WO2004014318A2 - Compositions de levothyroxine et procedes - Google Patents

Compositions de levothyroxine et procedes Download PDF

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Publication number
WO2004014318A2
WO2004014318A2 PCT/US2003/025170 US0325170W WO2004014318A2 WO 2004014318 A2 WO2004014318 A2 WO 2004014318A2 US 0325170 W US0325170 W US 0325170W WO 2004014318 A2 WO2004014318 A2 WO 2004014318A2
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WO
WIPO (PCT)
Prior art keywords
composition
levothyroxine
determined
standard
test
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PCT/US2003/025170
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English (en)
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WO2004014318A3 (fr
Inventor
Elaine A. Strauss
G. Andrew Franz
Philip A. Dimenna
Rocco L. Gemma
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King Pharmaceuticals, Inc.
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Priority to AU2003268078A priority Critical patent/AU2003268078A1/en
Publication of WO2004014318A2 publication Critical patent/WO2004014318A2/fr
Publication of WO2004014318A3 publication Critical patent/WO2004014318A3/fr

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    • 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
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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

Definitions

  • 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 Register that Hypothyroidism has a prevalence of 0.5 percent to 1.3 percent in adults. In 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 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.
  • thyroid hormone treatment 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.
  • Hyperthyroidism is a known risk factor for osteoporosis.
  • the dose be kept to the lowest effective dose.
  • thyroid hormone products that are consistent in potency and 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 tetraiodothyronine (T 4 , levothyroxine) or triiodothyronine (T 3 , 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 of the amino acid tyrosine.
  • T 4 contains four iodine atoms and is formed by the coupling of two molecules of diiodotyrosine (DIT).
  • T 3 contains three 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.
  • T 4 and T 3 thyroid hormone are available from a number of producers.
  • liothyronine sodium (T ) 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.
  • a veterinarian preparation of levothyroxine sodium 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 the synthetic T in Levoxyl ® is identical to that produced in the human thyroid gland.
  • the levothyroxine (T 4 ) sodium in Levoxyl ® has an empirical formula of 5 H1 0 L N NaO 4 • H 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 microcrystallme cellulose. Other tableting aids or excipients can be used in this formulation.
  • This '204 patent is incorporated by reference herein, in its entirety.
  • microcrystallme cellulose disclosed in '204 is AVICEL 101 ® , AVICEL 102 ® , AVICEL 103 ® , AVICEL 105 ® , trademarks of FMC Company of Newark, DE., and Microcrystallme Cellulose NF, or EMCOCEL ® , a trademark owned by Penwest Pharmaceuticals of Patterson, NY.
  • These microcrystallme cellulose products are prepared by re-slurrylng the cellulose and spray drying the product. This produces an ⁇ - helix spherical microcrystallme cellulose product.
  • U. S. Patents 5,955,105 and 6,056,975 disclose pharmaceutical preparations of levothyroxine and microcrystallme cellulose, along with other excipients.
  • the microcrystallme cellulose products used in the '105 and '975 patents were also the ⁇ - form Avicel microcrystallme cellulose products.
  • U. S. Patents 5,955,105 and 6,056,975 are incorporated by reference herein, in their entirety.
  • microcrystallme cellulose product is a ⁇ - sheet form microcrystallme 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 microcrystallme 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 microcrystallme cellulose is found in International Journal of Pharmaceutics 182 (199) 155 which is hereby incorporated by reference.
  • the Ceolus ® product ( ⁇ - sheet microcrystallme 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 ® microcrystallme cellulose at levels of from 30 to 45 weight % Ceolus ® product in the form of a tablet.
  • 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 drugs) 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.
  • 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 of the 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 of the active ingredient. In either case, the patient receives the wrong dosage, with possible serious consequences.
  • the use of the ⁇ -sheet microcrystallme 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 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 such a period, and more preferred compositions have a loss of potency of 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 abso ⁇ tion by the gastrointestinal (Gl) 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.
  • immediate release characteristics of the present invention facilitate dosing of patients who maybe 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
  • the invention features an immediate release pharmaceutical composition
  • an immediate release pharmaceutical composition comprising at least one levothyroxine salt, preferably one of such a salt.
  • 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.
  • 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% 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.
  • 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 of the invention have 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 of the agent is thus available for immediate release. In contrast, it is believed that many prior formulations 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, 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 % of the dosage weight composed of the ⁇ - 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 of the compositions of this invention, preferably between from about one to about five of same, more preferably about one of such compositions.
  • ⁇ - 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 % of the ⁇ - 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 oral levothyroxine
  • T3 thyroid hormone drugs
  • 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 99% (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 (experimental) or absence (control) of a carrier or excipient. A specifically preferred potency test is provided in Examples 1 and 3, below.
  • 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) 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 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 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.
  • the In(Cmax) is between from about 0.01 to about 5. See Examples 8 and 9 for more information.
  • 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.
  • T4 levothyroxine
  • 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 present invention include lactose or other sugars as a pharmaceutically acceptable carrier. It has been found however, that sugars such as lactose can react with active agents including the levothyroxine (T4) compositions of the present invention. For example, and without wishing to be bound to theory, it is believed that lactose is particularly damaging to T4 and T3 molecules via Schiff reactions.
  • T4 levothyroxine
  • the invention address this problem by providing compositions that are essentially sugar-free. Particular invention compositions are essentially free of lactose. Additionally, preferred pharmaceutical 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 inco ⁇ orated 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 inco ⁇ orating it into the levothyroxine pharmaceutical product.
  • the raw material is not granulated before inco ⁇ oration 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 abso ⁇ tion 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 of the compositions into pills. Practice of the invention is compatible with several ⁇ -form microcrystalline cellulose grades.
  • the ⁇ -form 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 3 to about 0.21 g/cm 3 .
  • the ⁇ -form microcrystalline cellulose are substantially non-conductive.
  • the ⁇ -form microcrystallme 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 microcrystallme 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.
  • 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.
  • references herein to the "standard impurity test” means a USP recognized assay for detecting and preferably quantitating active drug degradation products.
  • levothyroxine or liothyronine break-downs are to be monitored, such products include, but are not limited to, at least one of diiodothyronine (T2), triiodothyronine (T3), levothyroxine, triiodothyroacetic acid amide, triiodothyroethylamine, triiodothyroacetic acid, triiodothyroethyl alcohol, tetraiodothyroacetic acid amide, tetraiodothyroacetic acid, triiodothyroethane, and tetraiodothyroethane.
  • T2 diiodothyronine
  • T3 triiodothyronine
  • T3 triiodothyroacetic acid
  • tetraiodothyroacetic acid impurities diiodothyronine (T2), triiodothyronine (T3), triiodothyroacetic acid, and 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, antiuricemic drugs, and drugs or substances acting locally in the mouth.
  • 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 drags such as fluazepam, diazepam, temazepam, amitryptyline, dox
  • diltiazem 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 protamine sulfate, analgesic drugs such as acetylsalicyclic acid, acetaminophen, codeine phosphate, codeine sulfate, oxycodone, dihydrocodeine tartrate, oxydodeinone, mo ⁇ hine, heroin, nalbuphine, buto ⁇ hanol tartrate, pentazocine hydrochloride,
  • 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 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 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 of the 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 abso ⁇ tion.
  • 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 of the present invention may be administered to infants and children who cannot swallow intact tablets by crushing the tablet and suspending the freshly crashed 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.
  • 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 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.
  • 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 forais 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 drum dryer, then passing the dried product through a screen or mill for 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 % of the final composition.
  • the amount of ⁇ -form microcrystalline product is in the range of about 50 to 99 weight %.
  • the amount of ⁇ -form microcrystalline product is in the range of about 60 to 90 weight % of the 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 %. This is in substantial excess of the recommended levels of such materials.
  • the recommended loading of crosscarmellose is 0.5 to about 2% by weight.
  • 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 %.
  • 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 intermixing 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 of the 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.
  • 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.
  • compressible medicament tablets 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 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.
  • 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 ⁇ -form microcrystalline cellulose while Control 1 tablets comprise the traditional ⁇ -form microcrystalline cellulose.
  • the composition of Example 1 and Control 1 tablets are presented in Table 1 and stability test results in Table 2:
  • 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 drug stability data for a number of the above formulations: Table 5 - Stability Test - Potency at 25 ° C - % Label Claim
  • formulations of the present invention provide extreme stability for the levothyroxine activity over an extended shelf life for these pharmaceutical products.
  • Table 8 shows comparative dissolution data for all strengths of Levoxyl tablets.
  • 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.
  • 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 administered 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.
  • Mobile Phase 65:35:0.05 H20: CAN: H3P04 degassed and filtered; mobile phase composition may be altered to achieve a satisfactory resolution factor.
  • 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 5 A 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. 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.
  • 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.
  • Sodium Hydroxide 0.1 solution Dissolve 40g of NaOH pellets in 1000 ml HPLC grade water. Store in a plastic container.
  • 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.
  • Injection Volume 100 up: next injection after approx. 40 min.
  • the RSD must not be greater than 2.0% for each of the 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 j ust 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.
  • Standard Reference solution I Pipette 5.0 ml of Stock Standard Reference Solution into a 100 ml volumetric flask, dilute to volume with Solvent 2, stopper and mix well. The Final concentration of each component will be approximately 5mcg/mlL. 3. Standard Reference solution II (0.05%):
  • Test Preparation Crash 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 of the sample will be approximately 5 mcg/ml of levothyroxine.
  • 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.
  • Peaks on the sample chromatograph with areas less than a signal ratio of 5/1 will be considered none detected.
  • Area rs ⁇ - is the average area of the levothyroxine in the Standard reference solution II
  • Area i mpur i ty 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.
  • Area ref std I is the area of the levothyroxine in the standard reference solution
  • 2000 is the dilution of the reference solution.
  • 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
  • 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.
  • 0.1450g X 100 mcg/mg 2000 is the dilution of the reference solution.
  • Figure 6 A 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 hothryonine, 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.
  • 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 .
  • Assay Preparation Weigh and crash not less than the specified tablet quantity and calculate the average tablet weight. Tare a polypropylene weigh boat.
  • NGT 2.0% liothyronine calculated as follows:
  • 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).
  • 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.
  • 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.
  • the reference product was levothyroxine sodium (Synthroid ® ) 2 X 500 ⁇ g injection vials (Knoll Pharmaceutical Company) reconstituted and 600 ⁇ g administered orally.
  • the reference product used was the 500 ⁇ g injection instead of 200 ⁇ g due to the unavailability of sufficient quantities of 200 ⁇ g injection to conduct the study.
  • the batch number utilized in this study was 80130028.
  • Pharmacokinetic assessment consisted of the determination of total (bound + free) T4 and T3 concentrations in seram at specified time points following drag administration. From the seram data, the parameters AUC(O-t), Cmax, and Tmax were calculated.
  • Safety assessment included vital signs, clinical laboratory evaluation (including
  • 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, Infbaseline), 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
  • 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 COST ART 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 seram 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.
  • 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.
  • 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 assessment included monitoring of sitting vital signs, clinical laboratory measurements, thyroid-stimulating hormone (TSH), physical examination, electrocardiogram (ECG), and adverse events (AEs).
  • TSH thyroid-stimulating hormone
  • ECG electrocardiogram
  • AEs adverse events
  • 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.
  • test formulations appear to be safe and generally well tolerated when given to healthy adult volunteers.

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Abstract

L'invention concerne des compositions pharmaceutiques stables ainsi que des procédés de fabrication et d'administration de ces compositions. Dans un mode de réalisation, les compositions pharmaceutiques stabilisées contiennent des principes actifs pharmaceutiques tels que la lévothyroxine (T4) et la liothyronine (T3) sous forme sodée (médicaments hormonaux thyroïdiens), de préférence sous forme d'un solide à libération immédiate. L'invention concerne aussi des procédés de fabrication et d'utilisation de ces compositions stabilisées et à libration immédiate.
PCT/US2003/025170 2002-08-10 2003-08-08 Compositions de levothyroxine et procedes WO2004014318A2 (fr)

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US7829552B2 (en) 2003-11-19 2010-11-09 Metabasis Therapeutics, Inc. Phosphorus-containing thyromimetics
US10130643B2 (en) 2005-05-26 2018-11-20 Metabasis Therapeutics, Inc. Thyromimetics for the treatment of fatty liver diseases
US11202789B2 (en) 2016-11-21 2021-12-21 Viking Therapeutics, Inc. Method of treating glycogen storage disease
US11707472B2 (en) 2017-06-05 2023-07-25 Viking Therapeutics, Inc. Compositions for the treatment of fibrosis
US11787828B2 (en) 2018-03-22 2023-10-17 Viking Therapeutics, Inc. Crystalline forms and methods of producing crystalline forms of a compound

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7829552B2 (en) 2003-11-19 2010-11-09 Metabasis Therapeutics, Inc. Phosphorus-containing thyromimetics
US10130643B2 (en) 2005-05-26 2018-11-20 Metabasis Therapeutics, Inc. Thyromimetics for the treatment of fatty liver diseases
US10925885B2 (en) 2005-05-26 2021-02-23 Metabasis Therapeutics, Inc. Thyromimetics for the treatment of fatty liver diseases
US11202789B2 (en) 2016-11-21 2021-12-21 Viking Therapeutics, Inc. Method of treating glycogen storage disease
US11707472B2 (en) 2017-06-05 2023-07-25 Viking Therapeutics, Inc. Compositions for the treatment of fibrosis
US11787828B2 (en) 2018-03-22 2023-10-17 Viking Therapeutics, Inc. Crystalline forms and methods of producing crystalline forms of a compound

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