AU2002240394A1 - Levothyroxine compositions and methods - Google Patents

Description

Express Mail No. ET 862404069 US -1 LEVOTHYROXINE COMPOSITIONS AND METHODS U.S. Patent Application This application for U.S. patent is filed as an utility application under U.S.C., Title 35, §111(a). Related U.S. Patent Applications This application for U.S. patent relates to U.S. provisional application, which was filed on February 15, 2001 and assigned provisional Serial No. 60/269,009 and is entitled Stabilized Pharmaceutical and Thyroid Hormone Compositions and Method of Preparation. This application for U.S. patent also relates to U.S. provisional application, which was filed on February 15, 2001 and assigned provisional Serial No. 60/268,998 and is entitled Manufacture of Thyroid Hormone Tablets Having Consistent Active Moiety Amounts. Field of the Invention The invention generally relates to stable pharmaceutical compositions, and methods of making and administering such compositions. In one aspect, the invention features stabilized pharmaceutical compositions that include pharmaceutically active ingredients such as levothyroxine (T4) sodium and liothyronine (T3) sodium (thyroid hormone drugs), preferably in i immediate release solid dosage form. Also provided are methods for making and using such mediate release and stabilized compositions. ackground Thyroid hormone preparations of levothyroxine sodium and liothyronine sodium are harmaceutical preparations useful to the treatment of hypothyroidism and thyroid hormone placement therapy in mammals, for example, humans and dogs. Thyroid hormone preparations are used to treat reduced or absent thyroid function of any tiology, including human or animal ailments such as myxedema, cretinism and obesity. Hypothyroidism is a common condition. It has been reported in the United States Federal egister that Hypothyroidism has a prevalence of 0.5 percent to 1.3 percent in adults. In people >ver 60, the prevalence of primary hypothyroidism increases to 2.7 percent in men and 7.1 percent in women. Because congenital hypothyroidism may result in irreversible mental retardation, which can be avoided with early diagnosis and treatment, newborn screening for this disorder is mandatory in North America. Europe, and Japan. Thyroid hormone replacement therapy can be a chronic, lifetime endeavor. The dosage is established for each patient Individually. Generally, the initial dose is small. The amount is increased gradually until clinical evaluation and laboratory tests indicate that an optimal response has been achieved. The dose required to maintain this response is then continued. The age and general physical condition of the patient and the severity and duration of hypothyroid symptoms determine the initial dosage and the rate at which the dosage may be increased to the eventual maintenance level. It has been reported that the dosage increase should be very gradual in patients with myxedema or cardiovascular disease to prevent precipitation of angina, myocardial infarction, or stroke. It is important that thyroid hormone treatment have the correct dosage. Both under treatment and over-treatment can have deleterious health impacts. In the case of under-treatment, a sub-optimal response and hypothyroidism could result. Under-treatment has also been reported to be a potential factor in decreased cardiac contractility and increased risk of coronary artery disease. Conversely, over-treatment may result in toxic manifestations of hyperthyroidism such as cardiac pain, palpitations, or cardiac arrhythmia's. In patients with coronary heart disease, even a small increase in the dose of levothyroxine sodium may be hazardous in a particular. 2 ITyperthyroidism is a known risk factor for osteoporosis. Several studies suggest that sub inical hyperthyroidism in premenopausal women receiving thyroid hormone drugs for ,placement or suppressive therapy is associated with bone loss. To minimize the risk of steoporosis, it is preferable that the dose be kept to the lowest effective dose. Because of the risks associated with over-treatment or under-treatment with evothyroxine sodium, there is a need for thyroid hormone products that are consistent in potency nd bioavailability. Such consistency is best accomplished by manufacturing techniques that maintain consistent amounts of the active moiety during tablet manufacture. Thyroid hormone drugs are natural or synthetic preparations containing etraiodothyronine (T 4, levothyroxine) or triiodothyronine (T 3, liothyronine) or both, usually as heir pharmaceutically acceptable (e.g. sodium) salts. T 4 and T 3 are produced in the human hyroid gland by the iodination and coupling of the amino acid tyrosine. T 4 contains four iodine toms and is formed by the coupling of two molecules of diiodotyrosine (DIT). T 3 contains bree atoms of iodine and is formed by the coupling of one molecule of DIT with one molecule of monoiodotyrosine (MIT). Both hormones are stored in the thyroid colloid as thyroglobulin. Thyroid hormone preparations belong to two categories: (1) natural hormonal preparations derived from animal thyroid, and (2) synthetic preparations. Natural preparations include desiccated thyroid and thyroglobulin. Desiccated thyroid is derived from domesticated animals that are used for food by man (either beef or hog thyroid), and thyroglobulin is derived from thyroid glands of the hog. The United States Pharmacopoeia (USP) has standardized the total iodine content of natural preparations. Thyroid USP contains not less than (NLT) 0.17 percent and not more than (NMT) 0.23 percent iodine, and thyroglobulin contains not less than (NLT) 0.7 percent of organically bound iodine. Iodine content is only an indirect indicator of true hormonal biologic activity. Synthetic forms for both T 4-and T 3 thyroid hormone are available from a number of producers. For example, liothyronine sodium (T 3) tablets are available under the trademark Cytomel* from King Pharmaceuticals, Inc., St. Louis, Missouri. Levothyroxine sodium (T 4) is available under the tradename Levoxyl" from King Pharmaceuticals, Inc., under the tradename Synthroid* from Knoll Pharmaceutical, Mt. Olive, New Jersey, and under the tradename Unithroid* from Jerome Stevens Pharmaceuticals, Bohemia, New York. In addition a 3 erinarian preparation of levothyroxine sodium is available under the tradename Soloxine* m King Pharmaceuticals, Inc. Levoxyl* (levothyroxine sodium tabletsUSP) contain synthetic crystalline L-3,3',5,5 raiodothyronine sodium salt [levothyroxine

(T

4 ) sodium]. As indicated above, the synthetic T 4 Levoxyl* is identical to that produced in the human thyroid gland. The levothyroxine

(T

4 ) dium in Levoxylo has an empirical formula of C 15 Hio 14 N NaO4 H 2 0, molecular weight of 8.86 g/mol (anhydrous), and a structural formula as shown: 1 .- ' --

I-

(QId / H it is well known that the stability of thyroid hormone drugs is quite poor. They are ygroscopic and degrade in the presence of moisture or light, and under conditions of high temperature. The instability is especially notable in the presence of pharmaceutical excipients. uch as carbohydrates, including lactose, sucrose, dextrose and starch, as well as certain dyes. 'he critical nature of the dosage requirements, and the lack of stability of the active ingredients n the popular pharmaceutical formulations, have led to a crisis which has adversely effected the nost prescribed thyroid drug products. See, e.g., 62 Fed. Reg. 43535 (Aug. 14, 1997). It is desirable, therefore, to prepare a stabilized dosage of levothyroxine and liothyronine, which will have a longer shelf life that can be used in the treatment of human or animal thyroid hormone deficiency. U.S. Patent No. 5,22 5,204 (the '204 patent) is directed to improving the stability of levothyroxine sodium. In one embodiment disclosed by '204, stabilized levothyroxine sodium was prepared in a dry state by mixing levothyroxine sodium with a cellulose tableting agent using geometric dilution and subsequently combining this mixture with the same or a second cellulose tableting agent, such as microcrystalline cellulose. Other tableting aids or excipients can be used in this formulation. This '204 patent is incorporated by reference herein, in its entirety. The microcrystalline cellulose disclosed In '204 is AVICEL 101*, AVICEL 102", AVICEL 103*, AVICEL 105*, trademarks of FMC Company of Newark, DE., and 4 icrocrystalline Cellulose NF, or EMCOCEL*, a trademark owned by Penwest Pharmaceuticals Patterson, NY. These microcrystalline cellulose products are prepared by re-slurrying the lulose and spray drying the product. This produces an a- - helix spherical microcrystalline ilulose product. U. S. Patents 5,955,105 and 6,056,975 (the continuation of'105) disclose pharmaceutical eparations of levothyroxine and microcrystalline cellulose, along with other excipients. The icrocrystalline cellulose products used in the '105 and '975 patents were also the a - form vicel microcrystalline cellulose products. U. S. Patents 5,955,105 and 6,056,975 are incorporated by reference herein, in their entirety. Another microcrystalline cellulose product is a B - sheet form microcrystalline cellulose having a flat needle shape, marketed under the trademark CEOLUS KG801l by FMC Company f Newark, Delaware. The Ceolus* product has different morphology, and different performance characteristics, than those of the Avicel product. The B - sheet microcrystalline ellulose of the present invention is disclosed in U.S. Patent 5,574,150, which is hereby acorporated by reference. Further disclosure relating to B - sheet microcrystalline cellulose is found in International Journal of Pharmaceutics 182 (199) 155 which is hereby incorporated by -eference. The Ceolus* product (B - sheet microcrystalline cellulose) is disclosed by FMC, in its product bulletin dated October 1997, as being suitable for "smaller size tablets" and "exceptional irug carrying capacity." Th'e Ceolus* product was said to provide superior compressibility and drug loading capacity, that still exhibited effective flowability. The examples given in the Ceolus* bulletin were of vitamin C combined with Ceolus* microcrystalline cellulose at levels of from 30 to 45 weight % Ceolus" product in the form of a tablet. However, there have been problems using the Ceolus* product. For example, at higher levels of Ceolus* product concentration, flow problems were encountered in the process of compressing tablets, and the Ceolus* product was considered unsuitable for compression at higher concentrations than about 45 weight %. The is a definite need for solid levothyroxine (T4) and/or liothyronine (T3) (thyroid hormone drugs) pharmaceutical compositions, preferably in an immediate release solid dosage form, with the T4 and T3 in the form of their sodium salts that are. relatively stable. There is also 5 need for methods for making such immediate release and stabilized solid levothyroxine (T4) Ld/or liothyronine (T3) (thyroid hormone drugs) pharmaceutical compositions. Immary of the Invention The present invention overcomes and alleviates the above-mentioned drawbacks and sadvantages in the thyroid drug art through the discovery of novel oral levothyroxine (T4) id/or liothyronine (T3) (thyroid hormone drugs) pharmaceutical compositions and methods. Generally speaking, the present invention relates to stabilized solid as levothyroxine (T4) )dium and/or liothyronine (T3) sodium (thyroid hormone drugs) pharmaceutical compositions rid in particular, immediate release, stabilized pharmaceutical compositions that include harmaceutically active ingredients such as levothyroxine (T4) sodium and/or liothyronine (T3) odium (thyroid hormone drugs). Preferably but not necessarily, the novel pharmaceutical ompositions are provided in a solid dosage form, such as a tablet. The pharmaceUtical compositions of the present invention are useful for, among other things, as replacement or supplemental therapy in hypothyroidism of any etiology, except ransient hypothyroidism during the recovery phase of subacute thyroiditis, suppression of ituitary TSH secretion in the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, Hashimoto's thyroiditis, multinodular goiter and, as adjunctive therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer in warm blooded animals, especially humans including pediatrics. The present invention also provides methods for making such immediate release and stabilized levothyroxine (T4) sodium and/or liothyronine (T3) sodium (thyroid hormone drugs) pharmaceutical compositions. Also in accordance with the present invention, because of the extraordinary release characteristics of the preferred compositions, a method of administration to children and patients who have difficulty taking pills, wherein the solid composition having the appropriate dosage is simply put in an aqueous fluid, e.g., juice, where it dissolves in a matter of 1-3iminutes, and the patient can then ingest the fluid, and receive the appropriate dosage, is now made practical. The present invention has a wide range of important uses including providing pharmaceutically active levothyroxine ompositions with enhanced bioavailability, improved shelf life, and more reliable potency. 6 We have discovered immediate release pharmaceutical compositions that include as harmaceutically active ingredients at least one of levothyroxine and liothyronine, preferably at -ast one levothyroxine salt, as the major active ingredient. Such preferred immediate release compositions desirably provide at least about 85% (w/v) dissolution of the levothyroxine salt in ess than about 20 minutes as determined by standard assays disclosed herein. Surprisingly, it as been found that by combining the pharmaceutically active ingredients with specific additives n accordance with the invention, it is possible to formulate the compositions so that the ngredients are released almost immediately after ingestion or contact with an aqueous solution, ,.g., in a matter of minutes. Preferred invention compositions are stable and provide better shelf ife and potency characteristics than prior pharmaceutical compositions. The immediate release pharmaceutical compositions of the invention provide important ises .and advantages. A major advantage is the stability of the active ingredients in the composition. For example, while, as indicated above, prior formulations with sugars, starches, and various types of celluloses, including micro-cellular celluloses such as the Avicel products, have experienced substantial degradation of.the active ingredients, e.g. T4 sodium. To deal with this problem, pharmaceutical manufacturers have- over-formulated the T4-containing pharmaceutical compositions containing such active ingredients, so that the patient can obtain at least the prescribed dosage despite the carbohydrate-induced instability of the active ingredient. However, the patient who obtains the pharmaceutical immediately after it is made, receives an over-dosage of the active compound; whereas, the patient who has received the pharmaceutical after it has sat on the pharmacy shelf for an extended period, will receive an under-dosage of the active ingredient. In either, case, the patient receives the wrong dosage, with possible serious consequences. In sharp contrast, it has been surprisingly found that the use of the B-sheet microcrystalline cellulose in the compositions of the present invention substantially increase the stability of the thyroid hormone drugs, so that the patient obtains consistent potency over an extended shelf life, compared to prior thyroid hormone drug products. In this application, the term "stabilized", as applied to levothyroxine and/or liothyronine means that the loss of potency over the shelf life of the product is less than about 0.7 % potency per month, for at least about 18 months. Preferred compositions have a loss of potency of less than about 0.5% per month for 7 ch a period, and more preferred compositions have a loss of potency of less than about 0.3%. r month for such a period. Further, the compositions of the invention provide favorable pharmacokinetic Characteristics when compared to prior formulations. In particular, the immediate-release pharmaceutical compositions that include levothyroxine salt have are more quickly available for sorption by the gastrointestinal (GI) tract faster and are absorbed more completely than has ,retofore been possible. This invention feature substantially enhances levothyroxine oavailability, thereby improving efficacy and reliability of many standard thyroid hormone :placement strategies. Additionally, the desirable immediate release characteristics of the present invention cilitate dosing of patients who may be generally adverse to thyroid hormone replacement strategies involving solid dosing. More specifically, immediate release pharmaceutical compositions disclosed herein can be rapidly dissolved in an appropriate aqueous solution (e.g., rater, saline, juice) or colloidal suspension (e.g., baby formula or milk) for convenient administration to such patients. Illustrative of such patients include infants, children, and adults vho may experience swallowing difficulties. The invention thus makes standard thyroid hormone replacement strategies more flexible and reliable for such patients. Accordingly, and in one embodiment, the invention features an immediate release >harmaceutical composition comprising at least one levothyroxine salt, preferably one of such a ;alt. At least about 80% of the levothyroxine dissolves in aqueous solution in less than about 20 minutes as determined by a standard assay, disclosed herein. Preferably, at least about 80% of the levothyroxine is dissolved in the aqueous solution by about 15 minutes from the time that the composition, in pill form, is placed in the aqueous solution. More preferably, at least about 85% of the levothyroxine is released to the aqueous solution by about 10 minutes, most preferably by about 5 minutes after exposure of the composition to the aqueous solution. As shown below, compositions in accordance with the present invention can be formulated to release 85% of the levothyroxine within 2-3 minutes after exposure to the aqueous solution. It has been found that by combining one or more of the pharmaceutically active agents with B-form microcrystalline cellulose, it is possible to produce compositions with favorable immediate release characteristics. Without wishing to be bound to theory, it is believed that the agents do not bind well to certain grades of the B - sheet form microcrystalline cellulose. More 8 E the agent is thus available for immediate release. In contrast, it is believed that many prior rmulations have active agents that bind cellulose additives, making less available. The release characteristics of the compositions of the invention are also improved by the use of other agents, ,disciissed further below. Thus in one embodiment, the present invention relates to a stabilized pharmaceutical position comprising. a pharmaceutically active ingredient, such as levothyroxine, and the B heet form of microcrystalline cellulose, in the form of a solid dosage. More specifically, the resent invention relates to. a stabilized pharmaceutical composition comprising a harmaceutically active ingredient, such as levothyroxine sodium and/or liothyronine sodium, at east about 50 weight % of the dosage weight composed of the B - sheet form of microcrystalline ellulose, and, optionally, additional excipients, in a solid dosage form. In another aspect, the invention provides, an aqueous solution or colloidal suspension that includes at least one of the compositions of this invention, preferably between from about one to bout five of same, more preferably about one of such compositions. It has also been found that B - sheet microcrystalline cellulose grades having preferred ,ulk densities provide for more compact processing than use of other celluloses. That is, use of he B - sheet microcrystalline cellulose having bulk densities in accord with this invention helps o provide for higher compression ratios (initial volume/final volume). As discussed below, other invention aspects help reduce or avoid production of damaging compression heat that has damaged prior formulations made from high compression ratios. The compositions of the present invention generally also require less compressional force to form the tablets. Accordingly, the invention also provides methods for making an immediate release pharmaceutical composition comprising at least one levothyroxine salt, preferably one of such a salt. In one embodiment, the method includes at least one and preferably all of the following steps: a) mixing a levothyroxine salt with microcrystalline B-cellulose and preferably a crosscarmellose salt to make a blend; and b) compressing the blend in a ratio of initial volume to final volume of between from about 2:1 to about 5:1 to make the composition, preferably about 4:1. 9 In one embodiment, the method involves preparing an oral dosage form of a harmaceutically active ingredient comprising dry blending the pharmaceutically active igredient and at least about 50 weight % of the B - sheet form of microcrystalline cellulose, and ompressing the blend to form a solid dosage. These and other objects, features, and advantages of the present invention may be better understood and appreciated from the following detailed description of the embodiments thereof, elected for purposes of illustration and shown in the accompanying figures and examples. It hould therefore be understood that the particular embodiments illustrating the present invention re exemplary only and not to be regarded as limitations of the present invention. Brief Description of the Fig. The foregoing and other objects, advantages and features of the invention, and the manner in which the same are accomplished, will become more readily apparent upon consideration of the following detailed description of the invention taken in conjunction with the accompanying Figs., which illustrate a preferred and exemplary embodiment, wherein: Figures lA - IC illustrate various solid dosage forms such as cylindrical tablets and raised violin shaped tablets; Figure 2 illustrates a tableting die pair; Figure 3 pair; is graphical depiction of comparative dissolution data of various strengths of Levoxyl* tablets made in accordance with the invention. Figure 4A is an HPLC chromatogram showing a levothryoxine and liothyronine standards. Figure 4B is an HPLC chromatograph showing results of levothyroxine sodium sample made in accordance with the present invention. Figure 5A is a chromatogram showing various levothryoxine impurity standards. Figure 5B is a chromatograph showing results of levothyroxine sodium sample made in accordance with the present invention. 10 detailed Description By way of illustrating and providing a more complete appreciation of the present vention and rnany of the attendant advantages thereof, the following detailed description is ven concerning the novel oral levothyroxine (T4) and/or liothyronine (T3) (thyroid hormone ugs) pharmaceutical compositions and methods for use in warm-blooded animals, especially humans and children. As discussed, the invention relates to immediate release solid pharmaceutical positionss such as stabilized pharmaceutical compositions that include pharmaceutically jtive ingredients such as levothyroxine (T4) sodium and liothyronine (T3) sodium (thyroid ormone drugs), preferably in a solid dosage. form. Also provided are methods for making such mediate release and stabilized compositions. Aspects of the present invention have been disclosed in U.S. Provisional Application No. 0/269,08 9, entitled Stabilized Pharmaceutical and Thyroid Hormone Compositions and Method f Preparation and filed on February 15, 2001 by Franz, G.A. et al. The disclosure of said rovisional application is incorporated herein by reference. By the phrase "immediate release" is meant a pharmaceutical composition in which one >r more active agents therein demonstrates at least about 80% (w/v) dissolution, preferably >etween from about 90% (w/v) to about 95% (w/v), more preferably about 95% (w/v) to about )9% (w/v) or more within 15 to 20 minutes as determined by a standard dissolution test. Suitable standard dissolution tests are known in the field. See FDA, Center for Drug Research, Guidance for Industry, In Vivo Pharmacokinetics and Bioavailability Studies and In Vitro Dissolution Testing for Levothyroxine Sodium Tablets, available at www~fda.gov/cder/guidance/index.htm. A specifically 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 exhibit good stability as determined by a standard potency test. More specifically, such compositions exhibit a potency loss of less than about 15%, preferably less than about 10%, more preferably less than about 1% to about 5% as determined by the test. Potency can be evaluated by one or a combination of strategies known in the field. See the USP. A preferred potency test compares loss or conversion of the active agent in the presence 11 xperimental) or absence (control) of a carrier or excipient. A specifically preferred potency st is provided in Examples 1 and 3, below. In preferred embodiments, the pharmaceutical compositions of the invention include, as native agent, levothyroxine (T4), preferably a salt thereof such as levothyroxine sodium USP. uch compositions typically exhibit a levothyroxine (T4) plasma Cmax of between from about 2 ptg/dl to about 16 pg/dl, preferably as determined by the standard Cmax test. Preferably, the i(Cmax) of the levothyroxine (T4) plasma level is between from about 1 to about 3. The standard Cmax test can be performed by one or a combination of strategies known in ie field. See e.g., the USP. A preferred Cmax test is disclosed below in Examples 8 and 9. Additionally preferred compositions in accord with the invention provide a riiodothyronine (T3) plasma Cmax of between from about 0.1 ng/ml to about long/ml, referably 0.5 ng/ml to about 2ng/ml, as determined by the standard Cmax test. Typically, the n(Cmax) is between from about 0.01 to about 5. See Examples 8 and 9 for more information. Further preferred compositions exhibit a levothyroxine (T4) plasma Tmax of between i-om about 0.5 hours to about 5 hours, preferably as determined by a standard Tmax test. The standard Tmax test can be performed by procedures generally known in the field. See e.g., the JSP. A preferred Tmax test is disclosed below in Examples 8 and 9. Still further preferred compositions of the invention exhibit a triiodothyronine (T3) plasma Tmax of between from about 10 hours to about 20 hours, preferably about 12 to about 16 hours as determined by the standard Tmax test. Additionally preferred invention compositions feature a levothyroxine (T4) plasma AUC (0-t) of between from about 450 pg-hour/dl to about 600 pg-hour/dl, preferably 500 ig-hour/dl to about 550 pg-hour/dl as determined by a standard AUC (0-t) test. Preferably, the In[AUC(0 t)] is between from about 1 to about 10. Standard methods for performing AUC (0-t) test determinations are generally known in the field. See e.g., the USP. Examples 8 and 9 below provide a specifically preferred method of determining the AUC (0-t). Further preferred invention compositions feature a triiodothyronine (T3) AUC (0-t) of between from about 10 ng-hour/ml to about 100 ng-hour/ml, preferably 20 ng-hour/ml to about 60 ng-hour/ml, as determined by the standard AUC (0-t) test. Preferably, the In[AUC(0-t)] is between from about I to about 5. 12 As will be appreciated, many prior pharmaceutical formulations include lactose or other gars as a pharmaceutically acceptable carrier. It has been found however, that sugars such as ctose can react with active agents including the levothyroxine (T4) compositions of the present vention. For example, and without wishing to be bound to theory, it is believed that lactose is Lrticularly damaging to T4 and T3 molecules via Schiff reactions. The invention address this problem by providing compositions that are essentially sugar-free. Particular invention positionss are essentially free of lactose. Additionally, preferred pharmaceutical compositions of the invention are provided in rhich the active material is a non-granulated material. Prior levothyroxine compositions have een granulated in various size reduction machines to grains of less than, e.g., 5 - 20 microns verage particle size in order to be effectively incorporated into the administrable pharmaceutical imposition. The granulation process subjects the active material to degrading heat, which can ave adverse effects on the active material, as well as reducing the activity level. Prior manufacturers purchase micronized levothyroxine manufactured under DMF No. 4789, and then ;ranulate it before incorporating it into the levothyroxine pharmaceutical product. In the preferred method of the present invention, the raw material is not granulated before corporation into the pharmaceutical composition. Rather, the ingredients of the preferred >harmaceutical are mixed and the mixture is subjected to direct compression to form the pharmaceutical tablets of appropriate dosage. As a result, the activity of the active ingredient is rnot. degraded prior to the direct compression step. Bulk levothyroxine is obtained in a fine powdered form, preferably from Biochemie GmbH, A-6250 Kundl, Austria. More importantly, the use of the preferred process results in a product which is immediately dispersible in aqueous solution, to make the active ingredient available for absorption in the body. As used in this application, "non-granulated" means that the bulk USP compound is used without subjecting it to granulators or similar high energy size reduction equipment before being mixed with the other pharmaceutical components and formed into the appropriate pill. Preferably, the bulk active ingredient is mixed with the appropriate amounts of other ingredients and directly compressed into pill form. Since it is not necessary to granulate the material, it is not necessary to subject it to degrading temperatures in the process of forming the pharmaceutical compositions containing the active materials. In the present process we start with micronized active material, which merely needs to be blended with the B and other materials and then compressed. Others have to 13 'e granulated, and then dried, which steps interfere with the dissolution of the active material. 'he drying temperatures employed in manufacturing other active ingredients can cause degradation of the levothyroxine, as experienced in other available thyroxine. It has been found hat providing the invention compositions in a non-granulated format helps to reduce or liminate active agent degradation, presumably by facilitating a reduction in friction, and thus Legrading heat, during compression of the compositions into pills. Practice of the invention is compatible with several p-form microcrystalline cellulose grades. Preferably, the p-form microcrystalline cellulose has a bulk density of between from bout 0.10 g/cm 3 to about 0.35 g/cm 3 , more preferably between from about 0.15 g/cm 3 to about ).25 g/cm 3 , still more preferably between from about 0.17 g/cm 3 to about 0.23 g/cm 3 , most preferably between from about 0.19 g/cm 3 to about 0.21 g/cm 3 . Further preferred grades of the p-form microcrystalline cellulose are substantially non conductive. Preferably, the p-form microcrystalline cellulose has a conductivity of less than about 200 pS/cm, more preferably, less than about 75 pS/cm, still more preferably between from about 0.5 pS/cm to 50 pS/cm, most preferably between from about 15 p.S/cm to 30 p.S/cm. A specifically preferred p-form microcrystalline cellulose is sold by Asahi Chemical Industry Co., Ltd (Tokyo, Japan) as Ceolus (Type KG-801 and/or KG-802). Additionally preferred compositions of the invention have a post-packaging potency of between from about 95% to about 120%, preferably 98% to about 110% as determined by the standard potency test. The present invention is a pharmaceutical product that is in the form of a solid dosage, such as a sublingual lozenge, buccal tablet, oral lozenge, suppository or a compressed tablet. The pharmaceutically active ingredient is dry mixed with the p-form of the microcrystalline cellulose, optionally with additional excipients, and formed into a suitable solid dosage. Preferred tablets according to the invention have a total hardness of between from about 1 to about 30 KP, preferably about 6 to about 14 KP as determined by a standard hardness test. Methods for determining tablet hardness are generally known in the field. See e.g., the USP. A preferred standard hardness test is disclosed below in Example 4. Additionally preferred pharmaceutical compositions including those in tablet format preferably include less than about 10% total impurities, more preferably less than about 5% of same as determined by a standard impurity test. 14 Reference herein to the "standard impurity test" means a USP recognized assay for stecting and preferably quantitating active drug degradation products. In embodiments in hich levothyroxine or liothyronine break-downs are to be monitored, such products include, ut are not limited to, at least one of diiodothyronine (T2), triiodothyronine (T3),.levothyroxine, iiodothyroacetic acid amide, triiodothyroethylamine, triiodothyroacetic acid, triiodothyroethyl cool, tetraiodothyroacetic acid amide, tetraiodothyroacetic acid, triiodothyroethane, and .traiodothyroethane. Of particular interest are diiodothyronine (T2), triiodothyronine (T3), -ijodothyroacetic acid, and tetraiodothyroacetic acid impurities. A preferred impurity test for monitoring levothyroxine and liothyronine breakdown roducts involves liquid chromatography (LC) separation and detection, more preferably HPLC. pecifically preferred impurity tests are provided below in Examples 5 and 6 Further preferred compositions in accord with the invention include one or more standard isintegrating agents, preferably crosscarmellose, more preferably a salt of same. Still further referred compositions include a pharmaceutically acceptable additive or excipient such as a nagnesium salt. The present invention can be prepared as a direct compression formula, dry granulation Eormula, or as a wet granulation formula, with or without preblending of the drug, although preferably with preblending. The pharmaceutically active ingredient can be any type of medication which acts locally in the mouth or systemically, which is the case of the latter, can be administered orally to transmit the active medicament into the gastrointestinal tract and into the blood, fluids and tissues of the body. Alternatively, the medicament can be of any type of medication which acts through the buccal tissues of the mouth to transmit the active ingredient directly into the blood stream thus avoiding first liver metabolism and by the gastric and intestinal fluids which often have an adverse inactivating or destructive action on many active ingredients unless they are specially protected against such fluids as by means of an enteric coating or the like. The active ingredient can also be of a type of medication which can be transmitted into the blood circulation through the rectal tissues. Representative active medicaments include antacids, antimicrobials, coronary dilators, peripheral vasodilators, anti psychotropics, antimanics, stimulants, antihistamines, laxatives, decongestants, vitamins, gastrosedatives, antidiarrheal preparations, vasodilators, antiarrythmics, 15.

isoconstrictors and migraine treatments, anticoagulants and antithrombotic drugs, analgesics, 1tihypnotics, sedatives. anticonvulsants, neuromuscular drugs, hyper and hypoglycemic agents, tyroid and antithyroid preparations, diuretics, antispasmodics, uterine relaxants, mineral and nutritional additives, antiobesity drugs, anabolic drugs, erythropoietic drugs, antiasthematics, xpectorants, cough suppressants, mucolytics, antiuricemic drugs, and drugs or substances acting >cally in the mouth. Typical active medicaments include gastrointestinal sedatives such as metoclopranide nd propantheline bromide, antacids such as aluminum trisilicate, aluminum hydroxide and imetidine, asprin-like drugs such as phenylbutazone, indomethacin, and naproxen. ibuprofen, lurbiprofen, diclofenac, dexamethasone, prednisone and prednisolone, coronary vasodialator Irugs such as glyceryl trinitrate, isosorbide dinitrate and pentaerythritol tetranitrate, peripheral md cerebral vasodilators such as soloctidilum, vincamine, naftidrofuryl oxalate, comesylate, :yclandelate, papaverine and nicotinic acid,. antimicrobials, such as erythromycin stearate, :ephalexin, nalidixic acid, tetracycline hydrochloride, ampicillin, flucolaxacillin sodium, examine mandelate and hexamine hippurate, neuroleptic drugs such as fluazepam, diazepam, temazepam, amitryptyline, doxepin, lithium carbonate, lithium sulfate, chlorpromazine, thioridazine, trifluperazine, fluphenazine, piperothiazine, haloperidol, maprotiline hydrochloride, inipramine and desmethylimipramline, central nervous stimulants such as methylphenidate, ephedrine, epinephrine, isoproterenol, amphetamine sulfate and amphetamine hydrochloride, anitidrugs such as. diphenylhydramine, diphenylpyramine, chlorpheniramine and brompheniram ine, antidiarrheal drugs such as bisacodyl and magnesium hydroxide, the laxative drug, dioctyl sodium sulfosuccinate, nutritional supplements such as ascorbic acid, alpha tocopherol, thiamine and pyridoxine, antispasmotics such as dicyclomine and diphenoxylate, drugs effecting the rhythm of the heart such as verapamil, nifedepine. diltiazem, procainamide, disopyramide, bretylium tosylate, quinidine sulfate and quinidine gluconate, drugs used in the treatment of hypertension such as propranolol hydrochloride, guanethidine monosulphate, methyldopa, oxprenolol hydrochloride, captopril, Actace and hydralazine, drugs used in the treatment of migraine such as ergotamine, drugs effecting coagulability of blood such as epsilon aminocaproic acid and protanine sulfate, analgesic drugs such as acetylsalicyclic acid, acetaminophen, codeine phosphate, codeine sulfate, oxycodone, dihydrocodeine tartrate, oxydodeinone, morphine, heroin, nalbuphine, butorphanol tartrate, pentazocine hydrochloride, 16 yclazacine, pethidine, buprenorphine, scopolamine and mefenamic acid, antidrugs such as henytoin sodium and sodium valproate, neuromuscular drugs such as dantrolene sodium, substances used in the treatment of diabetes, such as tolbutamide, diabenase glucagon and insulin, drugs used in the treatment of thyroid gland dysfunction such as triiodothyronine, othyronine sodium, levothyroxilne sodium and related compounds, and propylthiouracil, iuretic drugs, such as furosemide, chlorthalidone, hydrochlorthiazide, spironolactone and riampterene, the uterine relaxant drugritodrine, appetite suppressants such as fenfluramine hydrochloride, phentermine and diethylproprion hydrochloride,antidrugs stimulants such as uminophylline, theophylline, salbutamol, orciprenaline sulphate and terbutaline sulphate, expectorant drug such as guaiphenesin, cough suppressants such as dextromethorphan and mescaline, mucolytic drugs such as carbocisteine, antiseptics such as cetylpyridinium chloride, tyrothricin and chlorhexidine, decongestant drugs such as phenylpropanolamine and pseudoephedrine, hypnotic drugs such as dichloralphenazone and nitrazepam,antidrugs H, blockers such as promethazine theociate, haernopoetic drugs such as ferrous sulphate, folic acid and calcium gluconate, uricosuric drugs such as sulphinpyrazine, allopurinol and probenecid and the like. It is understood that the invention is not restricted to the above medications. The amount of pharmaceutically active ingredient in the present composition can vary widely, as desired. Preferably, the active ingredient is present in a composition of the present invention in an effective dosage amount. Exemplary of a range that the active ingredient may be present in a composition in accordance with the present invention is from about 0.000001 to about 10 weight %. More preferably, the amount of active ingredient is present in the range of about 0.001 to 5 weight %. Of course, it should be understood that any suitable pharmaceutically acceptable form of the active ingredient can be employed in the compositions of the present invention, i.e., the free base or a pharmaceutically acceptable salt thereof, e.g., levothyroxine sodium salt, etc. When the pharmaceutically active moiety is levothyroxine sodium, the preferred amount of the active moiety in the composition is present in the range of about 0.00005 to about 5 weight %. The more preferred range is from about 0.001 to about 1.0 weight %, and the most preferred range is from about 0.002 to about 0.6 weight % levothyroxine. The minimum amount of levothyroxine can vary, so long as in effective amount is utilized to cause the desired pharmacological effect. Typically, the dosage forms have a content of levothyroxine in the range 17 f about 25 to 300 micrograms per 145 milligram pill for human applications, and about 100 to 00 micrograms per 145 mg pill for veterinary applications. In accordance with the present invention, a goal of levothyroxine replacement therapy is > achieve and maintain a clinical and biochemical euthyroid state, whereas a goal of suppressive ierapy is to inhibit growth and/or function of abnormal thyroid tissue. A dose of levothyroxine iat is adequate to achieve these goals depends of course on a variety of factors including the atient's age, body weight, cardiovascular status, concomitant medical conditions, including regnancy, concomitant medications, and the specific nature of the condition being treated. ience, the following recommendations serve only as dosing guidelines. It should be understood y those versed in this art that dosing should be individualized and adjustments made based on eriodic assessment of a patient's clinical response and laboratory parameters. Preferably, but not necessarily, when using levothyroxine to treat, it should be taken in he morning on an empty stomach, at least one-half hour before any food is eaten. In addition, evothyroxine is preferably taken at least about 4 hours apart from drugs that are known to nterfere with its absorption. Due to the long half-life of levothyroxine, the peak therapeutic effect at a given dose of levothyroxine sodium may not be attained for about 4 to about 6 weeks. In people older than 50 years, who have been recently treated for hyperthyroidism or who have been hypothyroid for only a short time (such as a few months), the average full replacement dose of levothyroxine sodium is approximately 1.7 mcg/kg/day (e.g.; about 100 to about 125 mcg/day for a 70 kg adult). Older patients may require less than 1 mcg/kg/day. Levothyroxine sodium doses greater than about 200 mcg/day may or may not be required. For most patients older than 50 years or for patients under 50 years of age with underlying cardiac disease, an initial starting dose of about 25 to about 50 mcg/day of levothyroxine sodium is recommended, with gradual increments in dose at about 6 to about 8 week intervals, as needed. The recommended starting dose of levothyroxine sodium in elderly patients with cardiac disease is about 12.5 to about 25 mcg/day, with gradual dose increments at about 4 to about 6 week intervals. The levothyroxine sodium dose is generally adjusted in about 12.5 to about 25 mcg increments until the patient with primary hypothyroidism is clinically euthyroid and the serum TSH has normalized. 18 In patients with severe hypothyroidism, the recommended initial levothyroxine sodium >se is about 12.5 to about 25 meg/day with increases of about 25 meg/day about every 2 to out 4 weeks, accompanied by clinical and laboratory assessment, until the TSH level is realizedd. In patients with secondary (pituitary)or tertiary (hypothalamic) hypothyroidism, the vothyroxine sodium dose should be titrated until the patient is clinically euthyroid and the -rum free-T4 level is restored to the upper half of the normal range. In children, levothyroxine therapy may be instituted at full replacement doses as soon as possible. Levothyroxine compositions of the present invention may be administered to infants nd children who cannot swallow intact tablets by crushing the tablet and suspending the freshly rushed tablet in a small amount (5-10 mL or 1-2 teaspoons) of water. This suspension can be administered by spoon or dropper. Foods that decrease absorption of levothyroxine, such as oybean infant formula, should not be used for administering levothyroxine sodium tablets. A recommended starting dose of levothyroxine sodium in newborn infants is about 10 to bout 15 mcg/kg/day. A lower starting dose (e.g., about 25 mcg/day) may be considered in infants at risk for cardiac failure, and the dose should be increased in 4-6 weeks as needed based >n clinical and laboratory response to treatment. In infants with very low (< about 5 mcg/dL) or detectable serum T 4 concentrations, a recommended initial starting dose is about 50 mcg/day >f levothyroxine sodium. As indicated above, levothyroxine therapy is usually initiated at full replacement doses, with the recommended dose per body weight decreasing with age (see Dose Table below). However, in children with chronic or severe hypothyroidism, an initial dose of about 25 mcg/day of levothyroxine sodium is recommended with increments of 25 mcg every 2-4 weeks until the desired effect is achieved. Hyperactivity in an older child may be minimized if the starting dose is one-fourth of the recommended full replacement dose, and the dose is then increased on a weekly basis by an amount equal to one-fourth the full-recommended replacement dose until the full recommended replacement dose is reached. 19 Dose Table: Levothyroidne Sodium Dosing Guidelines for Pediatric Hypothyroidism AGE Daily Dose per Kg Boy Weights. -3 months 10-15 mcg/kg/day -6 months 8-10 megfkg/day -12 months 6-8 mcg/kg/day -5 years 5-6 mcg /kg/day -12 years 4-5 mcgc/kg/day 12 years2-mcfkgda 1. mg/g/day r abdowth adpberty complete ' 1.7 meg/k/day 'he dose should be adjusted based on clinical response and laboratory parameters. Levothyroxine sodium tablets, USP, in accordance with the present invention may be applied as oval or violin-shaped, color-coded, potency marked tablets in, for example, 12 lengths as indicated in the Strength Table Strength Levothyroxine Table Tablets Strength Color mcg 25 Orange 50 'te 75 Purple 88 Olive 100 ellow 112 Rose 125 Brown 137 Dark Blue 150 Blue 175 r uiose 200 Pink 300 Green When the pharmaceutically active moiety is liothyronine sodium, the preferred amount of the active moiety in the composition is present in the range of about 0.000005 to 0.5 weight %. The more preferred range is from about 0.00001 to 0.1 weight %, and the most preferred range is from about 0.00004 to about 0.002 weight % liothyronine. The minimum amount-of lyothyronine can vary, so long as an effective amount is utilized to cause the desired pharmacological effect. 20 rpically, the dosage forms have a content of levothyroxine in the range of about 5 to 50 icrograms per 145 milligram pill for human applications. The B-form microcrystalline cellulose product of the present invention is prepared by rming a wet cake, drying the cake with a drum dryer, then passing the dried product through a green or mill for sizing which produces a B-sheet microcrystalline cellulose which has a flat -edle shape, as disclosed in U.S. Patent 5,574,150. Such B-sheet microcrystalline product is railable from Asahi Chemical of Japan and/or marketed by FMC Company of Newark, Del, ader the trademark Ceolus@. The morphology and performance characteristics of the Ceolus@ product are different from those of a - form microcellulose products (for example, Avicel® and mcocel®), and are suitable for preparing the present stabilized pharmaceutical composition. The amount of B-form microcrystalline product used in the present composition is at least 0 weight % of the final composition. Preferably, the amount of B-form microcrystalline product * in the range of about 50 to 99 weight %. Most preferably, the amount of 13-form icrocrystalline product is in the range of about 60 to.90 weight % of the final composition. Other suitable excipients for the present invention include fillers such as starch, alkaline norganic salts such as trisodium phosphate, tricalciun phosphate, calcium sulfate and sodium or nagnesium carbonate. The fillers can be preseiit in the present composition in the range of about )to 50 weight %. Suitable disintegrating agents include corn starch, cross-linked sodium carboxymethylcellulose (crosscarmellose) and cross-linked polyvinyipyrrolidone (crospovidone). A preferred disintegrating agent is crosscarmellose. The amount of disintegrating agent used is in the range of about 0 to 50 weight %. Preferably, the disintegrating agent is in the range of about 5 to 40 weight %, more preferably about 10 to about 30 weight %. This is in substantial excess of the recommended levels of such materials. For example, the recommended loading of crosscarmellose is 0.5 to about 2% by weight. However, it has been found that the higher loadings of the disintegrating agents substantially improves the ability of the product to disperse in aqueous media. Suitable gildents for use in the present invention include colloidal silicon dioxide and talc. The amount of gildent in the present composition is from about 0 to 5 weight %, and the preferred amount is about 0 to 2 weight %/. 21 Suitable lubricants include magnesium and zinc stearate. sodium stearate fumarate and dium and magnesium lauryl sulfate. A preferred lubricant is magnesium stearate. The amount E lubricant is typically in the range of about 0 to 5 weight %, preferably in the range of about 1 to 3 weight %. The oral pharmaceutical product is prepared by thoroughly intermixing the active moiety ad the B-form of microcrystalline cellulose, along with other excipients to form the oral dosage. ood grade dyes can also be added. For example, it is common to distinguish dosages of various otency by the color characteristics of such dyes. As discussed, a preferred immediate release pharmaceutical composition in tablet form acludes levothyroxine sodium. In a preferred embodiment, the composition includes at least ne of, preferably all of the following: a) between from about 0.01 mg/tablet to about 500 mg/tablet levothyroxine sodium (USP), b) between from about 100 mg/tablet to about 110 mg/tablet of microcrystalline B-cellulose, NF (Ceolus) having a bulk density of between from about 0.10 g/cm 3 to about 0.35 g/cm 3 , c) between from about 25mg/tablet to about 50mg/tablet of crosscarmellose sodium, NF (Ac-di-sol); and d) between from about 0.5 mg/tablet to about 5mg/tablet of magnesium stearate, NF. Preferably, the composition further comprises at least one pharmaceutically acceptable coloring agent. More particular methods according to the invention provide compositions having less than about 5% total impurities as determined by the standard impurity test. Preferably, the method further comprises forming a tablet, particularly those tablets having a raised violin configuration. The stabilized oral dosages of thyroid hormone are prepared by forming a trituration of the active moiety (i.e. levothyroxine sodium and/or liothyronine sodium) and B-form 22 icrocrystalline cellulose. The trituration is blended with B-form microcrystalline cellulose and additional excipients and compressed into oral dosages. Design of the tableting apparatus is important, in order to maintain consistency from one ral dosage to the next. The formulation batches are a blend of solid compositions of various shapes and sizes. Blending is used to achieve a measure of homogeneity. In particular the active iyroid moiety is desired to be evenly distributed throughout the batch. In a typical 410 kg batch, he amount of active moiety represents less than 1 kg of the total weight. For example, when roducing 145 mg tablets with a 300 mcg dosage, approximately 0.8 kg of a 410 kg batch is the active moiety. In addition each tablet is formulated to contain 100% label claim potency. It is- typical for compressible medicament tablets to be formed using a 2:1 fill to ompression ratio. However, for medicament tablets formed using the present invention a fill to impression ratio from 3.3:1 to 4:1 is needed to obtain desired tablet density. The B-form microcrystalline cellulose has a lower bulk density, as compared to other excipients. Higher tablet density can be accomplished by adjusting a tableting machine to increase the compression ratio. Tableting machines are commonly known to practitioners in the art and include those available from Manesty and Stokes. It has been found that making such adjustments to the compression ratio results in poor tablet surface finish as well as inconsistent tablet weights. Instead, the design of the tableting dies should be adjusted. It has been determined that during the filling of the tableting dies, a minimum of 5-6mm die overfill. In most cases this requires replacement of the usual tableting dies with dies which are an additional 2-3 mm deep. When using the extra-deep dies and a compression ratio of from 3.3:1 to 4.0:1, consistent weight tablets with good surface finish were produced. Preferably, the shape of the tablet is configured to increase heat transfer away from the tablet. More preferred tablets have a surface area per tablet of between from about 0.9 in? to about 0.15 in.

2 , preferably about 0.115in.

2 , to assist such heat transfer. -Additional tablet configurations are contemplated e.g., tablets that are beveled and/or include a notch. A preferred tablet shape is a raised violin configuration, as shown in Figure 1C. The following examples are given by way of illustration only and are not to be considered limitations of this invention or many apparent variations of which are possible without departing from the spirit or scope thereof. 23 Example 1 Stability Tests Stability testing was performed on samples of the thyroid hormone drug formulation used i manufacturing tablets with an active moiety of levothyroxine sodium. Tests were performed n direct compression formulations for dosage strength of 25 meg. Example 1 tablets comprise 1e f-form microcrystalline cellulose while Control I tablets comprise the traditional -for m iicrocrystalline cellulose. The composition of Example 1 and Control 1 tablets are presented in able I and stability test results in Table 2: Table I - Tablet Formulation for 25mcg Dosages of Levothyroxine Sodium Exa ple 1 Control 1 Component Tablet Tablet 0.0297 mg 0.0297 mg Levothyroxine Sodium, USP 108.55 mg B - sheet microcrystalline cellulose 108.55 mg p - form microcrystalline cellulose 35.079 mg 35.079 mg Crosscarnellose Sodium, NF 0.352 mg 0.352 mg FD&C Yellow #6 16% (14-20% 1068 mg 1.018 mg Magnesium Stearate, NF 145.0 mg 145.0 mg Total Table 2 - Stability Test - Potency at 25 0 C - % Label Claim lapsed Time 0 73 Days 13 months 15 months ample ITablet- 106.4 105.5 104.4 102.9 example 1 % Potency 0.0 0.9 % 2.0% 3.5% Lo~ss Change per Month 0.0 0.37 0.15 0.23 control 1 Tablet 99.2 89.5 85.0 83.2 control I % Potency Loss 0.0 2.7% 14.2 % 16.0 % %Change per Month 0.0 1.11 1.09 1.07 24 As seen in Table 2, the stability of pharmaceutical formulations of the present invention improved significantly by the use of the B - sheet microcrystalline cellulose. Potency loss of e present invention after 15 months is 3.5 %, versus 16.0 % potency loss experienced in a milar formulation with the a-form microcrystalline cellulose. The average loss- in potency per Lonth in the case of the compositions of the present invention was only about 0.2 % per month, compared to over 1% per month for the T4 products which included p-form microcrystalline :llulose, thus demonstrating a stability which is about 3 to 4 times better than the T4 products rhich utilized a-form microcrystalline cellulose. Tableting testing was performed on the formulation for Example 1 tablets. Initial results rith standard die depths provided a relative standard deviation of 2.2 to 3.5% tablet weight. With te use of the herein described extra deep tablet dies, the relative standard deviation is 1.2%. esting was performed on a Manesty tableting machine with compression ratios of from 3.3:1 to .0:1. Tablet quality is also dependent upon the storage of the B-sheet microcrystalline ellulose. Best results are achieved when the cellulose is received in drums or portable containers nstead of bags. The bag form suffers from compression during transportation from raw material uppliers. Test results for tableting are presented in attached Exhibit A. Additional examples of solid dosage formulations are illustrated in Tables 3 and 4. Stability testing data of additional examples are illustrated in Table 5. Table 3 - Tablet Formulation for Dosages of Levothyroxine Sodium (per tablet) 25 mcg Dosage 50 mcg Dosage 75 mcg Dosage Component 0.025 mg 0.0500 mg 0.0750 mg levothyroxule sodium 108.529 mg 108.856 mg 108.438 mg B-form microcrystalline cellulose 35.079 mg 35.079 mg 35.079 mg crosscarmellose sodium 0.352 mg 0.383 mg food grade dye 1.018 mg 1.018 mg 1.018 mg magnesium stearate 145 mg/tablet 145 mg/tablet 145 mg/tablet Total 25 Table 4 - Tablet Formulation for Dosages of Levothyroxine Sodium (per tablet) 30 cg osae 112 mcg Dosage 30mgDsg opnn 100 mg - 0.112 mg 030m eohr!iesoium 8.406 mug 107.71 1 mg 108.451 mg B-form microcrystalline cellulose 5.079 ng 35.079 mg3509m rscmelesoiu .388 mg 1.080 mg 0.142mg foodgradedye .018 mg 1.018 mg 1.1018 mg magnesium stearate 45 mg/tablet 145 mg/tablet 145 mg/tablet Total Table 5 shows drug stability data for a number of the above formulations: Table S - Stability Test - Potency at 25 0 C - % Label Claim Leo0 0 Na Levothyroxine r (months) Test Luiti 6 12 18 25 jig Dose 26.2 25.6 25.5 25.3 %Label. 111ai 8m 104. 102. 102. 101. % of Initial Result 1--. 97.5 97.3 96.6 lo Change 0.0 2.6 2.8 .6 % Change per month 0.0 0.43 0.23 0.2 50 ptG Dose 51.0 49. 48.9 48.4 % Label Claim 02. 99.7 97.7 96.7 % of Initial Result 100. 97.7 95.8 94.8 %0.0 2.3 4.3 5.3 % Change per month 0.0 0.38 0.36 0.29 112 pG Dose 113. 109. 105. %Label Claim 11 0. 97.8 94.5 % of Initial Result 100 . 96.6 93.4 % Change 0.0 0.3 3A 6.7 % Change per month 0. 0.05 0.28 0.37 200 pg Dose 202. 196. 198. 196. % Label Claim 101. 98.4 99.3 98.3 % of Initial Result 100. 973 98.2 97.2 % Change 00 27 17 2 % Change per month 0.14 0.15 26 Thus the formulations of the present invention provide extreme stability for the vothyroxine activity over an extended shelf life for these pharmaceutical products. Example 2 Dissolution Tests The following preferred method for testing potency will sometimes be referred to herein s method number: AM-004B Table 6 -Dissolution Test Procedure Chromatographic Conditions Mobile Phase: Degassed and filtered mixture o methanol and 0.1 phosphoric acid (60:40). Column: Cis3.9 nmxjNcm Flow Rate: 2.0 nl/minute Detector: Deuteriur set at 225 nm Injection Volume: 800 pL Syte Suitability: Chromatograph 6 replicate injecions of the stnadpreparation. SystemSuitability: Medium:0. hydrochloric acid containing 0.2% sodium lauryl sulfate; 500 ±5 ml; 37 =I 0.5 0 C This solution is very foamy; excessive mixing, shaking, and pouring will make reading the meniscus on the graduated cylinder difficult. Apparatus: Apparatus 2 (Paddles) Apparatus Cleaning: The apparatus is to be cleaned immediately after use or if left idle for more than 12 hours. Clean paddles by rinsing with distilled Paddle Speed: 5 p weasedrnileeixueo methanol and ditle0ae gi.1% hosphorwit Ibation Period: up to 45 minutes 27 Standard Solutions: Transfer about 50 mg USP Levothyroxine RS, accurately weighed, into a 100 ml volumetric flask. Add approximately 30 ml of methanol, dissolve and dilute to volume with methanol, mix. Using this solution, standard solutions are prepared in a volumetric flask using Dissolution Media, diluting to a concentration that comes near to the theoretical concentration of the tablet in 500 ml of Dissolution Media. Use a pipette to gently add the Dissolution media to prevent foaming. *Calculate and use the actual concentration in % Dissoluted equation Sample Preparation: One tablet is placed into each vessel of the dissolution apparatus. Sample each vessel after the incubation time, as stated above. Pass a portion of the sample through a 0.45 micron filter sufficient to equilibrate the filer. Filters are to be pre-qualified according to SOP (C1-730). Use a new filter for each vessel. Procedure: Inject 800 pl of standard and sample into the column and record the chromatograms. Measure the responses of the major peaks. Calculate the amount of Levothyroxine dissolved in each vessel by the formula below. -alculations: Sample Area x 798.86 x Amt. Std. Injected x 100% = % Dissoluted o Dissoluted Std. Area 776.87 Amt. Samp. Injected Where 798.86 = molecular weight of Levothyroxine as Sodium Salt 776.87 = molecular weight of Levothyroxine (as Base) Table 7- Acceptance Criteria STAGE #TESTED ACCEPTANCE CRITERIA Q =70% 6 Each unit is not less than Q + 5% S-2 6 Average of 12 units (S-I + S-2) is equal to or greater than Q, and no unit is less than Q-15% ~S-3 - 12 Average of 24 units (S-i + S-2 + S-3) is equal to or greater than Q and not more than 2 units are less than Q-15%, and no unit is less than Q-25% Table 8 shows comparative dissolution data for all strengths of Levoxyl t tablets. 28 Table 8 - Comparative Dissolution Data 0 minutes 1 minute 2.5 minute 5 minutes 7.5 minutes 10 minutes 25 mcg 0.0% 84.9% 93.7% 90.9% 88.6% 84.7% 50 meg 0.0% 82.8% 92.7% 91.8% 87.8% 84.4% 75 meg 0.0% 78.9% 93.6% 92.2% 88,3% 84.7% 88 mcg 0.0% 79.8% 95.6% 94.1 % 90.5% 86.9% 100 mcg 0.0%85.4% 94.8% 94.5% 90.7% 86.5% 112 mcg 0.0% 75.5% 91.1% 90.7% 87.0% 82.9% 125 mcg 0.0% 75.0% 96.5% 95.5% 91.7% 87.8% 137 mcg 0.0% 79.9% 93.9% 93.2% 89.4% 85.7% 150 mcg 0.0% 75.6% 91.9% 91.% 88.7% 84.6% 175 mcg 0.0% 84.2% 95.7% 93.5% 90.3% 85.5% 200 mcg 0.0% 76.5% 94.9% 94.6% 91.0% 87.6% 300 mcg 0.0% 74.5% 92.1% 91.4% 87.9% 84.0% Figure 4 depicts graphs showing the mean results for each of the tablet strengths of Levoxyl* tested. Each point is the mean of three dissolutions, testing 12 tablets per dissolution Dr n=36. The data is presented as percent of label claim dissoluted vs. dissolution time. The results demonstrate that the multi-point dissolution profiles for Levoxyl" tablets are similar across a wide variety of tablet strengths. Moreover, all strengths substantially exceed the requirements for immediate release oral dosage forms (i.e. at least 80% dissoluted with 15 - 20 minutes). In each dosage form, these pills were over 90% dissoluted within two and a half minutes. The extremely rapid dispersion rates for the tablets of the present invention make possible a simplified treatment method for infants or others who have difficulty swallowing pills. In this approach, the appropriate dosage for the patient in question, in an immediate release pill made in accordance with the present invention, is simply mixed with a suitable amount, e.g. 50 200 ml, of aqueous fluid, such as water, soft drinks, juice, milk, etc. The immediate release pill is easily dissoluted in the fluid, optionally with stirring or shaking, and simply administered to the patient. Example 3 Potency Test The following method for testing potency of the tablets will sometimes be referred to herein as method number: AM-003. Alternatively, the tablet potency can be tested according to method AM-021. Method number: AM-021 is the same as method number: AM-003, except the 29 iblets are dissolved whole without first grinding the tablets into a powder, as with method umber: AM-003. method Reference: USP 24 pp. 968-970 -hromatographic Conditions: Mobile Phase: 65:35:0.05 H20: CAN: H3PO4 degassed and filtered; mobile phase omposition may be altered to achieve a satisfactory resolution factor. column: ACN, 4.6 mm x 25 to 30 cm Flow Rate: 1.5 ml/minute Detector: Deuterium, set at 225 nm Injection Volume: 100 ml System SuitabilitY: Chromatograph 5 replicate injections of the standard preparation. Record the peak responses as directed under "Procedure". 1.0 RSD for the standard replicates must not be more than 2.0% for T4. 2.0 Calculate the resolution factor R on one of the five replicates. The R-value must be greater than or equal to 5.0 to proceed. See Method QC-009. 30 andard Preparation: Accurately weight 25 mg of USP Levothyroxine RS and transfer to an amber 250-mi jlumetric flask. Add approximately 50ml extraction mobile phase. Let stand for 20 minutes ith occasional swirling. Sonicate for 30 seconds. Gradually add more extraction solution and :peat sonication until no undissolved particles are observed. Dilute to volume with extraction )lution. Mix well. The concentration of T 4 is about 100 pg/ml. Also dissolve an accurately weighed quantity of USP Liothyronine RS to yield about 100 mg/ml, done as above with USP evothyroxine RS. Label this solution as stock T 3 -A. tock Standard dilution: * Pipette 10.0 ml stock T 3 -A into a 500 ml Type A volumetric flask. . Dilute to volume with Mobile Phase for a concentration of about 2 pg/ml. Mix well and label this solution as std. T 3 -B. Pipette 50.0 ml each from the T 4 and T 3 -B stock standards and transfer into a 500-ml Type A volumetric flask Dilute to volume with mobile phase and mix well. Label this standard as T 3 / T 4 working standard. The concentration of the working standard should be about 0.2 ig/ml T 3 and 10.0 ig/mlt T4. Note: Concentrations of Levothyroxine and Liothyronine require adjustments for water content. Assay Preparation: Weigh not less than the specified tablet quantity and calculate the average tablet weight. Crush tablets into a uniform fine powder with a mortar and pestle. Tare a polypropylene weigh boat. Accurately weigh (to 0.1 mg) a portion of the powder into the tared weigh boat using a preconditioned stainless steel scoop or spatula (either Teflon coated or uncoated). The spatula or scoop is preconditioned by dipping it into the powder. Use the Sample Calculation below to achieve 50 ml of a 10 pg/ml assay solution. 31 Record the sample weight taken. Carefully transfer the sample into an Erlenmeyer flask, reweigh the weigh boat and subtract the residual weight from the weight taken to obtain the actual sample weight. Pipette 50 ml of mobile phase into the flask. Cover the flask with parafilm, sonicate for approximately 10 seconds and vortex for approximately 235 seconds at a speed of 6 or greater. Observe sample preparation, and if clumping is noted, repeat the sonication and/or vortex steps. Centrifuge (-3,000rpm) for NLT 1 minute until a clear supernatant is achieved. Transfer a portion of the supernatant to an auto sampler vial. For In-Process granulation analysis, use the theoretical tablet weight (0.1455 g) in place of (weight of tablets/number of tablets) in the formula below. Sample Calculation: Weight of Tablets X l0pg/mI X 50ml= Amount to Weight Out per Assay Number of Tablets Dose (pg) Procedure: Separately inject 100 sl of the sample onto the column. Record the responses of the analyte peak and calculate % label claim as follows. Calculations: Sample Area x std conc. (gg) x 50 ml x avg. tablet weight in g x 79.6 = ue/dose x I00 = % Label Claim Standard Area (ml) Actual Sample wt in g 776.87 Label Claim Where 798.86 = molecular weight of Levothyroxine as the Sodium Salt 776.87 = molecular weight of Levothyroxine Standard Base Results: Figures 5A and 5B show HPLC chromatograms of levothyroxine and liothyronine controls (T3/T4 working standard, shown in Figure 5A) and an experimental sample made in accordance with the present invention as described above.(Figure 5B). The peaks in both chromatograms in the area of 1.325 to 3.1 correspond to materials in the solvent. The peak at 32 bout 7.2 in Fig. 5A shows the presence of T3. Fig. 5B shows the absence of T3, as well as the absence of other related products or degradation products of levothyroxine. examplee 4 Hardness Test The following preferred method for testing tablet hardness will sometimes be- referred to crein as method number: QC-005 Table 9 - QC-005 Hardness Test Procedure APPARATUS: Van-Keel hardness tester; Please refer to equipment Profile for instrument information. PROCEDURE: Lay the tablet flat with the score side up onto the instrument in between the jaw area. The tablet's score line should be perpendicular to the jaw's line for the tablet to be aligned properly. Refer to alignment diagram below. For Tamil-K caplets, place the caplet onto the instrument on its side. The caplet's score line should not be laying on the flat part of the testing area as with other tablets but should not be parallel to the jaw's line for the caplet to be aligned properly. Refer to alignment diagram below. Push the test button on the control panel. The jaws will automatically move the break the tablet. The force needed to break the tablet (KP) will read out on the digital display and print out on the print tape. Specifications: 6.0 - 14.0 kiloponds RESULTS: Typical results range from about 9.3 to about 12.3 kiloponds. Generally the hardness of the pills lies between about 6.0 and about 14.0 kiloponds. Preferably the pill hardness is from about 9 to about 13 kiloponds. Typical results of products made in accordance with the present invention are about 9.3, 11.3, 9.8, 10.2, 12.3, etc. Pharmaceutical tablets which incorporate granulated active ingredient are typically much higher in hardness, which may add to the difficulty of dissolving or dissoluting them. Pills which are lower in hardness generally present more problems of pill fragmentation during handling and storage. 33 Example 5 Impurity Tests Ihe following preferred method for testing tablet impurities is sometimes referenced herein as nethod number: SA-004 Table 10 - SA 004 Impurity Test Procedure Method Reference: Biochemie Method No. 1417-6, Report JMI-DP-002 Equipment: HPLC with a gradient system and a detector at a wavelength of 225 nn Reagents: Acetonitrile, HPLC grade Methanol, HPLC grade Water, HPLC grade Sodium Hydroxide, ACS reagent grade Sodium Hydroxide 0.1 solution: Dissolve 40g of NaOH pellets in 1000 ml HPLC grade water. Store in a plastic container. Phosphoric acid, 85% reagent grade Diiodothyronine reference material Liothyronine RS USP reference material Levothyroxine RS USP reference material Triiodothyroacetic acid reference material Tetraiodothyroacetic acid reference material Solvent 1: To 100.0 ml of 0.1 N Sodium Hydroxide solution add a 1:1 V/V mixture of methanol and water to make 1000 ml. Solvent 2: 77:23:0.1 H2): CANACN: H3PO4; Degassed and filtered; mobile phase composition a may be altered to achieve a satisfactory resolution factor. Extraction solution: Pipette 50 ml of solvent 1 into a 1000 ml volumetric flask dilute to volume with solvent 2, stopper and mix well. Chromatography Nucleosil 100-10CN, 250 mm long, 4.6 mm internal diameter, at ambient Column: temperature System: Gradient Elution Mobile phase A: 1000:1 H20:H3PO4 V/V Mobile phase B: Acetonitrile Gradient program: Time mm % of mobile phase A % of mobile phase B 0 77 23 13 77 23 34 15 65 35 24 65 35 26 77 23 Flow rate: 1.5 ml/min. Injection Volume: 100 up: next injection after approx. 40 min. Detector: UV, 225 nm System Suitability: Chromatograph 5 replicate injections of the Reference I Standard preparation, chromatograph 2 replicate injections of the Reference II Standard. Record the peak responses as directed under "Procedure". An extraction blank is to be run after the standards. 1 . The RSD must not be greater than 2.0% for each of the impurities in the standard reference solution 1. 2. The resolution factor between liothyronine and levothyroxine in thestandard. reference solution I must not be less than 5.0. 3. The Signal to Noise ratio must not be less than 5/1 for levothyroxine and impurities in the chromatogramn obtained with standard reference solution I2. 4. A peak of monochlorotriiodothyronine may occur just before the levothyroxine peak. Make sure that the degree of separation between this peak and of levothyroxine is at least sufficient to permit separate evaluations. Monochlorotriiodothyronine reference material is not available to be purchase by any vendor. Any calculation of monochlorotriiodothyronine impurity will be done by its retention time. Standards 1. Stock Standard Reference Solution: Preparation: Accurately weigh 10mg +/- 0.1 mg of each Diiodothyronine, Liothyronine, Levothyroxine, Triodothyroacetic acid and Tetraiodthyroacetic acid reference standards into a 1onml volumetric flask. Dissolve in Solvent 1 and dilute to volume, stopper and mix well. The concentration of each component will be approximately lO0mcg/mlL. 2. Standard Reference solution I: Pipette 5.0 ml -of Stock Standard Reference Solution into a 100 ml volumnetric flask, dilute to volume with Solvent 2, stopper and mix well. The Final concentration of each component will be approximately Smcg/mlL. 3. Standard Reference solution 11(0.05%): Pipette 2.0 ml of Standard Reference Solution I into a 1OO ml voluetric flask, dilute to volume with Solvent 2, stopper and mix well. The final concentration of each component will be approximately 0.1 mcg/mlL. 100 Test Preparation: Crush not less than 20 tablets. Tare a 250 ml Erlenmeyer flask. Accurately weigh to the newest 0.1 mg an equivalent of 500 mcg of levothyroxine sodium 35 (+1- 10%) into a 250 ml Erlenmeyer flask. Pipette 100.0 mcg of the Extraction solution into the flask cover the flask with parafilm, sonicate, vortex and then centrifuge the solution for 1 minute each.- The final concentration of the sample will be approximately 5 mcg/ml of levothyroxine. To calculate the amount to weigh for the test preparation use the following equation: 500 mcg X 0.1450g* = Amount to weight for the test prep tablet label claim (mcg) * where 0.1450 g = theoretical tablet weight Note: Analyst must keep all materials use in performing this assay until the results are calculated, checked, and recorded and it is verified that the test is acceptable. This includes the crush, the Erlenmeyer flask with Extraction solution, the centrifuge tube and the auto-sampler vial. If the analysis is running overnight, these materials should be sealed with parafilm and saved until results are obtained and the results are deemed acceptable Procedure: 1. Separately inject 100pl of the sample preparation onto the column. Record the response of the analyte peaks and the calculate % w/w using the equations below. 2. The chromatogram may need to be reprocessed to obtain optimal integration. A copy of the sample chromatograph is to be attached to the analytical packet. . 3. Peaks on the sample chromatograph with areas less than a signal ratio of 5/1 will be considered none detected. Calculations: Diiodothyroinine: Sample area X Std conc. (mcg) X 100ml X 100% xl.1l* =%w/w Std. Area ml Wsimpl (g) 1000000 mcg/g or Sample area X Std. Conc. (mca) X 0.01 X 1.11* =%w/w *where 1.11 is a correction factor Triiodothyroacetic Acid: Sample area X Std conc. (mct) X lO0ml X 100% = % w/w Std. Area ml Wsimpl (g) 1000000 mcg/g 36 or ample area X Std. Conc. (mc) X 0.01 = %w/w Std area , ml Wsimpl (g) Tetraiodothroacetic Acid: ample area X Std conc. (mcg) X 100ml X 100% x 1.16* = % w/w Std. Area ml Wsimpl (g) 1000000 mcg/g or ample area X Std. Conc.(mg) X 0_1 X 1.16* = %w/w Std area ml Wsimpl (g) where 1.16 is a correction factor Limit of Detection (LOD) Valnes impurity Limit of Detection Diiodothyronine (T2) 0.00625% Triiodothyroacetic Acid (Reverse T3) 0.003125% Tetraiodothyroacetic Acid (Reverse T4) 0.003125% Calculation of the theoretical area for 0.05% of levothyroxine sodium, based on the initial amount in mg of levathyroxine sodium in the whole sample weight. (Area rs XII 0.0 = Theoretical area for 0.05% of levothyroxine Na, based (.05) (T 4 std st.)(P)(1.0283) on the actual weight Where: Area, -is the average area of the levothyroxine in the Standard reference solution II A = is the initial weight of levothyroxine Na in mg represented by the sample weight. This is calculated by using this equation: = sample weight (g) X claim T 4 in mcg 0.1450gXlOOOmcg/mg 10.0 = theoretical initial weight of the Levothyroxine USP reference standard 0.500 = is the theoretical initial weight of the Levothyroxine NA to be tested, in mg

T

4 std. Wt. = the initial weight of the levothyroxine USP standard in mg P = the purity of the levothyroxine Na USP standard (%purityll00%) 1.0283 = conversion of levothyroxine into levothyroxine sodium Greatest unknown impurity (individually): (Area iyjtfflstd wt mg)(l.0 283 ) (P (100) = impurity (%) (Area ref std I) (A) (2000) Where: Area iuity is the area of the greatest unknown impurity in the test solution with an area greater than the theoretical area for 0.05% of the levothyroxine Na taken into account. 37 .0283 = conversion of levothyroxine into levothyroxine sodium P = the purity of the levothyroxine Na USP standard (% purity/100%) 100 is the dilution of the test solution Area ref std I is the area of the levothyroxine in the standard reference solution I A.= is the initial weight of levothyroxine Na in mg represented by the sample weight. This is calculated by using this equation: = sample weight (g) X claim T4 in meg 0.1450g X 1000 mcg/mg 2000 is the dilution of the reference solution. Total of other Unknown Impurities: (Sum area impurities)(T4 std wt mg)(L.0283) (P) (100)= Total Unknown impurities (%) (are ref std I) (A) (2000) Where: Sum area impurity is the sum of the areas of all the other unknown impurities in the test solution (only areas that are greater than the theoretical area for 0.05% of the levothryoxine sodium taken into account) T4 std. wt. = the initial weight of the levothyroxine USP standard in mg 1.0283 = conversion of levothyroxine into levothyroxine sodium P = the purity of the levothyroxine Na USP standard (% pursity/100%) 100 is the dilution of the test solution Area ref std I is the area of the levothyroxine in the standard reference solution I A = is the initial weight of levothyroxine Na in mg represented by the sample weight. This is calculated by using this equation: = sample weight (g) X claim T4 in mcg 0.1450g X 100 meg/mg 2000 is the dilution of the reference solution. Results of the test are shown in Figures 6A and 6B. Figure 6A shows an example of a chromatogram of Standard Reference Solution II, with exemplary peaks at about 5.4 for diiodo-1 thyronine, 8.4 for liothryonine, 12.8 for levothyroxine, 19.3 for triiodo thyroacetic acid, and 21.9 for tetraiodo thyroacetic acid. Figure 6B shows results of an experimental -sample of levothyroxine sodium, made in accordance with this invention. As can be seen, the sample had substantially only levothyroxine, with insignificant impurities. 38 sample 6 Liothyronine (T3) Tests The following preferred method for testing for Triiodothyronine is sometimes referenced rein as method number: QC-001 Table 11 - QC - 001 T3 Test Procedure Method Reference USP 24 p. 968-970 Chromatographic 65:35:0.05 H 2 0:CACN:H 3

PO

4 degassed and filtered; mobile phase Conditions: composition may be altered to achieve a satisfactory resolution factor. Mobile Phase: Column: CN, 4.6 mm x 25 to 30 cm Flow Rate: 2.0 minute/minute Detector: Deuterium, set at 225 nm Injection Volume: 100 iL System Suitability: Chromatograph 5 replicate injections of the standard preparation. Record the peak responses as directed under "Procedure". 1.0 RSD for the standard replicates must not be more than 2.0% for T 4 2.0 Calculate the resolution factor (R) on one of the five replicates. The R value must be greater than or equal to proceed. See Method QC-009. Standard Preparation: Accurately weigh 25 mg of USP Levothyroxine RS and transfer to a clear 250-m1L volumetric flask. Pipette 87.5 ml minute of acetonitrile in the flask. Swirl and then sonicate for less than a minute. Add portions of HPLC grade water to the flask with swirling and sonicating until the material has gone into solution. Be sure that there is no particulate material present. Do not dilute to volume at this point. The solution may be cold. Place into a room temperature water bath for ten minutes to allow the sample to warm to ambient temperature. Dilute to volume with HPLC grade water. Mix well. Label this solution as stock T4. The concentration of T4is about 100 pg/ml. Also dissolve an accurately weighed quantity of USP Liothyronine RS to yield about 100 pig/minute, done as above with USP Levothyroxine RS. Label this solution as stock T 3 -A. Stock Standard dilution: 1. Pipette 10.0 ml stock T 3 -A into a 500-mlL Type A volumetric flask. 2. Dilute to volume with Mobile Phase for a concentration of about 2 jig/ml. Mix well and label this solution as stock std. c-B. 3. Pipette 50.0 ml each from the T 4 andT 3 stock standards and transfer into 500-m1L Type A volumetric flask. Dilute to volume with mobile phase and mix well. Label this standard as

TI'T

4 working standard. The concentration of the working standard should be about 0.2 ig/ml 1T3 and 10.0 pg/nil T4. 39 Assay Preparation: Weigh and crush not less than the specified tablet quantity and calculate the average tablet weight. Tare a polypropylene weigh boat. Accurately weigh (to 0.1 mg) a portion of the powder into the tared weigh boat using a preconditioned stainless steel scoop or spatula (either Teflon coated or uncoated). The spatula or scoop is preconditioned by dipping it into the power. Use the Sample Calculation below to achieve 50 ml of a 10 -g/ml assay solution. Record the sample weight taken. Carefully transfer the sample into an Erlenmeyer flask, reweigh the weigh boat and subtract the residual weight from the weight taken to obtain the actual sample weight. Pipette 50 ml of mobile phase into the flask. Cover the flask with parafilm, sonicate for approximately 10 seconds and vortex for approximately 35 seconds at a speed of 6 or greater. Observe sample preparation, and if clumping is noted, repeat the sonication and/or vortex steps. Centrifuge (-3,000 rpm) for NLT 1 minute until a clear supernatant is achieved. Transfer a portion of the supernatant to an autosampler vial. For In-Process granulation analysis, use the theoretical tablet weight (0.1455 g) in place of (weight of tablets/number of tablets) in the formula below. Note Analyst must keep all materials used in performing this assay until the results are calculated, checked, and recorded, and it is verified that the test is acceptable. This includes the crush, the Erlenmeyer flask with Mobile Phase, the centrifuge tube and the autosampler vial. If the analysis is running overnight, these materials should be sealed with parafilm and saved until results are obtained and the result is deemed acceptable. Sample Calculation: Weight of Tablets X 10 pg/ml X 50 ml = Amount to Weigh Out per Assay Number of Tablets Dose (pg) Procedure: Separately inject 100 pl of the sample onto the column. Record the responses of the analyte peak. Calculations: Calculate the content of liothyronine using the following formula: Sample T. Area X Std T conc. (ug) x 50 ml= pg T3 Standard T3 Area (ml) The specification is NGT 2.0% liothyronine calculated as follows: Amt T, Assayed ( g) x 100 =% LIOTHYRONINE Amt T 4 Assayed ( g)* *This number is calculated using the T4 potency results as follows: 40 Sample T. Area X StdT conc. (ug) x 50 ml x 798.86= gg T 4 Standard T 4 Area (ml) 776.87 here 798.86 molecular weight of Levothyroxine as the Sodium Salt 776.87 molecular weight of Levothyroxine Standard Base NOTE: If the single active ingredient comprises 50% or more, by weight, of the dosage unit, use Method A; otherwise use Method B. METHOD: USP 24 <905> pp. 2000-2002. METHOD A: Content Uniformity as Determined by Weight Variation: Weight accurately 10 tablets, individually. From the results of the average potency of the active ingredient determined for the product (using the assay methods as stated in the individual monograph) calculate the content of active ingredient in each of the 10 tablets. CALCULATIONS: Individual = (Avg. potency) (Individual Wt.) Potency Avg. tablet weight NOTE: If the active ingredient(s) are less than 50% by weight of the tablet content, refer to the individual test method for potency for those products. METHOD B: Content Uniformity as Determined by Direct Assay of Active Ingredient: For Levothyroxine Sodium tablets the following procedure is followed. Individually weigh 10 tablets. Place the 10 individual tablets into round bottomed test tubes or flasks of the appropriate size as outlined in the chart below. Add the appropriate volume of extraction mobile comprised of water, acetonitrile, and phosphoric acid (65:35::0.05) to each test tube or flask as indicated in the chart below. Note: All test tubes are to be capped with screw on caps and all flasks are to be covered with parafilm as soon as mobile phase is added. Allow to stand at room temperature until the tablet completely crumbles. Secure all samples in a wrist action shaker. Test tubes are to be secured horizontally. Erlenmeyer flasks are to be secured vertically. Set the wrist shaker to the setting specified in the table. Shake sample for 3 minutes. Transfer about 10 ml of the sample preparation (or the entirety of smaller samples) to a centrifuge tube. Centrifuge samples for 1 minute at about 3000 rpm. Transfer samples to autosampler vials using disposable Pasteur pipettes. Utilize the HIPLC Method for levothyroxine separation (AM-003) for obtaining dosage uniformity, sample area, and standard area results. CALCULATIONS: Dosage Uniformity Result (% Label Claim) 798.86 X Area of Sample X Cone. of Std. X 100 = % Potency 776.87 Area of Std. Conc. Of Sample (see chart below) SPECIFICATIONS FOR METHOD A OR METHOD B S-1 The %/ active ingredient for 10 tablets tested must fall in the range of 85.0% - 115.0% and the RSD of the 10 tablets must not exceed 6.0%. 41 NOTE: If 1 unit in S-I fails to meet either of the specifications, but is no outside the range of 75% - 125%, test 20 more units and proceed to S-2. S-2 When n = 30, NGT one unit outside 85.0-115.0%, none outside 75.0-125.0% and RSD NGT 7.80%. Results: Results for a variety of dosages, using a sample size of 120 pills, are shown in Table 12: Table 12 -Dosage Consistency - 120 pill samples Dosage 25 pg 100 pg 300 pg Label Claim 103.5% 103.1% 102.9% Activity High 109.1 % 104.8 % 108.8% Low 98.0% 100.7% 96.5% RSD < 2.0 % 0.9% 2.2% The results confirm an extremely low amount of variability in active material content between the 120 pills tested. Generally the variability for a 120 pill sample should be between about 90 and about 110 % of claimed activity, preferably between about 95 % and about 105%. The RSD for a 120 pill sample should not be greater than 5%, and preferably is less than 3%. Example 7 Levothyroxine Sodium Release Specification and Analytical Methods The specifications for levothyroxine sodium tablets are stated in: USP 24 page 969-970 and Supplement 1 page 2638. The additional requirements are in place to ensure the tablet appearance, for the individual tablet strengths, is correct and the physical characteristics ensure a quality tablet. A. Analytical Methods: Ali the test methods utilized in the testing of levothyroxine sodium meet USP system suitability requirements. All Levoxyl* batches are tested for conformance to the following specifications. The Table 13 below lists the test parameter, specification and the test method employed. 42 Table 13 - USP Specifications Test Parameter Specification Test Method Tablet Potency 90.0-110.0% label claim* AM-003 Tablet Dissolution NULT 7580% label claim dissoluted in 145 minutes AM-004B Liothyronine NGT 2.0% QC-001 Content TLC Identification Compares to Standard RM-054 Uniformity of S-1: 85.0-115.0% RSD NGT 6.0% n=10 QC-003 Dosage Units (if NGT I unit fails, but no unit is outside range of 75.0-125.0% or if RSD fails proceed to S-2) S-2: When n=30 NGT 1 unit outside 85.0-115.0%, none outside 75.0-125.0% and RSD NGT 7.8% Additional Requirements: Test Parameter Specification Test Method Tablet Hardness 6.0-14.0 KP QC-005 Tablet Weight 142.0-149.0 mg QC-007 Tablet Appearance Color, imprint, score and shape conform to specific tablet QC-008 parameters as specified for the individual strengths Example 8 Bioavailability determination of Two Levothyroxine formulations The following example was performed along lines of a 1999 FDA publication entitled In Vivo Pharmacokinetics and Bioavailability Studies and In-Vitro Dissolution Testing for Levothyroxine Sodium Tablets. The example includes the following two studies. Study 1. Single-Dose Bioavailabilitv Study The objective of the study was to determine the bioavailability of Levoxyl* relative to a reference (oral solution) under fasting conditions. Study 2: Do e-Form Equivalence Study The objective of the study was to determine the dosage-form bioequivalence between three different strengths of Levoxyl* tablets (low, middle and high range). 43 Study Objective: To determine the bioavailability of levothyroxine sodium (Levoxyl*) 0.3 mg tablets manufactured by JONES PHARMA INCORPORATED, relative to Knoll Pharmaceutical Company's levothyroxine sodium 200 g (Synthroid") injection given as an oral solution following a single 0.6mg dose. Study Methodology: Single-dose, randomized, open-label, two-way crossover design Protocol Reference: 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 were enrolled in the study, and 27 subjects completed the study. All 30 subjects were included in the safety analysis and 27 subjects who completed the study were included in the pharmacokinetic analyses. Diagnosis and Main Criteria for Inclusion: All subjects enrolled in this study were judged by the investigator to be healthy volunteers who met all inclusion and exclusion criteria. Test Product. Dose, Duration, Mode of Administration, and Batch Number: The test product was levothyroxine sodium (Levoxyl*) 2 X 0.3mg tablets administered as a single oral dose. The batch number utilized in this study was TT26. Reference Product, Dose, Duration, Mode of Administration, and Batch Number: The reference product was levothyroxine sodium (Synthroid*) 2 X 500 pg injection vials (Knoll Pharmaceutical Company) reconstituted and- 600 pg administered orally. The reference 44 product used was the 500 jpg injection instead of 200 sg due to the unavailability of sufficient quantities of 200 pg injection to conduct the study. The batch number utilized in this study was 80130028. Criteria for Evaluation: Pharmacokinetics: Pharmacokinetic assessment consisted of the determination of total (bound + free) T4 and T3 concentrations in serum at specified time points following drug administration. From the serum data, the parameters AUC(0-t), Cmax, and Tmax were calculated. Safety: Safety assessment included vital signs, clinical laboratory evaluation (including TSH), physical examination, and adverse events (AEs) assessment. Statistical Methods Pharnacokinetics: Descriptive statistics (arithmetic mean, standard deviation (SD), coefficient of variation (CV), standard error of the mean (SE), sample size (N), minimum, and maximum) were provided for all pharmacokinetic parameters. The effects of baseline and baseline-by treatment interaction were evaluated using a parametric (normal-theory) general linear model (ANCOVA) with treatment, period, sequence, subject within sequence, In(baseline), and interaction between In (baseline) and treatment as factors, applied to the In-transformed pharmacokinetic parameters and Cmax. In the absence of significant In(baseline) and interaction between In(baseline) and treatment, these parameters were removed from the model. The two one-sided hypotheses were tested at the 5% level of significance for In[AUC(0-t)] and In(Cmax) by constructing 90% confidence intervals for the ratio of Treatment A to Treatment Safety: Frequency counts of all subjects enrolled in the study, completing the study, and discontinuing early were tabulated. Descriptive statistics were calculated for continuous 45 demographic variables, and frequency counts were tabulated for categorical demographic variables for each gender and overall. AEs were coded using the 5h Edition of the COSTART dictionary. AEs were summarized by the number and percentage of subjects experiencing each coded event, A summary of the total number of each coded event and as. a percentage of total AEs was also provided. Laboratory summary tables included descriptive statistics for continuous serum chemistry and hematology results at each time point. Out-of-range values were listed by subject for each laboratory parameter. Descriptive statistics for vital sign measurements at each time point and change from baseline to each time point were calculated by treatment group. Shifts from screening to post study results for physical examinations were tabulated. Pharmacokinetic Results - T4: ANCOVA analyses indicated that the effects of In(baseline) and interaction between In(baseline) and treatment were not significant. Thus, these factors were removed from the general linear model and an ANOVA with treatment, period, sequence, and subject within sequence was applied to the In-transformed Cmax and AUC(0-t) parameters. The arithmetic means of serum T4 pharmacokinetic parameters for Treatments A and B and the statistical comparison for In-transformed parameters are summarized in the following table. Summary of the Pharmacokinetic Parameters of Serum T4 for Treatments A and B Treatment A* Treatment B** Pharmacokinetic Arithmetic Arithmetic 90% % Mean Parameters Mean SD Mean SD CI Ratio Cmax (u g/dLL) 14.48 1.93 15.09 2.10 - - Tmax (hr) 2.17 0.810 1.62 0.502 AUC(0-t) ( g*hr/dl) 524.3 59.07 529.3 62.83 In (Cmax) 2.663 0.1434 2.705 0.1339 91.1- 94.5 98.1 In [AUC(0-t)] 6.256 0.1167 6.265 0.1169 95.6- 98.0 100.5 * Treatment A = 2 X 0.3mg Levoxyl* Tablets: test **Treatment B = 0.6mg Synthroid Reconstitute Oral Solution: reference 46 Pharmacokinetics Results - T3: ANCOVA analyses indicated that the effects of In(baseline) and interaction between In(baseline) and treatment were not significant and were removed from the ANOVA model, except for. In(baseline) on In(Cmax) which was significant and was kept in the model. An ANOVA with treatment, period, sequence, and subject within sequence, and In(baseline), when significant, was applied to the In-transformed Cmax and AUC(0-t) parameters. The arithmetic means of serum T3 pharmacokinetic parameters for Treatments A and B and the statistical comparison for In-transformed parameters are summarized in the following table. Summary of the Pharmacokinetic Parameters of Serum T3 for Treatments A and B Treatment A* Treatment B** Pharmacokinetic Arithmetic Arithmetic 90% % Mean Parameters Mean SD Mean SD CI Ratio Cmax (ng/ml) 1.165 0.156 1.140 0.119 -- - Tmax (hr) 14.6 15.2 16.3 17.0 -- - AUC(O-t) (ng*hr/ml) 51.25 6.163 50.07 5.311 --- - In (Cmax) 0.1444 0.1289 0.1255 0.1034 96.8- 100.0 103.4 In [AUC(O-t)] 3.930 0.1209 3.908 0.1059 97.7- 100.7 1_ _ i103.8 * Treatment A = 2 X 0.3mg Levoxyl* Tablets: test **Treatment B = 0.6mg Synthroid Reconstitute Oral Solution: reference Comparison of total T4 and T3 phannacokinetics following administration of Levoxyl 0 (Treatment A, test formulation) arid Synthroid (Treatment B, reference formulation) indicated that the test formulation met the requirements for bioequivalence with the reference formulation. The 90% confidence intervals for the comparisons of In(Cmax) and In[AUC(0-t)] for T4 and T3 were within the 80% to 125% range required for bioequivalence. In regard to subject safety, both treatments appeared to be equally safe and well tolerated. Examl 9 Bioavailability Study To Assess Single Dose Bioequivalence of Three Strengths of Levothyroxine 47 The following example was performed to determine the dosage-form bioequivalence between three different strengths of levothyroxine sodium (Levoxyl") tablets following a single 600 mcg dose. Study Metbodology: Single-dose, randomized, open-label, three-way crossover design. Protocol Reference: Guidance for Industry: In Vivo Pharmacokinetics and Bioavailability Studies and In Vitro Dissolution Testing for Levothyroxine Sodium Tablets (June 1999). This protocol was submitted in IND 59,177. Number of Subjects: A total of 28 subjects were enrolled in the study, and 24 subjects completed the study. All 28 subjects were included in the safety analysis and 24 subjects who completed the study were included in the pharmacokinetic analyses. Diagnosis and Main Criteria for Inclusion: All subjects enrolled in this study were judged by the investigator to be healthy volunteers who met all inclusion and exclusion criteria. Test Product, Dose, Duration. Mode of Administration, and Batch Number: Subjects randomized to Treatment A received a single oral dose of 12 X 50 meg levothyroxine sodium (Levoxyl) tablets, Lot No. TT24. Subjects randomized to Treatment B received 6 X 100 mcg levothyroxine sodium (Levoxyl*) tablets, Lot No.TT25. Subjects randomized to Treatment C received 2 X 300 mcg levothyroxine sodium (Levoxyl*) tablets, Lot No. TT26. Test products were manufactured by JMI-Daniels, a subsidiary of Jones Pharma Incorporated. 48 Pharmacokinetics: Pharmacokinetic assessment consisted of the determination of total (bound + free) T4 and T3 concentrations in serum at specified time points following drug administration. From the serum data, the parameters AUC(O-t), Cmax, and Tmax were calculated. Safety: Safety assessment included monitoring of sitting vital signs, clinical laboratory measurements, thyroid-stimulating hormone (TSH), physical examination, electrocardiogram (ECG), and adverse events (AEs). Statistical Methods. Pharmacokinetics: Descriptive statistics (arithmetic mean, standard deviation (SD), coefficient of variation (CV), standard error of the mean (SEM), sample size (N), minimum, and maximum) were provided for all pharmacokinetic parameters. A parametric (normal-theory) general linear model with treatment, period, sequence, and subject within sequence as factors was applied to the In transformed Cmax and AUC(O-t).' The two one-sided hypotheses were tested at the 5% level of significance for In[AUC(O-t)] and In(Cmax) by constructing 90% confidence intervals for the ratios of Treatment A to Treatment B, Treatment A to Treatment C, and Treatment B to Treatment C. Safety: Frequency counts of all subjects enrolled in the study, completing the study, and discontinuing early were tabulated. Descriptive statistics were calculated for continuous demographic variables, and frequency counts were tabulated for categorical demographic variables for each gender and overall. AEs were coded using the 5h Edition of the COSTART dictionary. AEs were summarized by the number and percentage of subjects experiencing each coded event. A summary of the total number of each coded event and as a percentage of total AEs was also provided. Laboratory summary tables included descriptive statistics for continuous serum chemistry and hematology results at each time point. Out-of-range values were listed by subject 49 for each laboratory parameter. Descriptive statistics for vital sign measurements at each time point and change from baseline to each time point were calculated by treatment group. Shifts from screening to post study results for physical examinations were tabulated. Pharmacokinetic Resulta - T4: The arithmetic means of serum T4 pharmacokinetic parameters for Treatments A and B and the statistical comparison for the In-transformed parameters are summarized in the following table. Summary of the Pharmacokinetic Parameters of Serum T4 for Treatments A and B Treatment A* Treatment B** Pharmacokinetic Arithmetic Arithmetic 90% CI % Mean Parameters Mean SD Mean SD Ratio Cmax (pg/dl) 13.70 1.82 14.13 1.48 ---- Tmax (hr) 2.37 1.04 1.98 0.827 --- AUC(O-t) ( g*hr/dI) 509.0 58.36 528.3 72.41 --- In (Cmax) 2.609 0.1378 2.643 0.1095 93.6- 96.8 100.1 In [AUC(O-t)] 6.226 0.1200 6.261 0.1379 93.4- 96.7 100.0 * Treatment A 12 X 50 meg Levoxyl* Tablets **Treatment B 6 X 100 mcg Levoxyl*P Tablets The arithmetic means of serum T4 pharmacokinetic parameters for Treatments A and C and the statistical comparison for the In-transformed parameters are summarized in the following table. 50 Summary of the Pharmacokinetic Parameters of Serum T4 for Treatments A and C Treatment A* Treatment C** Pharmacokinetic Arithmetic Arithmetic 90% CI % Parameters Mean SD Mean SD - -Mean Ratio Cmax ( g/dI) 13.70 1.82 14.15 1.50 -- Tmax (hr) 2.37 1.04 2.40 1.09 ---- -- AUC(O-t) 509.0 58.36 528.7 57.13 -- ( g*hr/dL1) In (Cmax) 2.609 0.1378 2.644 0.1085 93.6- 96.8 100.1 In [AUC(O-t)] 6.226 0.1200 6.265 0.1089 93.1-99.7 96.4 * Treatment A = 12 X 50 mcg Levoxyl* Tablets **Treatment C =2 X 300 mcg Levoxyl* Tablets The arithmetic means of serum T4 pharmacokinctic parameters for Treatments B and C and the statistical comparison for the In-transformed parameters are summarized in the following table. Pharmacokinetic Results - T4 (Continued): Summary of the Pharmacokinetic Parameters of Serum T4 for Treatments B and C Treatment B* Treatment C** Pharmacokinetic Arithmetic Arithmetic 90% CI % Mean Parameters Mean SD Mean SD Ratio Cmax ( g/dl) 14.13 1.48 14.15 1.50 -- -- Tmax (hr) 1.98 0.827 2.40 1.09 --- -- AUC(O-t) ( ghr/dl) 528.3 72.41 528.7 57.13 --- -- In (Cmax) 2.643 0.1095 2.644 0.1085 96.7-103.4 100.0 In [AUC(O-t)] 6.261 0.1379 6.265 0.1089 96.4-103.1 99.7 * Treatment B = 6 X 100 mcg Levoxyl* Tablets **Treatment C = 2 X 300 mcg Levoxyl* Tablets Pharmacokinetic Results - T3: 51 The arithmetic means of serum T3 pharmacokinetic parameters for Treatments A and B and the statistical comparison for the In-transformed parameters are summarized in the following table. Summary of the Pharmacokinetic Parameters of Serum T3 for Treatments A and B Treatment A* Treatment B** Pharmacokinetic Arithmetic Arithmetic 90% CI % Mean Parameters Mean SD Mean SD Ratio Cmax (ug/ml) 1.173 0.138 1.142 0.133 --- -- Tmax (hr) 12.9 19.0 12.1 16.1 -- -- AUC(O-t) 49.43 6.872 50.35 8.994 --- (ng*hr/mI) In (Cmax) 0.1523 0.1226 0.1264 0.1194 98.1- 102.6 ; 107.3 In [AUC(0-t)] 3.890 0.1538 3.905 0.1731 93.1- 98.5 1 _104.3 * Treatment A = 12 X 50 mcg Levoxyl* Tablets **Treatment B = 6 X 100 mcg Levoxyl* Tablets The arithmetic means of serum T3 pharmacokinetic parameters for Treatments A and C and the statistical comparison for the In-transformcd parameters are summarized in the following table. Pharmacokinetic Results - T3 (Continued): Summary of the Pharmacokinetic Parameters of Serum T3 for Treatments A and C Treatment A* Treatment C** Pharmacokinetic Arithmetic Arithmeti 90% CI % Mean Parameters Mean SD - c SD Ratio Mean Cmax (ng/ml) 1.173 0.138 1.167 0.169 -- -- Tmax (br) 12.9 19.0 11.5 16.4 --- AUC(O-t) 49.43 6.872 49.36 7.680

-

(ng*hr/ml) In (Cmax) 0.1523 0.1226 0.1437 0.1491 96.3-105.4 100.7 In [AUC(O-t)] 3.890 0.1538 3.886 0.1705 94.7-106.2 100.3 * Treatment A = 12 X 50 mcg Levoxyl* Tablets **Treatment C = 2 X 300 meg Levoxyl* Tablets 52 The arithmetic means of serum T3 pharmacokinetic parameters for Treatments B and C and the statistical comparison for the In-transformed parameters are summarized in the following table. Summary of the Pharmacokinetic Parameters of Serum T3 for Treatments B and C Treatment B* Treatment C** Pharmacokinetic Arithmetic Arithmetic 90% CI % Parameters Mean SD Mean SD Mean Ratio Cmax (ng/ml) 1.142 0.133 1.167 0.169 ---- Tmax (hr) 12.1 16.1 11.5 16.4 --- AUC(0-t) (ng*hr/ml) 50.35 8.994 49.36 7.680 --- -- In (Cmax) 0.1264 0.1194 0.1437 0.1491 93.9- 98.2 102.7 In [AUC(O-t)] 3.905 0.1731 3.886 0.1705 96.2- 101.8 1 _107.8 * Treatment B = 6 X 100 mcg Levoxyl* Tablets **Treatment C = 2 X 300 nicg Levoxyl* Tablets Safety Results: There was a total of 59 treatment-emergent AEs reported by 15 (54%) of the 28 subjects dosed with study treatment. Incidence of AEs was similar across treatments. -Headache was the most frequently reported event. The majority of the AEs were mild in intensity. There was one subject who experienced a serious adverse event of chest pain, considered by the Investigator to be unrelated to treatment. No trends were noted in vital signs, -clinical laboratory results, or ECGs to suggest treatment-related differences. Comparison of total T4 and T3 pharmacokinetics following administration of 12 X 50 mcg Levoxyl* tablets (Treatment A) and 6 X 100 mcg Levoxyl* tablets (Treatment B) indicated that the two formulations met the requirements for bioequivalence. The 90% confidence intervals for the comparisons of In(Cmax) and In[AUC(0-t)] for T4 and T3 were within the 80% to 125% range required for bioequivalence. Comparison of total T4 and T3 pharmacolinetics following administration of 12 X 50 mcg Levoxyl* tablets (Treatment A) and 2 X 300 mcg Levoxyl* tablets (Treatment C) indicated that the two formulations met the requirements for bioequivalence. The 90% confidence 53 intervals for the comparisons of In(Cmax) and In[AUC(0-t)] for T4 and T3 were within the 80% to 125% range required for bioequivalence. Comparison of total T4 and T3 pharmacokinetics following administration of 6 X 100 mcg Levoxyl* tablets (Treatment B) and 2 X 300 meg Levoxyl* tablets (Treatment C) indicated that the two formulations met the requirements for bioequivalence. The 90% confidence intervals for the comparisons of In(Cmax) and ln[AUC(0-t)] for T4 and T3 were within the 80% to 125% range required for bioequivalence. The test formulations appear to be safe and generally well tolerated when given to healthy adult volunteers. Example 10 Levothyroxine sodium (Levoxyl@) Tablet Compositions The following preferred levothroxine sodium compositions in tablet form were made along lines disclosed herein. Levoxyl® 25 meg Tablets Color: orange; Markings: (front) dp/25 (back) LEVOXYL@ Component Quantity in mg/Tablet Levothyroxine Sodium, USP 0.025 mg p - Form Microcrystalline Cellulose, NF (Ceolus) 108.529 mg Croscarmellose Sodium, NF (Ac-di-sol) 35.079 mg FD&C Yellow # 6 0.352 mg Magnesium Stearate, NF 1.018 mg Levoxyl@ 50 meg Tablets Color: white; Markings: (front) dp/50 (back) LEVOXYL® Component Quantity in mg/Tablet Levothyroxine Sodium, USP 0.050 mg j3- Form Microcrystalline Cellulose, NF (Ceolus) 108.856 mg Croscarmellose Sodium, NF (Ac-di-sol) 35.079 mg Magnesium Stearate, NF 1.018 mg 54 Levoxyl@ 75 meg Tablets Color: purple; Markings: (front) dp/75 (back) LEVOXYL@ Component Quantity in mg/Tablet Levothyroxine Sodium, USP 0.075 mg f- Form Microcrystalline Cellulose, NF (Ceolus) 108.438 mg Croscarnellose Sodium, NF (Ac-di-sol) 35.079 mg Lake Blend # LB-1609 0.383 mg (Blend of D&C Red # 30 and FD&C Blue # 1) Magnesium Stearate, NF 1.018 mg Levoxyl@ 88 mcg Tablets Color: olive; Markings: (front) dp/88 (back) LEVOXYL@ Component Quantity in mg/Tablet Levothyroxine Sodium, USP 0.088 mg j3- Form Microcrystalline Cellulose, NF (Ceolus) 108.311 mg Croscarmellose Sodium, NF (Ac-di-sol) 35.079 mg Lake Blend # LB-1607 0.507 mg (Blend of FD&C Yellow # 6, D&C Red # 30 and FD&C Blue # 1) Magnesium Stearate, NF 1.018 mg Levoxyl@ 100 meg Tablets Color: yellow; Markings: (front) dp/100 (back) LEVOXYL® Component Quantity in mg/Tablet Levothyroxine Sodium, USP 0.100 mg fp- Form Microcrystalline Cellulose, NF (Ceolus) 108.406 mg Croscarmellose Sodium, NF (Ac-di-sol) 35.079 mg Lake Blend # LB-282 (Blend of FD&C Yellow # 6 0.388 mg and D&C Yellow # 10) Magnesium Stearate, NF 1.018 mg Levoxyl® 112 meg Tablets Color: rose; Markings: (front) dp/112 (back).LEVOXYL® Component Quantity in mgtTablet Levothyroxine Sodium, USP 0.112mg p - Form Microcrystalline Cellulose, NF (Ceolus) 107.711 mg Croscarmellose Sodium, NF (Ac-di-sol) 35.079 mg Lake Blend # LB-1610.(Blend of FD&C Yellow # 6, 1.080 mg D&C Red # 30 and FD&C Red # 40) Magnesium Stearate, NF 1.018 mg 55 Levoxyl® 125 meg Tablets Color: brown; Markings: (front) dp/125 (back) LEVOXYL@ Component Quantity in mg/Tablet Levothyroxine Sodium, USP 0.125 mg D- Form Microcrystalline Cellulose, NF (Ceolus) 108.701 mg Croscarmellose Sodium, NF (Ac-di-sol) 35.079 mg Lake Blend # LB-1617 (Blend of D&C Yellow # 10 0.080 mg and FD&C Red # 40) Magnesium Stearate, NF 1.018 mg Levoxyl@ 137 meg Tablets Color: dark blue; Markings: (front) dp/137 (back) LEVOXYL@ Component Quantity in mg/Tablet Levothyroxine Sodium, USP 0.137 mg fp- Form Microcrystalline Cellulose, NF (Ceolus) 108.288 mg Crosearmellose Sodium, NF (Ac-di-sol) 35.079 mg FD&C Blue # 1 0.478 mg Magnesium Stearate, NF 1.018 mg Levoxyl® 150 mcg Tablets Color: blue; Markings: (front) dp/150 (back) LEVOXYL® Component Quantity in mgffablet Levothyroxine Sodium, USP 0.150 mg p- Form Microcrystalline Cellulose, NF (Ceolus) 108.645 mg Croscarmellose Sodium, NF (Ac-di-sol) 35.079 mg Lake Blend # LB-1612 (Blend of D&C Red # 30 and 0.108 mg FD&C Blue # 1) Magnesium Stearate, NF 1.018mg Levoxyl® 175 meg Tablets Color: turquoise; Markings: (front) dp/175 (back) LEVOXYL@ Component Quantity in mgFablet Levothyroxine Sodium, USP 0.175 mg p3- Form Microcrystalline Cellulose, NF (Ceolus) 108.397 mg Croscarmellose Sodium, NF (Ac-di-sol) 35.079 mg Lake Blend # LB-334 (Blend of D&C Yellow # 10, 0.334 mg and FD&C Blue # 1) Magnesium Stearate, NF 1.018mg 56 Levoxyl@ 200 mcg Tablets Color: pink; Markings: (front) dp/200 (back) LEVOXYL@ Component Quantity in mg/Tablet Levothyroxine Sodium, USP 0.200 mg j3- Form Microcrystalline Cellulose, NF (Ceolus) 108.515 mg Croscarmellose Sodium, NF (Ac-di-sol) 35.079 mg Lake Blend # LB-1613 (Blend of D&C Yellow # 10 0.188 mg and D&C Red # 30) Magnesium Stearate, NF 1.018 mg Levoxyl® 300 mcg Tablets Color: green; Markings: (front) dp/300 (back) LEVOXYL@ Component Quantity in mg/Tablet Levothyroxine Sodium, USP 0.300 mg p3- Form Microcrystalline Cellulose, NF (Ceolus) 108.451 mg Croscarmellose Sodium, NF (Ac-di-sol) 35.079 mg Lake Blend # LB-1614 (Blend of FD&C Yellow # 6, 0.142 mg D&C Yellow # 10 and FD&C Blue # 1) Magnesium Stearate, NF 1.018 mg While the present invention has been described in the context of preferred embodiments and examples, it will be readily apparent to those skilled in the art that other modifications and variations can be made therein without departing from the spirit or scope of the present invention. For example, the active moiety levothyroxine sodium can be changed to liothyronine sodium and similar products and still be considered as part of the claimed invention. Accordingly, it is not Intended that the present invention be limited to the specifics of the foregoing description of the preferred embodiments and examples, but rather as being limited only by the scope of the invention as defined In the claims appended hereto. Having described our invention, we claim: 57

Claims (99)

1. 3. The composition of claims 1, wherein at least about 85% of the levothyroxine dissolves in iqueous solution by about 10 to about 15 minutes as determined by the standard dissolution test.
2. 4. The composition of claims 2, wherein at least about 85% of the levothyroxine dissolves in aqueous solution by about 10 to about 15 minutes as determined by the standard dissolution est.
3. 5. The composition of claims 1, wherein the composition exhibits a levothyroxine (T4) plasma Cmax of between from about 10 pg/dL to about 20 pg/dL as determined by a standard Cmax test.
4. 6. The composition of claims 2, wherein the composition exhibits a levothyroxine (T4) plasma Cmax of between from about 10 sg/dL to about 20 sLg/dL as determined by a standard Cmax test.
5. 7. The composition of claims 3, wherein the composition exhibits a levothyroxine (T4) plasma Cmax of between from about 10 pg/dL to about 20 pg/dL as determined by a standard Cmax test.
6. 8. The composition of claim 4, wherein the composition exhibits a levothyroxine (T4) plasma Cmax of between from about 12 ptg/dL to about 16 pg/dL as determined by the standard Cmax test.
7. 9. The composition of claims 4, wherein the In(Cmax) of the levothyroxine (T4) plasma level is between from about 1 to about 3. 58
8. 10. The composition of claims 5, wherein the In(Cmax) of the levothyroxine (T4) plasma level is between from about 1 to about 3.
9. 11. The composition of claims 1, wherein the composition exhibits a triiodothyronine (T3) plasma Cmax of between from about 0.1 ng/mL to about 1Ong/mL as determined by the standard Cmax test.
10. 12. The composition of claim 1, wherein the composition exhibits a triiodothyronine (T3) plasma Cmax of between from about 0.5 ng/mL to about 2ng/mL as determined by the standard Cmax test.
11. 13. The composition of claims 1, wherein the In(Cmax) is between from about 0.01 to about 5.
12. 14. The composition of claims 1, wherein the composition exhibits a levothyroxine (T4) plasma Tmax of between from about 0.5 hours to about 5 hours as determined by a standard Tmax test.
13. 15. The composition of claim 1, wherein the composition exhibits a levothyroxine (T4) plasma Tmax of between from about 1 hour to about 3 hours as determined by the standard Tmax test.
14. 16. The composition of claims 1, wherein the composition exhibits a triiodothyronine (T3) plasma Tmax of between from about 10 hours to about 20 hours as determined by the standard Tmax test.
15. 17. The composition of claim 1, wherein the composition exhibits a triiodothyronine (T3) plasma Tmax of between from about 12 hours to about 16 hours as determined by the standard Tmax test. 59
16. 18. The composition of claims 1, wherein the composition features a levothyroxine (T4) plasma AUC (0-t) of between from about 450 jg-hour/dL to about 600 pg-hour/dL.
17. 19. The composition of claim 1, wherein the composition features a levothyroxine (T4) AUC [0-t) of between from about 500 gg-hour/dL to about 550 pg-hour/dL.
18. 20. The composition of claims 1, wherein the In[AUC(0-t)] is between from about I to about 10.
19. 21. The composition of claims 1, wherein the composition features a triiodothyronine (T3) AUC (0-t) of between from about 10 ng-hour/mL to about 100 ng-hour/mL.
20. 22. The composition of claim 1, wherein the composition features a triiodothyronine (T3) AUC (0-t) of between from about 20 ng-hour/mL to about 60 ng-hour/mL.
21. 23. The composition of claims 1, wherein the In[AUC(0-t)] is between from about I to about 5.
22. 24. The composition of claims 1, wherein the composition is essentially sugar free.
23. 25. The composition of claims 1, wherein the composition is essentially non-granular.
24. 26.- The composition of claims 1, wherein the composition further comprises microcrystalline B-cellulose.
25. 27. The composition of claim 26, wherein the microcrystalline B-cellulose has a bulk density of between from about 0.10 g/cm 3 to about 0.35 g/cm 3 .
26. 28. The composition of claims 26, wherein the microcrystalline B-cellulose has a bulk density of between from about 0.15 g/cm 3 to about 0.25 g/cm 3 . 60
27. 29. The composition of claims 26, wherein the microcrystalline B-cellulose has a bulk density )f between from about 0.17 g/cm 3 to about 0.23 gcm 3 .
28. 30. The composition of claims 26, wherein the microcrystalline B-cellulose has a bulk density >f between from about 0.19 g/cm 3 to about 0.21 g/cm 3 .
29. 31. The composition of claims 26, wherein the microcrystalline B-cellulose has a :onductivity of less than about 200 pS/cm.
30. 32. The composition of claim 26, wherein the microcrystalline B-cellulose has a conductivity f less than about 75 pS/cm.
31. 33. The composition of claims 26, wherein the microcrystalline B-cellulose has a conductivity of between from about 0.5 pS/cm to 50 pS/cm.
32. 34. The composition of claims 26, wherein the microcrystalline B-cellulose has a conductivity of between from about 15 pS/cm to 30 pS/cm.
33. 35. The composition of claims 1, wherein the composition has a post-packaging potency of between from about 95% to about 120% as determined by a standard potency test.
34. 36.- The composition of claim 35, wherein the composition has a post-packaging potency of between from about 98% to about 110% as determined by the standard potency test.
35. 38. The composition of claims 1, wherein the composition is formulated as a tablet.
36. 39. The composition of claim 38, wherein the tablet has a total hardness of between from about 1 to about 30 KP as determined by a standard hardness test.
37. 40. The composition of claim 38, wherein tablet has a total hardness of between from about 5 to about 15 KP as determined by a standard hardness test. 61
38. 41. The composition of claims 38, wherein the tablet is configured to increase heat transfer away from the tablet.
39. 42. The composition of claim 38, wherein the tablet has a surface area of between from about 0.9 in 2 to about 0.15 in. 2 .
40. 43. The composition of claim 38, wherein the tablet has a surface area of about 0.115 in?.
41. 44. The composition of claims 38, wherein the tablet is beveled.
42. 45. The composition of claim 38, wherein the tablet further comprises a score.
43. 46. The composition of claims 38, wherein the tablet has a raised violin configuration.
44. 47. The composition of claims 1, wherein the composition features less than about 10% total impurities as determined by a standard impurity test.
45. 48. The composition of claim 1, wherein the composition features less than about 5% total impurities as determined by the standard impurity test.
46. 49. The composition of claims 47, wherein the impurities comprise at least one of diiodothyronine (T2), triiodothyronine (T3), triiodothyroacetic acid amide, triiodothyroethylamine, triiodothyroacetic acid, triiodothyroethyl alcohol, tetraiodothyroacetic acid aide, tetraiodothyroacetic acid, triiodothyroethane, and tetraiodothyroethane.
47. 50. The composition of claims 48, wherein the impurities comprise at least one of diiodothyronine (T2), triiodothyronine (T3), triiodothyroacetic acid aide, triiodothyroethylamine, triiodothyroacetic acid, triiodothyroethyl alcohol, tetraiodothyroacetic acid aide, tetraiodothyroacetic acid, triiodothyroethane, and tetraiodothyroethane. 62
48. 51. The composition of claims 47, wherein the impurities detected in the assay consist of diiodothyronine (T2), triiodothyronine (T3), triiodothyroacetic acid, and tetraiodothyroacetic acid.
49. 52. The composition of claims 48, wherein the impurities detected in the assay consist of diiodothyronine (T2), triiodothyronine (T3), triiodothyroacetic acid, and tetraiodothyroacetic acid.
50. 53. The composition of claims 1, wherein the composition further comprises a pharmaceutically acceptable croscarmellose salt.
51. 54. The composition of claims 1, wherein the composition further comprises a pharmaceutically acceptable magnesium salt.
52. 55. The composition of claims 53, wherein the composition further comprises a pharmaceutically acceptable magnesium salt. 63
53. 56. An immediate release pharmaceutical composition in tablet form comprising levothyroxine sodium, the composition comprising: a) between from about 0.01 mg/tablet to about 500 mg/tablet levothyroxine sodium (USP); b) between from about 100 mg/tablet to about 110 mg/tablet of microcrystalline B cellulose, NF (Ceolus@) having a bulk density of between from about 0.10 g/cm 3 to about 0.35 g/cm 3 ; c) between from about 25mg/tablet to about 50mg/tablet of croscarmellose sodium, NF (Ac-di-sol); and d) between from about 0.5 mg/tablet to about 5mg/tablet of magnesium stearate, NF.
54. 57. The composition of claim 56, wherein the composition further comprises at least one' pharmaceutically acceptable coloring agent.
55. 58. An aqueous solution comprising at a composition of claim 1.
56. 59. An aqueous solution comprising at a composition of claim 56.
57. 60. The aqueous solution of claim 58, wherein the solution is adapted for child or infant use. 64
58. 61. A method of making an immediate release pharmaceutical composition comprising a levothyroxine salt, the method comprising a) mixing a levothyroxine salt with microcrystalline B-cellulose and a croscarmellose salt to make a blend; and b) compressing the blend in a ratio of initial volume to final volume of between from about 2:1 to about 5:1 to make the composition.
59. 62. The method of claim 61, wherein the ratio of initial'voime to final volume is about 4:1.
60. 63. The method of claims 61, wherein the composition features less than about 5% total impurities as determined by the standard impurity test.
61. 64. The method of claims 61, wherein the method further comprises forming a tablet.
62. 65. The method of claim 58, wherein the tablet has a raised violin configuration. 65
63. 66. A method of making a stabilized pharmaceutical composition comprising a levothyroxine salt, the method comprising a) mixing a levothyroxine salt with microcrystalline B-cellulose and a croscarmellose salt to make a blend; and b) compressing the blend in a ratio of initial volume to final volume of between from about 2:1 to about 5:1 to make the composition.
64. 67. The method of claim 66, wherein the ratio of initial volume to final volume is about 4:1.
65. 68. The method of claims 66, wherein the composition features less than about 5% total impurities as determined by the standard impurity test.
66. 69. The method of claims 66, wherein the method further comprises forming a tablet.
67. 70. The method of claim 66, wherein the tablet has a raised violin configuration. 66
68. 71. A stabilized, immediate release pharmaceutical composition comprising a levothyroxine.
69. 72. A method of preparing a stabilized, immediate release pharmaceutical composition of claim 71 comprising (a) forming a blend by blending the levothyroxine and B - sheet form of microcrystalline cellulose, and (b) forming therefrom a solid dosage.
70. 73. A method of claim 72, wherein the solid dosage is formed by compressing the blend in a tableting machine.
71. 74. A method of claim 72, wherein the blend is compressed in a ratio of initial volume to final volume from 3.3:1 to 4.0:1.
72. 75. A method of claim 72, wherein the levothyroxine is levothyroxine sodium.
73. 76. A method of claim 72, wherein the stabilized, immediate release pharmaceutical composition further includes liothyronine.
74. 77. A method of claim 76, wherein the liothyronine is liothyronine sodium. 67
75. 78. A stabilized pharmaceutical composition comprising levothyroxine, wherein the composition exhibits a levothyroxine (T4) plasma Cmax of between from about 10 .g/dl to about 20 ptg/dl as determined by a standard Cmax test.
76. 79. A composition of claim 78, wherein the composition exhibits a levothyroxine (T4) plasma Cmax of between from about 12 pg/dl to about 16 pg/dl as determined by the standard Cmax test.
77. 80. A composition of claims 78, wherein the In(Cmax) of the levothyroxine (T4) plasma level is between from about I to about 3.
78. 81. A composition of claims 79, wherein the In(Cmax) of the levothyroxine (T4) plasma level is between from about I to about 3. 68
79. 82. A stabilized pharmaceutical composition comprising levothyroxine, wherein the composition exhibits a triiodothyronine (T3) plasma Tmax of between from about 10 hours to about 20 hours as determined by the standard Tmax test.
80. 83. A composition of claim 82, wherein the composition exhibits a triiodothyronine (T3) plasma Tmax of between from about 12 hours to about 16 hours as determined by the standard Tmax test. 69 4. A stabilized immediate release pharmaceutical composition comprising levothyroxine, vherein the composition exhibits a levothyroxine (T4) plasma Tmax of between from about 0.5 tours to about 5 hours as determined by a standard Tmax test. :5. A composition of claim 85, wherein the composition exhibits a levothyroxine (T4) 21asma Tmax of between from about 1 hour to about 3 hours as determined by the standard Fmax test. 70 6. A pharmaceutical composition, comprising the product of dissolution of a preparation omprising levothyroxine, cross-linked sodium carboxymethylcellulose, and B-form nicrocrystalline cellulose, in an aqueous medium. 37, A composition of claim 86, wherein the preparation comprises about 0.001 to 1% by eight levothyroxine, about. 5 to about 40% by weight cross-linked sodium ,arboxymethylcellulose, and at least about 50% by weight of B-form microcrystalline cellulose. 71 18. An immediate release pharmaceutical composition comprising levothyroxine, wherein at east about 85% of the levothyroxine dissolves in aqueous solution in less than about 20 minutes is determined by a standard dissolution test. 39. A composition of claim 1, wherein at least about 80% of the levothyroxine dissolves in iqueous solution by about 15 minutes as determined by the standard dissolution test. 72 )0. A stabilized pharmaceutical composition comprising levothyroxine, wherein at least bout 85% of the levothyroxine dissolves in aqueous solution in less than about 20 minutes as determined by a standard dissolution test. 1. A composition of claim 90, wherein at least about 80% of the levothyroxine dissolves in queous solution by about 15 minutes as determined by the standard dissolution test. 73 2. An immediate release pharmaceutical composition comprising levothyroxine, wherein he composition is essentially sugar free. 74 3. A stabilized pharmaceutical composition comprising levothyroxine, wherein the imposition is essentially sugar free. 75 4. An immediate release pharmaceutical composition comprising levothyroxine, wherein he composition is essentially non-granular. 76 5. A stabilized pharmaceutical composition comprising levothyroxine, wherein the omposition is essentially non-granular. 77 6. An immediate release pharmaceutical composition comprising levothyroxine, wherein he composition has a post-packaging potency of between from about 95% to about 120% as determined by a standard potency test. )7. A composition of claim 96, wherein the composition has a post-packaging potency of between from about 98% to about 110% as determined by the standard potency test. 78
81. 98. A stabilized pharmaceutical composition comprising levothyroxine, wherein the omposition has a post-packaging potency of between from about 95% to about 120% as detennined by a standard potency test.
82. 99. A composition of claim 96, wherein the composition has a post-packaging potency of between from about 98% to about 110% as determined by the standard potency test. 79 00. An immediate release pharmaceutical composition comprising levothyroxine, wherein he composition is formulated as a tablet. .01. A composition of claim 100, wherein the tablet has a total hardness of between from bout 1 to about 30 KP as determined by a standard hardness test.
83. 102. A composition of claim 100, wherein tablet has a total hardness of between from about 5 o about 15 KP as determined by a standard hardness test. 80
84. 103. A stabilized pharmaceutical composition comprising levothyroxine, wherein the :omposition is formulated as a tablet.
85. 104. A composition of claim 103, wherein the tablet has a total hardness of between from about 1 to about 30 KP as determined by a standard hardness test.
86. 105. A composition of claim 103, wherein tablet has a total hardness of between from about 5 to about 15 KP as determined by a standard hardness test. 81 06. An immediate release pharmaceutical composition comprising levothyroxine, wherein he tablet is configured to increase heat transfer away from the tablet.
87. 107. A composition of claim 106, wherein the tablet has a surface area of between from about ).9 in. to about 0.15 in.
88. 108. A composition of claims 106, wherein the tablet is beveled.
89. 109. A composition of claim 106, wherein the tablet is scored.
90. 110. A composition of claims 106, wherein the tablet has a raised violin configuration. 82 i11. A stabilized pharmaceutical composition comprising levothyroxine, wherein the tablet is configured to increase heat transfer away from the tablet.
91. 112. A composition of claim 106, wherein the tablet has a surface area of between from about 2 2 0.9 in. to about 0.15 in.2
92. 113. A composition of claims 106, wherein the tablet is beveled.
93. 114. A composition of claim 106, wherein the tablet is scored.
94. 115. A composition of claims 106, wherein the tablet has a raised violin configuration. 83 16. A method of instructing a human to take an immediate release pharmaceutical omposition in tablet form comprising levothyroxine for reduced or absent thyroid function, said method comprising: instructing the human to take a certain number of the immediate release pharmaceutical evothyroxine tablets a selected number of times daily to treat reduced or absent thyroid function. 17. A method according to claim 116, wherein said reduced or absent thyroid function is used by an etiology selected from the group consisting of myxedema, cretinism and obesity. 84 18. A method of instructing a human to take a stabilized, immediate release pharmaceutical >mposition in tablet form comprising levothyroxine for reduced or absent thyroid function, said ethod comprising: instructing the human to take a certain number of the immediate release pharmaceutical vothyroxine tablets a selected number of times daily to treat reduced or absent thyroid function. 19. A method according to claim 118, wherein said reduced or absent thyroid function is aused by an etiology selected from the group consisting of myxedema, cretinism and obesity. 85 20. A method of instructing a human to take an effective amount of an immediate release harmaceutical composition in tablet form comprising levothyroxine to treat a thyroid indication elected from the group consisting of replacement or supplemental therapy in hypothyroidism, uppression of pituitary TSH secretion, prevention of euthyroid goiters and adjunctive therapy in he management of thyrotropin-dependent well-differentiated thyroid cancer said method omprising administering to the human an effective number of the immediate release pharmaceutical evothyroxine tablets a selected number of times daily to treat said thyroid indication. 86 21. A method of instructing a human to take an effective amount of a stabilized, immediate elease pharmaceutical composition in tablet form comprising levothyroxine to treat a thyroid ndication selected from the group consisting of replacement or supplemental therapy in hypothyroidism, suppression of pituitary TSH secretion, prevention of euthyroid goiters and adjunctive therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer, said method comprising administering to the human an effective number of the stabilized, immediate release pharmaceutical levothyroxine tablets a selected number of times daily to treat said thyroid indication. 87 22. A method of treating a human with an immediate release pharmaceutical composition in ablet form comprising levothyroxine for reduced or absent thyroid function, said method ;omprisimg: administering to the human an effective number of the immediate release pharmaceutical evothyroxine tablets a selected number of times daily to treat reduced or absent thyroid function.
95. 123. A method according to claim 122, wherein said reduced or absent thyroid function is caused by an etiology selected from the group consisting of myxedema, cretinism and obesity. 88
96. 124. A method of treating a human with a stabilized, immediate release pharmaceutical omposition in tablet form comprising levothyroxine for reduced or absent thyroid function, said method comprising: administering to the human an effective number of the immediate release pharmaceutical evothyroxine tablets a selected number of times daily to treat reduced or absent thyroid function.
97. 125. A method according to claim 124, wherein said reduced or absent thyroid function is caused by an etiology selected from the group consisting of myxedema, cretinism and obesity. 89
98. 126. A method of treating a human with an effective amount of an immediate release pharmaceutical composition in tablet form comprising levothyroxine for a thyroid indication selected from the group consisting of replacement or supplemental therapy in hypothyroidism, suppression of pituitary TSH secretion, prevention of euthyroid goiters and adjunctive therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer, said method comprising administering to the human an effective number of the immediate release pharmaceutical levothyroxine tablets a selected number of times daily to treat said thyroid indication 90
99. 127. A method of treating a human with an effective amount of a stabilized, immediate release pharmaceutical composition in tablet form comprising levothyroxine to treat a thyroid indication selected from the group consisting of replacement or supplemental therapy in hypothyroidism, suppression of pituitary TSH secretion, prevention of euthyroid goiters and_ adjunctive therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer, said method comprising: administering to the human an effective number of the stabilized, immediate release pharmaceutical levothyroxine tablets a selected number of times daily to treat said thyroid indication. 91