levoxil® tablets (Treatment C) shows that the two formulations are bioequivalent It was shown that it meets the requirements of The 90% confidence interval for the T4 and T3 ln (Cmax) and ln [AUC (0-t)] comparisons was within the 80% to 125% range required for bioequivalence.

  Comparison of total T4 and T3 pharmacokinetics after administration of 6 × 100 mcg levoxil® tablets (treatment B) and 2 × 300 mcg levoxil® tablets (treatment C) shows that the two formulations are bioequivalent It was shown that it meets the requirements of The 90% confidence interval for the comparison of ln (Cmax) and ln [AUC (0-t)] for T4 and T3 was within the range of 80% to 125% required for bioequivalence.

  Study prescriptions appear safe and are usually well tolerated when given to healthy adult volunteers.

Levothyroxine Sodium (Levoxil®) Tablet Composition A preferred levothyroxine sodium composition in the following tablet form was prepared according to the method disclosed herein.

  Although the present invention has been described in connection with preferred embodiments and examples, it will be readily appreciated by those skilled in the art that other modifications and changes may be made herein without departing from the spirit or scope of the invention. . For example, the active partial levothyroxine sodium may be changed to liothyronine sodium and similar formulations may be further considered part of the claimed invention. Accordingly, the invention is not intended to be limited to the specific details of the preferred embodiments and examples described above, but only by the scope of the invention as defined in the claims appended hereto. Is done.

The foregoing and other objects, advantages and features of the invention, and the manner in which they are accomplished, are described in the following detailed description of the invention, taken in conjunction with the accompanying drawings which illustrate preferred and exemplary embodiments. It will be easier to understand if you consider it.
Illustrate various solid dosage forms such as columnar tablets and swollen violin-type tablets. A tableting mold is illustrated. Figure 2 illustrates comparative dissolution data for various strengths of Levoxil (R) tablets made in accordance with the present invention. 2 is an HPLC chromatogram showing levothyroxine and liothyronine standards. 2 is an HPLC chromatogram showing the results of a levothyroxine sodium sample prepared according to the present invention. 2 is an HPLC chromatogram showing various levothyroxine impurity standards. 2 is an HPLC chromatogram showing the results of a levothyroxine sodium sample prepared according to the present invention.

Claims (126)

  An immediate-acting pharmaceutical composition comprising a levothyroxine salt.   2. The composition of claim 1, wherein at least about 85% levothyroxine dissolves in the aqueous solution in less than about 30 minutes as measured by a standard dissolution test.   The composition of claim 1, wherein at least about 85% levothyroxine dissolves in the aqueous solution in about 10 minutes to about 15 minutes as measured by a standard dissolution test.   3. The composition of claim 2, wherein at least about 85% levothyroxine dissolves in the aqueous solution in about 10 minutes to about 15 minutes as measured by a standard dissolution test.   2. The composition of claim 1, wherein the levothyroxine (T4) plasma Cmax value measured by a standard Cmax test ranges from about 10 [mu] g / dL to about 20 [mu] g / dL.   4. The composition of claim 2, wherein the levothyroxine (T4) plasma Cmax value measured by a standard Cmax test is in the range of about 10 [mu] g / dL to about 20 [mu] g / dL.   4. The composition of claim 3, wherein the levothyroxine (T4) plasma Cmax value measured by a standard Cmax test ranges from about 10 [mu] g / dL to about 20 [mu] g / dL.   5. The composition of claim 4, wherein the levothyroxine (T4) plasma Cmax value measured by a standard Cmax test ranges from about 12 [mu] g / dL to about 16 [mu] g / dL.   5. The composition of claim 4, wherein the levothyroxine (T4) plasma level has an ln (Cmax) value in the range of about 1 to about 3.   6. The composition of claim 5, wherein the levothyroxine (T4) plasma level ln (Cmax) value is in the range of about 1 to about 3.   2. The composition of claim 1, wherein the triiodothyronine (T3) plasma Cmax value measured by a standard Cmax test ranges from about 0.1 ng / mL to about 10 ng / mL.   2. The composition of claim 1, wherein the triiodothyronine (T3) plasma Cmax value measured by a standard Cmax test is in the range of about 0.5 ng / mL to about 2 ng / mL.   The composition of claim 1, wherein the ln (Cmax) value is in the range of about 0.01 to about 5.   2. The composition of claim 1, wherein the levothyroxine (T4) plasma Tmax value measured by a standard Tmax test is in the range of about 0.5 hours to about 5 hours.   2. The composition of claim 1, wherein the levothyroxine (T4) plasma Tmax value measured by a standard Tmax test is in the range of about 1 hour to about 3 hours.   2. The composition of claim 1, wherein the triiodothyronine (T3) plasma Tmax value measured by a standard Tmax test is in the range of about 10 hours to about 20 hours.   2. The composition of claim 1, wherein the triiodothyronine (T3) plasma Tmax value measured by a standard Tmax test is in the range of about 12 hours to about 16 hours.   2. The composition of claim 1, wherein the levothyroxine (T4) plasma AUC (0-t) value is in the range of about 450 [mu] g-hr / dL to about 600 [mu] g-hr / dL. 2. The composition of claim 1, wherein the levothyroxine (T4) plasma AUC (0-t) value is in the range of about 500 [mu] g-hr / dL to about 550 [mu] g-hr / dL.   2. The composition of claim 1, wherein the ln [AUC (0-t)] value is in the range of about 1 to about 10.   The composition of claim 1, wherein the triiodothyronine (T3) AUC (0-t) value is in the range of about 10 ng-hr / mL to about 100 ng-hr / mL.   2. The composition of claim 1, wherein the triiodothyronine (T3) AUC (0-t) value is in the range of about 20 ng-hr / mL to about 60 ng-hr / mL.   The composition of claim 1, wherein the ln [AUC (0-t)] value is in the range of about 1 to about 5.   2. The composition of claim 1 that is substantially free of sugar.   2. The composition of claim 1, wherein the composition is substantially non-granular.   The composition of claim 1, further comprising microcrystalline β-cellulose. Bulk density of the microcrystalline β- cellulose is in the range of about 0.10 g / cm ³ ~ about 0.35 g / cm ^3, The composition of claim 26. 27. The composition of claim 26, wherein the volume density of the microcrystalline [beta] -cellulose is in the range of about 0.15 g / cm < ³ > to about 0.25 g / cm < ³ >. Bulk density of the microcrystalline β- cellulose is in the range of about 0.17 g / cm ³ ~ about 0.23 g / cm ^3, The composition of claim 26. 27. The composition of claim 26, wherein the volume density of the microcrystalline [beta] -cellulose is in the range of about 0.19 g / cm < ³ > to about 0.21 g / cm < ³ >.   27. The composition of claim 26, wherein the conductivity of the microcrystalline [beta] -cellulose is less than about 200 [mu] S / cm.   27. The composition of claim 26, wherein the conductivity of the microcrystalline [beta] -cellulose is less than about 75 [mu] S / cm.   27. The composition of claim 26, wherein the microcrystalline [beta] -cellulose has a conductivity in the range of about 0.5 [mu] S / cm to 50 [mu] S / cm.   27. The composition of claim 26, wherein the conductivity of the microcrystalline [beta] -cellulose is in the range of about 15 [mu] S / cm to 30 [mu] S / cm.   The composition of claim 1, wherein the post-packaging titer, as measured by a standard titer test, is in the range of about 95% to about 120%.   36. The composition of claim 35, wherein the post-packaging titer as measured by a standard titer test is in the range of about 98% to about 110%.   2. The composition of claim 1 formulated as a tablet.   40. The composition of claim 38, wherein the total hardness of the tablet as measured by a standard hardness test is in the range of about 1 to about 30 KP.   40. The composition of claim 38, wherein the total hardness of the tablet as measured by a standard hardness test is in the range of about 5 to about 15 KP.   40. The composition of claim 38, wherein the tablet is configured to enhance heat transfer from the tablet. Surface area of the tablet is in the range of about 0.9in ² ~ about 0.15in ^2, composition of claim 38. Surface area of the tablet is about 0.115in ^2, composition of claim 38.   40. The composition of claim 38, wherein the tablet is chamfered.   40. The composition of claim 38, wherein the tablet further comprises a score line.   40. The composition of claim 38, wherein the tablet is in the swelled violin form.   The composition of claim 1, wherein the total impurity amount measured by a standard impurity test is less than about 10%.   The composition of claim 1, wherein the total impurity content measured by a standard impurity test is less than about 5%.   Impurities are diiodothyronine (T2), triiodothyronine (T3), triiodothyroacetamide, triiodothyroethylamine, triiodothyroacetic acid, triiodotyroethyl alcohol, tetraiodothyroacetamide, tetraiodothyroacetic acid, triiodothyroethane, and 48. The composition of claim 47, comprising at least one of tetraiodothyroethane.   Impurities are diiodothyronine (T2), triiodothyronine (T3), triiodothyroacetamide, triiodothyroethylamine, triiodothyroacetic acid, triiodotyroethyl alcohol, tetraiodothyroacetamide, tetraiodothyroacetic acid, triiodothyroethane, and 49. The composition of claim 48, comprising at least one of tetraiodothyroethane.   48. The composition of claim 47, wherein the impurities detected in the assay comprise diiodothyronine (T2), triiodothyronine (T3), triiodothyroacetic acid, and tetraiodothyroacetic acid.   49. The composition of claim 48, wherein the impurities detected in the assay comprise diiodothyronine (T2), triiodothyronine (T3), triiodothyroacetic acid, and tetraiodothyroacetic acid.   2. The composition of claim 1, further comprising a pharmaceutically acceptable croscarmellose salt.   The composition of claim 1 further comprising a pharmaceutically acceptable magnesium salt.   54. The composition of claim 53, further comprising a pharmaceutically acceptable magnesium salt. A tablet-like immediate-acting pharmaceutical composition comprising levothyroxine sodium,
a) about 0.01 mg / tablet to about 500 mg / tablet of levothyroxine sodium (USP);
b) from about 100 mg / tablet to about 110 mg / tablet, microcrystalline β-cellulose, NF (Ceolus®) having a volume density of about 0.10 g / cm ³ to about 0.35 g / cm ³ ;
c) about 25 mg / tablet to about 50 mg / tablet croscarmellose sodium, NF (Ac-di-sol); and d) about 0.5 mg / tablet to about 5 mg / tablet magnesium stearate, NF
A composition comprising   57. The composition of claim 56, further comprising at least one pharmaceutically acceptable colorant.   An aqueous solution comprising the composition according to claim 1.   57. An aqueous solution comprising the composition of claim 56.   59. An aqueous solution according to claim 58 adapted for use by children or infants. A method for producing a rapid-acting pharmaceutical composition comprising a levothyroxine salt,
a) Mixing levothyroxine salt with microcrystalline β-cellulose and croscarmellose salt to make a blend; and b) bringing the blend into a ratio of initial volume to final volume ranging from about 2: 1 to about 5: 1. A method comprising compressing to make a composition.   62. The method of claim 61, wherein the ratio of initial volume to final volume is about 4: 1.   62. The method of claim 61, wherein the composition is characterized by less than about 5% total impurities as determined by standard impurity testing.   64. The method of claim 61, further comprising forming a tablet.   59. The method of claim 58, wherein the tablet is a swollen violin type. A process for producing a stabilized pharmaceutical composition comprising a levothyroxine salt, comprising:
a) Mixing levothyroxine salt with microcrystalline β cellulose and croscarmellose salt to make a blend; and b) mixing the blend with an initial volume to final volume ratio of about 2: 1 to about 5: 1. A method comprising compressing to make a composition.   68. The method of claim 66, wherein the ratio of initial volume to final volume is about 4: 1.   68. The method of claim 66, wherein the composition is a composition characterized in that the total impurity amount as measured by a standard impurity test is less than about 5%.   68. The method of claim 66, further comprising forming a tablet.   68. The method of claim 66, wherein the tablet is in an expanded violin form.   A stabilized rapid-acting pharmaceutical composition comprising levothyroxine. A process for producing a stabilized immediate-acting pharmaceutical composition according to claim 71,
a) preparing a formulation by formulating levothyroxine and β-sheet type microcrystalline cellulose; and b) preparing a solid dosage formulation therefrom.   73. The method of claim 72, wherein the solid dosage formulation is formed by tableting the formulation with a tablet press.   73. The method of claim 72, wherein the formulation is tableted such that the ratio of initial volume to final volume is between 3.3: 1 and 4.0: 1.   73. The method of claim 72, wherein the levothyroxine is levothyroxine sodium.   73. The method of claim 72, wherein the stabilized rapid-acting pharmaceutical composition further comprises liothyronine.   77. The method of claim 76, wherein the liothyronine is liothyronine sodium.   A stabilized pharmaceutical composition comprising levothyroxine, wherein the levothyroxine (T4) plasma Cmax value measured by a standard Cmax test ranges from about 10 μg / dl to about 20 μg / dl.   79. The composition of claim 78, wherein the levothyroxine (T4) plasma Cmax value measured by a standard Cmax test is in the range of about 12 [mu] g / dl to about 16 [mu] g / dl.   79. The composition of claim 78, wherein the levothyroxine (T4) plasma level has an ln (Cmax) value in the range of about 1 to about 3.   80. The composition of claim 79, wherein the levothyroxine (T4) plasma level ln (Cmax) value is in the range of about 1 to about 3.   A stabilized pharmaceutical composition comprising levothyroxine, wherein the triiodothyronine (T3) plasma Tmax value measured by a standard Tmax test is in the range of about 10 hours to about 20 hours.   83. The composition of claim 82, wherein the triiodothyronine (T3) plasma Tmax value measured by a standard Tmax test is in the range of about 12 hours to about 16 hours.   A stabilized rapid-acting pharmaceutical composition comprising levothyroxine, wherein the levothyroxine (T4) plasma Tmax value measured by a standard Tmax test is in the range of about 0.5 hours to about 5 hours. .   85. The composition of claim 84, wherein the levothyroxine (T4) plasma Tmax value measured by a standard Tmax test is in the range of about 1 hour to about 3 hours.   A pharmaceutical composition comprising an elution product of a formulation comprising levothyroxine, cross-linked sodium carboxymethylcellulose, and β-type microcrystalline cellulose in an aqueous medium.   The formulation comprises about 0.001 to 1 wt% levothyroxine, about 5 to about 40 wt% crosslinked sodium carboxymethylcellulose, and at least about 50 wt% β-type microcrystalline cellulose. 86. The composition according to 86.   A fast-acting pharmaceutical composition comprising levothyroxine, wherein at least about 85% levothyroxine dissolves in an aqueous solution in less than about 20 minutes as measured by a standard dissolution test.   2. The composition of claim 1, wherein at least about 80% levothyroxine is dissolved in the aqueous solution by about 15 minutes as measured by a standard dissolution test.   A stabilized pharmaceutical composition comprising levothyroxine, wherein at least about 85% levothyroxine dissolves in an aqueous solution in less than about 20 minutes as measured by a standard dissolution test.   94. The composition of claim 90, wherein at least about 80% levothyroxine dissolves in the aqueous solution by about 15 minutes as measured by a standard dissolution test.   A fast-acting pharmaceutical composition comprising levothyroxine substantially free of sugar.   A stabilized pharmaceutical composition comprising levothyroxine substantially free of sugar.   A fast-acting pharmaceutical composition comprising levothyroxine that is substantially non-granular.   A stabilized pharmaceutical composition comprising levothyroxine that is substantially non-granular.   An immediate-acting pharmaceutical composition comprising levothyroxine having a post-packaging titer measured by a standard titer test in the range of about 95% to about 120%.   99. The composition of claim 96, wherein the post-packaging titer as measured by the standard titer test is in the range of about 98% to about 110%.   A stabilized pharmaceutical composition comprising levothyroxine having a post-packaging titer measured by a standard titer test in the range of about 95% to about 120%.   99. The composition of claim 98, wherein the post-packaging titer as measured by a standard titer test is in the range of about 98% to about 110%.   An immediate-acting pharmaceutical composition comprising levothyroxine, formulated as a tablet.   101. The composition of claim 100, wherein the tablet has a total hardness as measured by a standard hardness test in the range of about 1 to about 30 KP.   101. The composition of claim 100, wherein the total hardness of the tablet as measured by a standard hardness test is in the range of about 5 to about 15 KP.   A stabilized pharmaceutical composition comprising levothyroxine, formulated as a tablet.   104. The composition of claim 103, wherein the total hardness of the tablet as measured by a standard hardness test is in the range of about 1 to about 30 KP.   104. The composition of claim 103, wherein the total hardness of the tablet as measured by a standard hardness test is in the range of about 5 to about 15 KP.   A fast-acting pharmaceutical composition comprising levothyroxine, wherein the tablet is configured to enhance heat transfer from the tablet. Surface area of the tablet is in the range of about 0.9in ² ~ about 0.15in ^2, The composition of claim 106.   107. The composition of claim 106, wherein the tablet is chamfered.   107. The composition of claim 106, wherein the tablet is scored.   107. The composition of claim 106, wherein the tablet is in the swollen violin form.   A stabilized pharmaceutical composition comprising levothyroxine, wherein the tablet is configured to enhance heat transfer from the tablet. Surface area of the tablet is in the range of about 0.9in ² ~ about 0.15in ^2, The composition of claim 111.   112. The composition of claim 111, wherein the tablet is chamfered.   112. The composition of claim 111, wherein the tablet is scored.   112. The composition of claim 111, wherein the tablet is in the swelled violin form. A method of instructing a human to take a tablet-form immediate-acting pharmaceutical composition comprising levothyroxine for reduced or absent thyroid function, comprising:
A method comprising instructing a human to take a specified quantity of said immediate-acting pharmaceutical levothyroxine tablet a selected number of times daily to treat a decrease or absence of thyroid function.   117. The method of claim 116, wherein the reduced or lack of thyroid function is caused by a cause selected from the group consisting of myxedema, cretinism and obesity. A method of instructing a human to take a tablet-form stabilized immediate-acting pharmaceutical composition comprising levothyroxine for reduced or absent thyroid function comprising:
A method comprising instructing a human to take a specified quantity of said immediate-acting pharmaceutical levothyroxine tablet a selected number of times daily to treat a decrease or absence of thyroid function.   119. The method of claim 118, wherein the reduced or lack of thyroid function is caused by a cause selected from the group consisting of myxedema, cretinism and obesity.   Selected from the group consisting of replacement therapy or replacement therapy in hypothyroidism, suppression of pituitary TSH secretion, prevention of normal thyroid function goiter and adjuvant therapy in the management of thyroid-stimulating hormone-dependent differentiated thyroid cancer, A method of instructing a human to take a tablet-form immediate-acting pharmaceutical composition comprising an effective amount of levothyroxine to treat a thyroid indication, the amount effective for the human to treat a thyroid indication Administering the said immediate-acting pharmaceutical levothyroxine tablet of a selected number of times daily.   Selected from the group consisting of replacement therapy or replacement therapy in hypothyroidism, suppression of pituitary TSH secretion, prevention of normal thyroid function goiter and adjuvant therapy in the management of thyroid stimulating hormone-dependent differentiated thyroid cancer, A method for instructing a human to take a tableted stabilized immediate-acting pharmaceutical composition comprising an effective amount of levothyroxine for treating a thyroid indication, said thyroid indication being treated A method comprising administering to a human a selected number of daily doses of an effective amount of the stabilized rapid-acting pharmaceutical levothyroxine tablet. A method of treating a human using a tablet-form immediate-acting pharmaceutical composition comprising levothyroxine for the reduction or lack of thyroid function, the amount effective for treating the reduction or absence of thyroid function Administering the said immediate-acting pharmaceutical levothyroxine tablet of a selected number of times daily.   123. The method of claim 122, wherein the reduced or lack of thyroid function is caused by a cause selected from the group consisting of myxedema, cretinism and obesity.   A method of treating a human with a tablet-form stabilized immediate-acting pharmaceutical composition comprising levothyroxine for reduced or absent thyroid function, for treating reduced or absent thyroid function Administering to a human an effective amount of said immediate-acting pharmaceutical levothyroxine tablet a selected number of times daily.   129. The method of claim 124, wherein the reduced or lack of thyroid function is caused by a cause selected from the group consisting of myxedema, cretinism and obesity.   Selected from the group consisting of replacement therapy or replacement therapy in hypothyroidism, suppression of pituitary TSH secretion, prevention of normal thyroid function goiter and adjuvant therapy in the management of thyroid stimulating hormone-dependent differentiated thyroid cancer, A method of treating a human with a tablet-form immediate-acting pharmaceutical composition comprising an effective amount of levothyroxine for thyroid indication, wherein the effective amount is administered to the human to treat said thyroid indication Administering the immediate-acting pharmaceutical levothyroxine tablet a selected number of times daily. Selected from the group consisting of replacement therapy or replacement therapy in hypothyroidism, suppression of pituitary TSH secretion, prevention of normal thyroid function goiter and adjuvant therapy in the management of thyroid-stimulating hormone-dependent differentiated thyroid cancer, A method of treating a human with a tablet-like stabilized rapid-acting pharmaceutical composition comprising an effective amount of levothyroxine for treating a thyroid indication, wherein the thyroid indication is treated Administering to a human a selected number of daily doses of an effective amount of the stabilized immediate release pharmaceutical levothyroxine tablet.

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