Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
2000-03-30
2002-06-04
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S464000, C424S465000, C514S960000
Reexamination Certificate
active
06399101
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is directed to therapeutic agents for the treatment of hormone disorders and the method for preparing those agents. More specifically, the present invention relates to stable pharmaceutical preparations containing thyroxine drugs, especially levothyroxine sodium, which is the sodium salt of the levo isomer of thyroxine. L-thyroxine is the principal hormone secreted by the normal thyroid gland. The thyroid gland is stimulated to secrete thyroid hormones by the action of thyroid stimulating hormone (TSH), which is produced in the anterior pituitary gland. TSH secretion is then controlled by thyrotropin-releasing hormone (TRH), produced in the hypothalamus. Thyroid hormones circulating in the blood act as feedback inhibitors of both TSH and TRH secretion.
Thyroxine may be obtained from the thyroid gland of domesticated animals, or alternatively, the hormone can be prepared synthetically. Levothyroxine and other thyroid hormones are known to serve as specific replacement therapy when the thyroid function has been reduced or is completely absent for a variety of disease states, including, for instance, myxedema, cretinism and obesity. Levothyroxine is also indicated as a pituitary TSH suppressant in the treatment or prevention of euthyroid goiters.
2. Brief Description of Related Art
Pharmaceutical preparations containing levothyroxine hormone are known to exhibit deficiencies with regard to uniformity, stability and shelf life. More specifically, levothyroxine sodium hormone is hygroscopic and degrades rapidly under conditions of high humidity or in the presence of other moisture sources or light and under conditions of high temperature. Moreover, levothyroxine is known to degrade in the presence of certain pharmaceutical excipients such as carbohydrates, including lactose, sucrose, dextrose and starch, as well as certain dyes.
Commercial preparations currently marketed include Levothroid®, Levoxyl®, Synthroid® and Levo-T®. These products, which include lactose as the major component of the excipient matrix, exhibit poor characteristics with regard to stability and uniformity. As noted in the
Handbook of Pharmaceutical Excipients
, Second Edition, p. 257, a Maillard-type condensation reaction is likely to occur between lactose and compounds with a primary amine group to form brown-colored products. Accordingly, it has been found that lactose reacts with levothyroxine resulting in degradation of the drug. It is believed that the amino group of the L-tyrosine portion of the levothyroxine molecule reacts with the glycosidic hydroxyl group of the glucose unit of the lactose excipient, undergoing the Maillard reaction. This degradation of levothyroxine results in decreased stability for the drug formulation. There is, then, a need in the art for a levothyroxine formulation which does not utilize lactose or other excipients which can react with the levothyroxine and lead to degradation of the drug.
A few attempts have been made to prepare thyroxine formulations without the excipients of the commercial products described above. U.S. Pat. No. 5,225,204, issued to Chen et al, describes a dosage formulation complex of hydrated levothyroxine sodium which includes Poloxamer or polyvinylpyrrolidone and is granulated with a polar organic solvent before being uniformly adsorbed on a cellulose compound. Other embodiments of the '204 patent describe a levothyroxine sodium formulation prepared with the use of an organic solvent or in a dry state by mixing levothyroxine sodium with a cellulose complexing agent and subsequently combining this mixture with a cellulose carrier. No data on the stability of these formulations was provided.
U.S. Pat. No. 5,955,105, issued to Knoll Pharmaceutical Company, describes thyroid hormone preparations stabilized by an inorganic salt, a carbohydrate having a molecular weight of greater than 500, or glycine. Suitable carbohydrate binders include microcrystalline cellulose, maltodextrin, starch and hydroxypropyl cellulose having a molecular weight between 80,000 and 1,150,000. Preferred embodiments of the invention were prepared in the substantial absence of lactose, glucose, sucrose, polyvinylpyrrolidone, and/or a Poloxamer. According to the '105 patent, the levothyroxine formulations of U.S. Pat. No. 5,225,204 did not provide suitable stability. Example 1 involved the use of PVP and example 2 involved dry mixing levothyroxine sodium with hydroxypropyl cellulose with subsequent combination of this mixture with a microcrystalline cellulose carrier. These examples of the '204 patent were repeated by the applicants of the '105 patent and the formulations were subjected to stability tests. The results of these tests are provided in the '105 patent.
U.S. Pat. No. 5,635,209, issued to Vintage Pharmaceuticals, Inc., is directed to a stabilized composition of levothyroxine sodium medication containing potassium iodide and a microcrystalline cellulose. This formulation may also include a disintegrant, a lubricant and a dye. The composition of the '209 patent is undesirable since it includes the extra ingredient potassium iodide, which distorts the results of a determination of the stability of the levothyroxine sodium.
U.S. Pat. No. 5,753,254, issued to Knoll Aktiengesellschaft, relates to a solid fast dispersing dosage form wherein the therapeutic agents containing thyroid hormones have a formulation including the hormone, a disintegrating agent, a flavoring agent and a lubricating agent. The disintegrating agent may be starch, agar, bentonite, cellulose, microcrystalline cellulose, methylcellulose, carmellose, croscarmellose sodium, alginic acid, guar gum, silicon dioxide and sodium lauryl sulphate. The flavoring agent may be a sweetening agent, a peppermint oil and/or fruit flavor, a flavor enhancing agent or an ingredient which induces the formation of saliva, such as an organic acid like citric and malic acid. The lubricating agent may be magnesium stearate, calcium stearate, stearic acid and mixtures thereof. Optional ingredients may also be present. This formulation is intended to be fast dissolving and stability issues are not discussed.
Each of these patents attempts to remedy the deficiencies of the commercial levothyroxine products by using various excipients besides the standard lactose. Microcrystalline cellulose (MCC) is widely used as a filler and binder for pharmaceutical formulations prepared by both wet granulation and direct compression processes. However, as set forth in the '105 patent, the combination of levothyroxine and microcrystalline cellulose as disclosed in the '204 patent did not provide adequate stability. Moreover, microcrystalline cellulose used in direct compression tableting has a number of limitations, such as low bulk density, high lubricant sensitivity, poor flow characteristics and the influence of moisture on the compression characteristics.
Thus, there is still a need in the art for a stable, uniform formulation of levothyroxine which can be readily formed into dosage forms and which is substantially free of the disadvantages, defects and limitations of the formulations disclosed in the art.
An object of the present invention is to provide a stable thyroid hormone preparation which can be readily formed into a dosage formulation. A further object of this invention is to provide a stabilized preparation of a thyroid hormone which resists degradation by light, heat, humidity or association with commonly used excipients. Another object of the present invention is to provide a novel pharmaceutical preparation and a manufacturing process therefor to improve the product performance of levothyroxine sodium tablets in terms of uniformity, stability and shelf life.
A further object of the invention is to provide a pharmaceutical preparation in which an excipient provides a matrix to capture and protect levothyroxine sodium in order to stabilize the preparation. Another object of the present invention is to provide a process for
Bruno Maria S.
Frontanes Ramon A.
Garcia Hector L.
Perez Maria A.
Simamora Pahala
Burns Doane Swecker & Mathis L.L.P.
Mova Pharmaceutical Corp.
Nguyen Helen
Webman Edward J.
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