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WO2003028624A2 - Compositions de levothyroxine et procedes - Google Patents

Compositions de levothyroxine et procedes Download PDF

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Publication number
WO2003028624A2
WO2003028624A2 PCT/US2002/025752 US0225752W WO03028624A2 WO 2003028624 A2 WO2003028624 A2 WO 2003028624A2 US 0225752 W US0225752 W US 0225752W WO 03028624 A2 WO03028624 A2 WO 03028624A2
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WO
WIPO (PCT)
Prior art keywords
levothyroxine
composition
standard
cmax
test
Prior art date
Application number
PCT/US2002/025752
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English (en)
Other versions
WO2003028624A3 (fr
Inventor
G. Andrew Franz
Elaine A. Strauss
Phillip A. Dimenna
Rocco L. Gemma
Original Assignee
King Pharmaceuticals, Inc
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Publication date
Application filed by King Pharmaceuticals, Inc filed Critical King Pharmaceuticals, Inc
Priority to AU2002362468A priority Critical patent/AU2002362468A1/en
Publication of WO2003028624A2 publication Critical patent/WO2003028624A2/fr
Publication of WO2003028624A3 publication Critical patent/WO2003028624A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4

Definitions

  • 60/312,273 is entitled Levothyroxine Compositions Having Unique Tmax Properties
  • Serial No. 60/312,206 is entitled Levothyroxine Compositions Having Unique Triiodothyronine Tmax Properties
  • Serial No. 60/312,289 is entitled Unique Levothyroxine Aqueous Materials.
  • the invention generally relates to stable pharmaceutical compositions, and methods of making and administering such compositions.
  • 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 an immediate release solid- dosage form.
  • pharmaceutically active ingredients such as levothyroxine (T4) sodium and liothyronine (T3) sodium (thyroid hormone drugs)
  • T3 thyroid hormone drugs
  • Thyroid hormone preparations of levothyroxine sodium and liothyronine sodium are pharmaceutical preparations useful to the treatment of hypothyroidism and. thyroid hormone replacement therapy in mammals, for example, humans and dogs.
  • Thyroid hormone preparations are used to treat reduced or absent thyroid function of any etiology, 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
  • hypothyroidism has a prevalence of 0.5 percent to 1.3 percent in adults, h people over 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 ofthe 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.
  • under-treatment 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. Hyperthyroidism is a known risk factor fbr osteoporosis. Several studies suggest that sub clinical hyperthyroidism in premenopausal women receiving thyroid hormone drugs for replacement or suppressive therapy is associated with bone loss.
  • the dose be kept to the lowest effective dose. Because of the risks associated with over-treatment or under-treatment with levothyroxine sodium, there is a need for thyroid hormone products that are consistent in potency and bioavailability. Such consistency is best accomplished by manufacturing techniques that maintain consistent amounts ofthe active moiety during tablet manufacture.
  • Thyroid hormone drugs are natural or synthetic preparations containing tetraiodothyronine (T , levothyroxine) or triiodothyronine (T __, liothyronine) or both, usually as their pharmaceutically acceptable (e.g. sodium) salts.
  • T 4 and T 3 are produced in the human thyroid gland by the iodination and coupling ofthe amino acid tyrosine.
  • T 4 contains four iodine atoms and is formed by the coupling of two molecules of diiodotyrosine (DIT).
  • T 3 contains three 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.
  • liothyronine sodium (T 3 ) tablets are available under the trademark Cytomel ® from King Pharmaceuticals, Inc., St. Louis, Missouri.
  • Levothyroxine sodium (T ) 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.
  • a veterinarian preparation of levothyroxine so ⁇ Tum is available under the tradename Soloxine ® from King Pharmaceuticals, Inc.
  • Levoxyl ® (levothyroxine sodium tablets,USP) contain synthetic crystalline L-3,3',5,5 '- tetraiodothyronine sodium salt [levothyroxine (T 4 ) sodium].
  • T 4 tetraiodothyronine sodium salt
  • the levothyroxine (T 4 ) sodium in Levoxyl ® has an empirical formula of C ⁇ 5 H 10 L; NNaO 4 • H 2 O, molecular weight of 798.86 g/mol (anhydrous), and a structural formula as shown:
  • thyroid hormone drugs are quite poor. They are hygroscopic 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. such as carbohydrates, including lactose, sucrose, dextrose and starch, as well as certain dyes.
  • pharmaceutical excipients such as carbohydrates, including lactose, sucrose, dextrose and starch, as well as certain dyes.
  • the critical nature of the dosage requirements, and the lack of stability of the active ingredients in the popular pharmaceutical formulations, have led to a crisis which has adversely effected the most prescribed thyroid drug products. See, e.g., 62 Fed. Reg. 43535 (Aug. 14, 1997).
  • U.S. Patent No. 5,22 5,204 (the '204 patent) is directed to improving the stability of levothyroxine sodium.
  • 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 ® ,
  • microcrystalline cellulose products used in the '105 and '975 patents were also the ⁇ - form Avicel 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 ⁇ - sheet form microcrystalline cellulose having a flat needle shape, marketed under the trademark CEOLUS KG801 ® by FMC Company of Newark, Delaware.
  • the Ceolus ® product has different morphology, and different performance characteristics, than those of the Avicel product.
  • the ⁇ - sheet microcrystalline cellulose of the present invention is disclosed in U.S. Patent 5,574,150, which is hereby incorporated by reference. Further disclosure relating to ⁇ - sheet microcrystalline cellulose is found in InternationalJournal of Pharmaceutics 182 (199) 155 which is hereby incorporated by reference.
  • the Ceolus ® product ( ⁇ - sheet microcrystalline cellulose) is disclosed by FMC, in its product bulletin dated October 1997, as being suitable for "smaller size tablets” and "exceptional drug carrying capacity.”
  • the 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.
  • Ceolus ® product 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 %.
  • T4 and T3 thyroid hormone drugs
  • T4 and T3 thyroid hormone drugs
  • T4 and T3 in an immediate release solid dosage form
  • T4 and T3 in the form of their sodium salts that are relatively stable.
  • T4 and T3 in the form of their sodium salts that are relatively stable.
  • T4 and T3 in the form of their sodium salts that are relatively stable.
  • T4 and T3 in the form of their sodium salts that are relatively stable.
  • T4 and T3 in the form of their sodium salts that are relatively stable.
  • T4 and T3 in the form of their sodium salts that are relatively stable
  • the present invention overcomes and alleviates the above-mentioned drawbacks and disadvantages in the thyroid drug art through the discovery of novel oral levothyroxine (T4) and/or liothyronine (T3) (thyroid hormone drags) pharmaceutical compositions and methods.
  • T4 oral levothyroxine
  • T3 liothyronine
  • the present invention relates to stabilized solid as levothyroxine (T4) sodium and/or liothyronine (T3) sodium (thyroid hormone drugs) pharmaceutical compositions and in particular, immediate release, stabilized pharmaceutical compositions that include pharmaceutically active ingredients such as levothyroxine (T4) sodium and/or liothyronine (T3) sodium (thyroid hormone drugs).
  • the novel pharmaceutical compositions are provided in a solid dosage form, such as a tablet.
  • compositions of the present invention are useful for, among other things, as replacement or supplemental therapy in hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis, suppression of pituitary 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.
  • T4 immediate release and stabilized levothyroxine
  • T3 liothyronine
  • 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 1-3 minutes, and the patient can then ingest the fluid, and receive the appropriate dosage, is now made practical.
  • an aqueous fluid e.g., juice
  • the present invention has a wide range of important uses including providing pharmaceutically active levothyroxine compositions with enhanced bioavailability, improved shelf life, and more reliable potency.
  • immediate release pharmaceutical compositions that include as pharmaceutically active ingredients at least one of levothyroxine and liothyronine, preferably at least 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 less than about 20 minutes as determined by standard assays disclosed herein.
  • compositions so that the ingredients are released almost immediately after ingestion or contact with an aqueous solution, e.g., in a matter of minutes.
  • Preferred invention compositions are stable and provide better shelf life and potency characteristics than prior pharmaceutical compositions.
  • the immediate release pharmaceutical compositions of the invention provide important uses and advantages.
  • a major advantage is the stability of the active ingredients in the composition.
  • prior formulations with sugars, starches, and various types of celluloses, including micro-cellular celluloses such as the Avicel products have experienced substantial degradation ofthe active ingredients, e.g. T4 sodium.
  • 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.
  • 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 ofthe active ingredient. In either case, the patient receives the wrong dosage, with possible serious consequences.
  • the use of the ⁇ -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.
  • the term "stabilized", as applied to levothyroxine and/or liothyronine means that the loss of potency over the shelf life ofthe 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 sucn a period, and more preierre ⁇ compositions nave a loss ol potency ot less than about 0.3% per month for such a period.
  • compositions of the invention provide favorable pharmacokinetic characteristics when compared to prior formulations.
  • the immediate release pharmaceutical compositions that include levothyroxine salt have are more quickly available for absorption by the gastrointestinal (GI) tract faster and are absorbed more completely than has heretofore been possible.
  • This invention feature substantially enhances levothyroxine bioavailability, thereby improving efficacy and reliability of many standard thyroid hormone replacement strategies.
  • the desirable immediate release characteristics of the present invention facilitate dosing of patients who may be generally adverse to thyroid hormone replacement strategies involving solid dosing.
  • immediate release pharmaceutical compositions disclosed herein can be rapidly dissolved in an appropriate aqueous solution (e.g., water, saline, juice) or colloidal suspension (e.g., baby formula or milk) for convenient administration to such patients.
  • aqueous solution e.g., water, saline, juice
  • colloidal suspension e.g., baby formula or milk
  • infants, children, and adults who may experience swallowing difficulties e.g., infants, children, and adults who may experience swallowing difficulties.
  • the invention thus makes standard thyroid hormone replacement strategies more flexible and reliable for such patients.
  • the invention features an immediate release pharmaceutical composition
  • a levothyroxine salt preferably one of such a salt.
  • At least about 80% ofthe levothyroxine dissolves in aqueous solution in less than about 20 minutes as determined by a standard assay, disclosed herein.
  • 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.
  • at least about 85% ofthe 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.
  • 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.
  • compositions with favorable immediate release characteristics it is believed that by combining one or more of the pharmaceutically active agents with ⁇ -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 ⁇ - sheet form microcrystalline cellulose. More o ⁇ me agent is thus available for immediate release, m contrast, it is believed that many prior formulations have active agents that bind cellulose additives, making less available. The release characteristics ofthe compositions ofthe invention are also improved by the use of other agents, as discussed further below.
  • the present invention relates to a stabilized pharmaceutical composition
  • a stabilized pharmaceutical composition comprising a pharmaceutically active ingredient, such as levothyroxine, and the ⁇ - sheet form of microcrystalline cellulose, in the form of a solid dosage.
  • a pharmaceutically active ingredient such as levothyroxine sodium and/or liothyronine sodium, at least about 50 weight % ofthe dosage weight composed ofthe ⁇ - sheet form of microcrystalline cellulose, and, optionally, additional excipients, in a solid dosage form.
  • the invention provides an aqueous solution or colloidal suspension that includes at least one ofthe compositions of this invention, preferably between from about one to about five of same, more preferably about one of such compositions. It has also been found that ⁇ - sheet microcrystalline cellulose grades having preferred bulk densities provide for more compact processing than use of other celluloses. That is, use of the ⁇ - sheet microcrystalline cellulose having bulk densities in accord with this invention helps to 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.
  • the invention also provides methods for making an immediate release pharmaceutical composition comprising at least one levothyroxine salt, preferably one of such a salt.
  • the method includes at least one and preferably all of the following steps: a) mixing a levothyroxine salt with microcrystalline ⁇ -cellulose and preferably a crosscarmellose salt to make a blend; and
  • the method involves preparing an oral dosage form of a pharmaceutically active ingredient comprising dry blending the pharmaceutically active ingredient and at least about 50 weight % ofthe ⁇ - sheet form of microcrystalline cellulose, and compressing the blend to form a solid dosage.
  • Figures 1A - 1C 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.
  • T4 novel oral levothyroxine
  • T3 liothyronine
  • the invention relates to immediate release solid pharmaceutical compositions such as stabilized pharmaceutical compositions that include pharmaceutically active ingredients such as levothyroxine (T4) sodium and liothyronine (T3) sodium (thyroid hormone drugs), preferably in a solid dosage form. Also provided are methods for making such immediate release and stabilized compositions.
  • pharmaceutically active ingredients such as levothyroxine (T4) sodium and liothyronine (T3) sodium (thyroid hormone drugs)
  • T3 thyroid hormone drugs
  • immediate release a pharmaceutical composition in which one or more active agents therein demonstrates at least about 80% (w/v) dissolution, preferably between from about 90% (w/v) to about 95% (w/v), more preferably about 95% (w/v) to about
  • a pharmaceutical composition of the invention is “stable” or “stabilized” if one or more ofthe 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
  • the pharmaceutical compositions of the invention include, as active agent, levothyroxine (T4), preferably a salt thereof such as levothyroxine sodium USP.
  • T4 levothyroxine
  • Such compositions typically exhibit a levothyroxine (T4) plasma Cmax of between from about 12 ⁇ g/dl to about 16 ⁇ g/dl, preferably as determined by the standard Cmax test.
  • the In(Cmax) ofthe 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 the field. See e.g., the USP.
  • a preferred Cmax test is disclosed below in Examples 8 and 9.
  • compositions in accord with the invention provide a triiodothyronine (T3) plasma Cmax of between from about 0.1 ng/ml to about lOng/ml, preferably 0.5 ng/ml to about 2ng/ml, as determined by the standard Cmax test.
  • T3 triiodothyronine
  • the In(Cmax) is between from about 0.01 to about 5.
  • Further preferred compositions exhibit a levothyroxine (T4) plasma Tmax of between from 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 USP. A preferred Tmax test is disclosed below in Examples 8 and 9.
  • 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.
  • 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.
  • compositions feature a levothyroxine (T4) plasma AUC (0-t) of between from about 450 ⁇ g-hour/dl to about 600 ⁇ g-hour/dl, preferably 500 ⁇ g-hour/dl to about 550 ⁇ g-hour/dl as determined by a standard AUC (0-t) test.
  • T4 plasma AUC (0-t) of between from about 450 ⁇ g-hour/dl to about 600 ⁇ g-hour/dl, preferably 500 ⁇ g-hour/dl to about 550 ⁇ g-hour/dl as determined by a standard AUC (0-t) test.
  • the In[AUC(0- t)] is between from about 1 to about 10.
  • 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.
  • T3 AUC triiodothyronine
  • the In[AUC(0-t)] is between from about 1 to about 5.
  • compositions of the invention are provided in which the active material is a non-granulated material.
  • Prior levothyroxine compositions have been granulated in various size reduction machines to grains of less than, e.g., 5 - 20 microns average particle size in order to be effectively incorporated into the administrable pharmaceutical composition.
  • the granulation process subjects the active material to degrading heat, which can have 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 granulate it before incorporating it into the levothyroxine pharmaceutical product.
  • the raw material is not granulated before incorporation into the pharmaceutical composition. Rather, the ingredients of the preferred pharmaceutical 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 not 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.
  • 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.
  • 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 be granulated, and then dried, which steps interfere with the dissolution of the active material.
  • the drying temperatures employed in manufacturing other active ingredients can cause degradation of the levothyroxine, as experienced in other available thyroxine. It has been found that providing the invention compositions in a non-granulated format helps to reduce or eliminate active agent degradation, presumably by facilitating a reduction in friction, and thus degrading heat, during compression ofthe compositions into pills.
  • the ⁇ -fo ⁇ n microcrystalline cellulose has a bulk density of between from about 0.10 g/cm 3 to about 0.35 g/cm 3 , more preferably between from about 0.15 g/cm 3 to about
  • 0.25 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 to about 0.21 g/cm .
  • the ⁇ -form microcrystalline cellulose are substantially non- conductive.
  • the ⁇ -form microcrystalline cellulose has a conductivity of less than about 200 ⁇ S/cm, more preferably, less than about 75 ⁇ S/cm, still more preferably between from about 0.5 ⁇ S/cm to 50 ⁇ S/cm, most preferably between from about 15 ⁇ S/cm to 30 ⁇ S/cm.
  • a specifically preferred ⁇ -form microcrystalline cellulose is sold by Asahi Chemical Industry Co., Ltd (Tokyo, Japan) as Ceolus (Type KG-801 and or KG-802).
  • 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 ⁇ -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.
  • Reference herein to the "standard impurity test” means a USP recognized assay for detecting and preferably quantitating active drug degradation products.
  • such products include, but are not limited to, at least one of diiodothyronine (T2), triiodothyronine (T3), levothyroxine, t ⁇ iodothyroacetic aci " amide, tri ⁇ odothyroethyiamine, triiodothyroacetic acid, triiodothyroethyl alcohol, tetraiodothyroacetic acid amide, tetraiodothyroacetic acid, triiodothyroethane, and tetraiodothyroethane.
  • T2 diiodothyronine
  • T3 triiodothyronine
  • T3 triiodothyroacetic acid
  • tetraiodothyroacetic acid impurities A preferred impurity test for monitoring levothyroxine and liothyronine breakdown products involves liquid chromatography (LC) separation and detection, more preferably HPLC. Specifically preferred impurity tests are provided below in Examples 5 and 6
  • compositions in accord with the invention include one or more standard disintegrating agents, preferably crosscarmellose, more preferably a salt of same. Still further preferred compositions include a pharmaceutically acceptable additive or excipient such as a magnesium salt.
  • the present invention can be prepared as a direct compression formula, dry granulation formula, 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.
  • 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, vasoconstrictors and migraine treatments, anticoagulants and antithrombotic drugs, analgesics, antihypnotics, sedatives, anticonvulsants, neuromuscular drugs, hyper and hypoglycemic agents, thyroid and antithyroid preparations, diuretics, antispasmodics, uterine relaxants, mineral and nutritional additives, antiobesity drugs, anabolic drugs, erythropoietic drugs, antiasthematics, expectorants, cough suppressants, mucolytics, antiuncemic drugs
  • Typical active medicaments include gastrointestinal sedatives such as metoclopramide and propantheline bromide, antacids such as aluminum trisilicate, aluminum hydroxide and cimetidine, asprin-like drugs such as phenylbutazone, indomethacin, and naproxen.
  • gastrointestinal sedatives such as metoclopramide and propantheline bromide
  • antacids such as aluminum trisilicate, aluminum hydroxide and cimetidine
  • asprin-like drugs such as phenylbutazone, indomethacin, and naproxen.
  • ibuprofen ibuprofen, flurbiprofen, diclofenac, dexamethasone, prednisone and prednisolone, coronary vasodialator drugs such as glyceryl trinitrate, isosorbide dinitrate and pentaerythritol tetranitrate, peripheral and cerebral vasodilators such as soloctidilum, vincamine, naftidrofuryl oxalate, comesylate, cyclandelate, papaverine and nicotinic acid, antimicrobials, such as erythromycin stearate, cephalexin, nalidixic acid, tetracycline hydrochloride, ampicillin, flucolaxacillin sodium, hexamine mandelate and hexamine hippurate, neuroleptic drugs such as fluazepam, diazepam, temazepam, amitryptyline, doxe
  • diltiazem diltiazem, procainamide, disopyramide, bretylium tosylate, quinidine sulfate and quinidine gluconate
  • drags used in the treatment of hypertension such as propranolol hydrochloride, guanethidine monosulphate, methyldopa, oxprenolol hydrochloride, captopril, Actace and hydralazine
  • drags used in the treatment of migraine such as ergotamine
  • drags effecting coagulability of blood such as epsilon aminocaproic acid and protamine sulfate
  • analgesic drags such as acetylsalicyclic acid, acetaminophen, codeine phosphate, codeine sulfate, oxycodone, dihydrocodeine tartrate, oxydodeinone, morphine, heroin, nalbuphine, buto ⁇
  • the amount of pharmaceutically active ingredient in the present composition can vary widely, as desired.
  • 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 %.
  • 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.
  • the preferred amount ofthe 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 an effective amount is utilized to cause the desired pharmacological effect.
  • the dosage forms have a content of levothyroxine in the range of about 25 to 300 micrograms per 145 milligram pill for human applications, and about 100 to 800 micrograms per 145 mg pill for veterinary applications.
  • a goal of levothyroxine replacement therapy is to achieve and maintain a clinical and biochemical euthyroid state, whereas a goal of suppressive therapy is to inhibit growth and/or function of abnormal thyroid tissue.
  • a dose of levothyroxine that is adequate to achieve these goals depends of course on a variety of factors including the patient's age, body weight, cardiovascular status, concomitant medical conditions, including pregnancy, concomitant medications, and the specific nature ofthe condition being treated. Hence, the following recommendations serve only as dosing guidelines. It should be understood by those versed in this art that dosing should be individualized and adjustments made based on periodic assessment of a patient's clinical response and laboratory parameters.
  • levothyroxine when using levothyroxine to treat, it should be taken in the morning on an empty stomach, at least one-half hour before any food is eaten.
  • levothyroxine is preferably taken at least about 4 hours apart from drags that are known to interfere with its absorption.
  • the peak therapeutic effect at a given dose of levothyroxine sodium may not be attained for about 4 to about 6 weeks.
  • the average full replacement dose of levothyroxine sodium is approximately 1.7 mcg/kg/day (e.g., about 100 to about 125 meg/day for a 70 kg adult). Older patients may require less than 1 mcg/kg/day. Levothyroxine sodium doses greater than about 200 meg/day may or may not be required.
  • an initial starting dose of about 25 to about 50 meg/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 meg/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 meg increments until the patient with primary hypothyroidism is clinically euthyroid and the serum TSH has normalized.
  • the recommended initial levothyroxine sodium dose is about 12.5 to about 25 meg/day with increases of about 25 meg/day about every 2 to about 4 weeks, accompanied by clinical and laboratory assessment, until the TSH level is normalized.
  • the levothyroxine sodium dose should be titrated until the patient is clinically euthyroid and the serum free-T 4 level is restored to the upper half of the normal range.
  • levothyroxine therapy may be instituted at full replacement doses as soon as possible.
  • Levothyroxine compositions ofthe present invention may be administered to infants and children who cannot swallow intact tablets by crashing the tablet and suspending the freshly crushed 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 abso ⁇ tion of levothyroxine, such as soybean 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 about 15 mcg/kg/day.
  • a lower starting dose (e.g., about 25 meg/day) may be considered in infants at risk for cardiac failure, and the dose should be increased in 4-6 weeks as needed based on clinical and laboratory response to treatment, hi infants with very low ( ⁇ about 5 mcg/dL) or undetectable serum T 4 concentrations, a recommended initial starting dose is about 50 meg/day of levothyroxine sodium.
  • levothyroxine therapy is usually initiated at full replacement doses, with the recommended dose per body weight decreasing with age (see Dose Table below).
  • an initial dose of about 25 meg/day of levothyroxine sodium is recommended with increments of 25 meg 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 ofthe 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.
  • Levothyroxine sodium tablets, USP, in accordance with the present invention may be supplied as oval or violin-shaped, color-coded, potency marked tablets in, for example, 12 strengths as indicated in the Strength Table
  • 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.
  • the dosage forms have a content of levothyroxine in the range of about 5 to 50 micrograms per 145 milligram pill for human applications.
  • the ⁇ -form microcrystalline cellulose product of the present invention is prepared by forming a wet cake, drying the cake with a dram dryer, then passing the dried product through a screen or mill tor sizing which produces a ⁇ -sheet microcrystalline cellulose which has a flat needle shape, as disclosed in U.S. Patent 5,574,150.
  • ⁇ -sheet microcrystalline product is available from Asahi Chemical of Japan and/or marketed by FMC Company of Newark, Del, under the trademark Ceolus®.
  • the mo ⁇ hology and performance characteristics of the Ceolus® product are different from those of ⁇ - form microcellulose products (for example, Avicel® and Emcocel®), and are suitable for preparing the present stabilized pharmaceutical composition.
  • the amount of ⁇ -form microcrystalline product used in the present composition is at least 50 weight % ofthe final composition.
  • the amount of ⁇ -fonn microcrystalline product is in the range of about 50 to 99 weight %.
  • the amount of ⁇ -fonn microcrystalline product is in the range of about 60 to 90 weight % ofthe final composition.
  • suitable excipients for the present invention include fillers such as starch, alkaline inorganic salts such as trisodium phosphate, tricalcium phosphate, calcium sulfate and sodium or magnesium carbonate.
  • the fillers can be present in the present composition in the range of about 0 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 %.
  • the disintegrating agent is in the range of about 5 to 40 weight %, more preferably about 10 to about 30 weight %.
  • the recommended loading of crosscarmellose is 0.5 to about 2%> by weight.
  • the higher loadings of the disintegrating agents substantially improves the ability ofthe 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 %.
  • Suitable lubricants include magnesium and zinc stearate. sodium stearate fumarate and sodium and magnesium lauryl sulfate. A preferred lubricant is magnesium stearate.
  • the amount of lubricant is typically in the range of about 0 to 5 weight %>, preferably in the range of about 0.1 to 3 weight %.
  • the oral pharmaceutical product is prepared by thoroughly mtermixing the active moiety and the ⁇ -form of microcrystalline cellulose, along with other excipients to form the oral dosage. Food grade dyes can also be added. For example, it is common to distinguish dosages of various potency by the color characteristics of such dyes.
  • a preferred immediate release pharmaceutical composition in tablet form includes levothyroxine sodium, hi a preferred embodiment, the composition includes at least one of, preferably all ofthe following:
  • 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.
  • the composition further comprises at least one pharmaceutically acceptable coloring agent.
  • 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 ⁇ -form microcrystalline cellulose. The trituration is blended with ⁇ -form microcrystalline cellulose and additional excipients and compressed into oral dosages.
  • the formulation batches are a blend of solid compositions of various shapes and sizes. Blending is used to achieve a measure of homogeneity.
  • the active thyroid moiety is desired to be evenly distributed throughout the batch, hi a typical 410 kg batch, the amount of active moiety represents less than 1 kg of the total weight. For example, when producing 145 mg tablets with a 300 meg dosage, approximately 0.8 kg of a 410 kg batch is the active moiety.
  • 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 compression ratio. However, for medicament tablets formed using the present invention a fill to compression ratio from 3.3:1 to 4:1 is needed to obtain desired tablet density.
  • the ⁇ -form microcrystalline cellulose has a lower bulk density, as compared to other excipients.
  • 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 ofthe 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.
  • 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. 2 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 lC.
  • Example 1 tablets comprise the ⁇ -f ⁇ rm microcrystalline cellulose while Control 1 tablets comprise the traditional -for m microcrystalline cellulose.
  • the stability of pharmaceutical formulations of the present invention is improved significantly by the use of the ⁇ - sheet microcrystalline cellulose.
  • Potency loss of the present invention after 15 months is 3.5 %, versus 16.0 %> potency loss experienced in a similar formulation with the ⁇ -form microcrystalline cellulose.
  • the average loss in potency per month in the case of the compositions of the present invention was only about 0.2 % per month, as compared to over 1% per month for the T4 products which included ⁇ -form microcrystalline cellulose, thus demonstrating a stability which is about 3 to 4 times better than the T4 products which utilized ⁇ -form microcrystalline cellulose.
  • Tableting testing was performed on the formulation for Example 1 tablets. Initial results with standard die depths provided a relative standard deviation of 2.2 to 3.5% tablet weight. With the use of the herein described extra deep tablet dies, the- relative standard deviation is 1.2%. Testing was performed on a Manesty tableting machine with compression ratios of from 3.3:1 to 4.0:1.
  • Tablet quality is also dependent upon the storage of the ⁇ -sheet microcrystalline cellulose. Best results are achieved when the cellulose is received in drums or portable containers instead of bags. The bag form suffers from compression during transportation from raw material suppliers. Test results for tableting are presented in attached Exhibit A.
  • Table 5 shows drag stability data for a number ofthe above formulations:
  • formulations of the present invention provide extreme stability for the levothyroxine activity over an extended shelf life for these pharmaceutical products.
  • Example 2
  • Table 8 shows comparative dissolution data for all strengths of Levoxyl ® tablets.
  • 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.
  • 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 admimstered to the patient.
  • 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 tablets are dissolved whole without first grinding the tablets into a powder, as with method number: AM-003.
  • Chromatograph 5 replicate injections of the standard preparation. Record the peak responses as directed under "Procedure”.
  • T 3 / T working standard Dilute to volume with mobile phase and mix well. Label this standard as T 3 / T working standard.
  • concentration of the working standard should be about 0.2 ⁇ g/ml T 3 and 10.0 ⁇ g/ml T 4 .
  • 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 about 7.2 in Fig. 5 A 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.
  • the hardness of the pills lies between about 6.0 and about 14.0 kiloponds.
  • 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 inco ⁇ orate 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.
  • HPLC grade water Store in a plastic container.
  • 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: H3P04; 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.
  • Injection Volume 100 up: next injection after approx. 40 min.
  • Chromatograph 5 replicate injections ofthe Reference I Standard preparation, chromatograpri 2 replicate injections ofthe Reference II Standard. Record the peak responses as directed under "Procedure”. An extraction blank is to be run after the standards.
  • the RSD must not be greater than 2.0% for each ofthe impurities in the standard reference solution I.
  • the resolution factor between liothyronine and levothyroxine in thestandard reference solution I must not be less than 5.0.
  • the Signal to Noise ratio must not be less than 5/1 for levothyroxine and impurities in the chromatogram obtained with standard reference solution II.
  • 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.
  • Standard Reference Solution Preparation: Accurately weigh 10 mg +/- 0.1 mg of each Diiodothyronine, Liothyronine, Levothyroxine, Triiodothyroacetic acid and Tetraiodthyroacetic acid reference standards into a 100ml volumetric flask. Dissolve in Solvent 1 and dilute to volume, stopper and mix well. The concentration of each component will be approximately lOOmcg/mlL.
  • Test Preparation Crush not less than 20 tablets. Tare a 250 ml Erlenmeyer flask. Accurately weigh to the nearest 0.1 mg an equivalent of 500 meg of levothyroxine sodium (+/- 10%) into a 250 ml Erlenmeyer flask. Pipette 100.0 meg 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 ofthe sample will be approximately 5 meg/ml of levothyroxine.
  • Procedure 1. Separately inject lOO ⁇ l ofthe sample preparation onto the column. Record the response ofthe analyte peaks and the calculate % w/w using the equations below.
  • the chromatogram may need to be reprocessed to obtain optimal integration.
  • a copy ofthe sample chromatograph is to be attached to the analytical packet.
  • Triiodothyroacetic Acid Sample area X Std Cone, (meg) X 100ml X 100% % w/w
  • Area rs - is the average area ofthe levothyroxine in the Standard reference solution II
  • Wt. the initial weight ofthe levothyroxine USP standard in mg
  • P the purity ofthe levothyroxine Na USP standard (%purity/100%)
  • 1.0283 conversion of levothyroxine into levothyroxine sodium
  • Area i mpu ri ty is the area of the greatest unknown impurity in the test solution with an area greater than the theoretical area for 0.05% ofthe levothyroxine Na taken into account.
  • Area ref std I is the area ofthe levothyroxine in the standard reference solution
  • Sum area impurity is the sum ofthe areas of all the other unknown impurities in the test solution
  • Area ref std I is the area ofthe levothyroxine in the standard reference solution I
  • A is the initial weight of levothyroxine Na in mg represented by the sample weight.
  • 0.1450gX 100 mcg/mg 2000 is the dilution ofthe reference solution.
  • Results of the test are shown in Figures 6 A 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 Hotliryonine, 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.
  • composition may be altered to achieve a satisfactory resolution factor.
  • the R value must be greater than or equal to proceed.
  • Standard Preparation Accurately weigh 25 mg of USP Levothyroxine RS and transfer to a clear 250-mlL 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 T 4 . The concentration of T 4 is about 100 ⁇ g/ml.
  • T 3 /T 4 working standard Dilute to volume with mobile phase and mix well. Label this standard as T 3 /T 4 working standard.
  • concentration ofthe working standard should be about 0.2 ⁇ g/ml T 3 and 10.0 ⁇ g/ml T 4 .
  • Assay Preparation Weigh and crash not less than the specified tablet quantity and calculate the average tablet weight. Tare a polypropylene weigh boat.
  • Procedure Separately inject 100 ⁇ l ofthe sample onto the column. Record the responses ofthe analyte peak.
  • NGT 2.0% liothyronine calculated as follows:
  • 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 ofthe 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 ofthe 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 HPLC Method for levothyroxine separation (AM-003) for obtaining dosage uniformity, sample area, and standard area results.
  • AM-003 HPLC Method for levothyroxine separation
  • CALCULATIONS Dosage Uniformity Result (% Label Claim)
  • the results confirm an extremely low amount of variability in active material content between the 120 pills tested.
  • 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%.
  • the objective of the study was to determine the bioavailability of Levoxyl ® relative to a reference (oral solution) under fasting conditions.
  • the objective of the study was to determine the dosage-form bioequivalence between three different strengths of Levoxyl ® tablets (low, middle and high range).
  • Test Product Dose. Duration. Mode of Administration, and Batch Number:
  • test product was levothyroxine sodium (Levoxyl ® ) 2 X 0.3mg tablets admimstered as a single oral dose.
  • the batch number utilized in this study was TT26.
  • the reference product was levothyroxine sodium (Synthroid ® ) 2 X 500 ⁇ g injection vials
  • Pharmacokinetic assessment consisted ofthe 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 vital signs, clinical laboratory evaluation (including TSH), physical examination, and adverse events (AEs) assessment.
  • TSH clinical laboratory evaluation
  • AEs adverse events
  • Descriptive statistics (arithmetic mean, standard deviation (SD), coefficient of variation (CV), standard error ofthe mean (SE), sample size (N), mi-oimum, 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. hi 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 demographic variables, and frequency counts were tabulated for categorical demographic variables for each gender and overall.
  • AEs were coded using the 5 th 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 tor 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.
  • 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 meg levothyroxine sodium (Levoxyl ® ) tablets, Lot No.TT25. Subjects randomized to Treatment C received 2 X 300 meg levothyroxine sodium (Levoxyl ® ) tablets, Lot No. TT26. Test products were manufactured by JMI-Daniels, a subsidiary of Jones Pharma Inco ⁇ orated.
  • Pharmacokinetics consisted ofthe detennination of total (bound + free) T4 and
  • T3 concentrations in serum at specified time points following drag administration were calculated.
  • Safety assessment included monitoring of sitting vital signs, clinical aboratory measurements, thyroid-stimulating hormone (TSH), physical examination, electrocardiogram (ECG), and adverse events (AEs).
  • TSH thyroid-stimulating hormone
  • ECG electrocardiogram
  • AEs adverse events
  • Descriptive statistics (arithmetic mean, standard deviation (SD), coefficient of variation (CN), standard error of the mean (SEM), sample size ( ⁇ ), minimum, and maximum) were provided for all pharmacokinetic parameters.
  • SD standard deviation
  • CN coefficient of variation
  • SEM standard error of the mean
  • ⁇ minimum, and maximum
  • 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 5 th 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 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.
  • Pharmacokinetic Results - T3 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 ofthe EarmacoKinetic Parameters of Serum T3 for Treatments A and B
  • 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 pharmacokinetics following administration of 12 X 50 meg Levoxyl ® tablets (Treatment A) 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 In[AUC(0-t)] for T4 and T3 were within the 80% to 125% range required for bioequivalence.
  • test formulations appear to be safe and generally well tolerated when given to healthy adult volunteers.

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Abstract

La présente invention porte en général sur des compositions pharmaceutiques et sur leurs procédés de fabrication et d'administration. Selon une forme d'exécution, l'invention se caractérise par des compositions pharmaceutiques stabilisées qui comprennent des ingrédients actifs d'un point de vue pharmaceutique tels que lévothyroxine (T4) sodium et liothyronine (T3) sodium (médicaments de l'hormone thyroïdienne), de préférence de forme galénique solide à libération immédiate. L'invention porte également sur des procédés de fabrication et d'utilisation de ces compositions stabilisées et à libération immédiate.
PCT/US2002/025752 2001-08-14 2002-08-14 Compositions de levothyroxine et procedes WO2003028624A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002362468A AU2002362468A1 (en) 2001-08-14 2002-08-14 Levothyroxine compositions and methods

Applications Claiming Priority (11)

Application Number Priority Date Filing Date Title
US31227301P 2001-08-14 2001-08-14
US31211401P 2001-08-14 2001-08-14
US31228701P 2001-08-14 2001-08-14
US31211301P 2001-08-14 2001-08-14
US31218401P 2001-08-14 2001-08-14
US31248301P 2001-08-14 2001-08-14
US60/312,273 2001-08-14
US60/312,287 2001-08-14
US60/312,184 2001-08-14
US60/312,113 2001-08-14
US60/312,114 2001-08-14

Publications (2)

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WO2003028624A2 true WO2003028624A2 (fr) 2003-04-10
WO2003028624A3 WO2003028624A3 (fr) 2003-11-06

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PCT/US2002/025854 WO2003061557A2 (fr) 2001-08-14 2002-08-14 Compositions pharmaceutiques a base de levothyroxine, methodes de fabrication et d'administration associees
PCT/US2002/025752 WO2003028624A2 (fr) 2001-08-14 2002-08-14 Compositions de levothyroxine et procedes

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AU (1) AU2002341555A1 (fr)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6645526B2 (en) 2001-11-13 2003-11-11 Mylan Pharmaceuticals, Inc. Storage stable thyroxine active drug formulations and methods for their production
US7052717B2 (en) 2001-11-13 2006-05-30 Mylan Pharmaceuticals Inc. Storage stable thyroxine active drug formulations and methods for their production

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1365745A2 (fr) 2001-02-15 2003-12-03 King Pharmaceuticals, Inc. Compositions pharmaceutiques stabilisees, compositions d'hormone de thyroide et technique de preparation
US7101569B2 (en) 2001-08-14 2006-09-05 Franz G Andrew Methods of administering levothyroxine pharmaceutical compositions
US7829552B2 (en) 2003-11-19 2010-11-09 Metabasis Therapeutics, Inc. Phosphorus-containing thyromimetics
JP2008542301A (ja) 2005-05-26 2008-11-27 メタバシス・セラピューティクス・インコーポレイテッド 脂肪性肝疾患の処置のための甲状腺ホルモン様薬剤
US11202789B2 (en) 2016-11-21 2021-12-21 Viking Therapeutics, Inc. Method of treating glycogen storage disease
CA3064940A1 (fr) 2017-06-05 2018-12-13 Viking Therapeutics, Inc. Compositions pour le traitement d'une fibrose
JP2021518403A (ja) 2018-03-22 2021-08-02 バイキング・セラピューティクス・インコーポレイテッド 化合物の結晶形態及び化合物の結晶形態を生成する方法
EP3890747A4 (fr) 2018-12-05 2022-08-03 Viking Therapeutics, Inc. Compositions pour le traitement de la fibrose et de l'inflammation
US20230023032A1 (en) * 2020-01-13 2023-01-26 Amneal Complex Products Research Llc Sustained release compositions comprising liothyronine
US11964048B2 (en) 2020-12-18 2024-04-23 Amneal Complex Products Research Llc Sustained release compositions comprising liothyronine

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9401892D0 (en) * 1994-02-01 1994-03-30 Boots Co Plc Therapeutic agents
BR9611306A (pt) * 1995-11-14 1999-12-28 Knoll Pharmaceuticals Co Preparação farmacêutica e, composto farmacêutica estável.
US6190696B1 (en) * 1998-06-08 2001-02-20 Pieter J. Groenewoud Stabilized thyroxine medications

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6645526B2 (en) 2001-11-13 2003-11-11 Mylan Pharmaceuticals, Inc. Storage stable thyroxine active drug formulations and methods for their production
US6936274B2 (en) 2001-11-13 2005-08-30 Mylan Pharmaceuticals, Inc. Storage stable thyroxine active drug formulations and methods for their production
US7052717B2 (en) 2001-11-13 2006-05-30 Mylan Pharmaceuticals Inc. Storage stable thyroxine active drug formulations and methods for their production
US7195779B2 (en) 2001-11-13 2007-03-27 Mylan Pharmaceuticals Inc. Storage stable thyroxine active drug formulations and methods for their production

Also Published As

Publication number Publication date
WO2003061557A2 (fr) 2003-07-31
WO2003061557A3 (fr) 2003-11-06
AU2002341555A1 (en) 2003-09-02
WO2003028624A3 (fr) 2003-11-06

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