Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-11-13
2003-11-11
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S400000, C424S464000, C424S468000, C424S489000, C424S499000, C424S502000, C514S567000
Reexamination Certificate
active
06645526
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates generally to the field of medicinal formulations, and more particularly to methods of preparing storage stable pharmaceutical compositions in unit dosage form of levothyroxine sodium with increased shelf life and compositions made by these methods.
2. Description of the Background Art
Thyroxine active drugs are known for both therapeutic and prophylactic treatment of thyroid disorders. For example, levothyroxine sodium is prescribed for thyroid hormone replacement therapy in cases of reduced or absent thyroid function in e.g., ailments such as myxedema, cretinism and obesity. See, for example, Post and Warren in
Analytical Profiles of Drug Substances,
Vol. 5, Florey (ed.); Academic Press, New York (1976), pp. 226-281. Levothyroxine sodium is quite unstable, hygroscopic and degrades rapidly when subjected to high humidity, light or high temperature. See, for example, Won,
Pharm. Res.
9(1):131-137, 1992. Because of the chemicophysical properties of the drug, formulations of levothyroxine sodium have extremely short stability duration, worsened under conditions of high humidity and temperature. Tablets may decompose approximately 1 percent per month. Gupta et. al.,
J. Clin. Pharm. Ther.
15:331-335, 1990. The stability problem has been so widespread that some drug companies marketing levothyroxine sodium tablets have been forced to recall various batches due to lack of stability.
Formulations containing levothyroxine sodium have been known in the art since the late 1950s. There have been recent attempts to develop more stable dosage formulations of levothyroxine sodium. For example, U.S. Pat. No. 5,635,209 discloses levothyroxine sodium in combination with potassium iodide as part of a stabilizing excipient. In the manufacture of this formulation, levothyroxine sodium was first mixed with microcrystalline cellulose, and then added to a dried granulation of potassium iodide and microcrystalline cellulose. The formulation purportedly provided increased active drug potency over a three month period in comparison to then commercially available formulations.
U.S. Pat. No. 5,225,204 discloses a complex of levothyroxine sodium and a cellulose, polyvinylpyrrolidone or Poloxamer. The formulation may be prepared by dissolving the drug complex in a polar organic solvent, adding a cellulose carrier to the liquid, and drying the resulting mixture to obtain a complex of levothyroxine sodium and polyvinylpyrrolidone or Poloxamer adsorbed on the cellulose carrier.
Although purportedly increasing the stability of the formulation, the deposition onto cellulose may have resulted in some increased stability due to improved content uniformity. Tests of such combinations yielded stability results at best equal to commercially available preparations such as those described in U.S. Pat. No. 5,955,105, and in some cases substantially worse.
The inventors of this stabilized composition teach one of skill in the art away from the use of carbohydrates in levothyroxine sodium formulations, stating that instability of the dosage form was the result of an interaction between the active drug substance and carbohydrate excipients.
The inventors of U.S. Pat. No. 5,955,105 also teach that the instability of thyroxine drugs is due to an interaction between the drug and the excipient. These inventors incorporated into the formulation a soluble glucose polymer designed to eliminate the interaction between the drug and other excipients contained in the final blend.
Because of degradation of the active ingredient in currently available formulations of levothyroxine sodium, new methods of formulating solid dosage forms of this drug would be highly desirable. Although different methods for producing a formulation stable enough to meet requirements for shelf-life have been attempted, no method has been entirely successful. There is, then, a great need for new formulations of thyroxine active drugs with increased stability and shelf life.
SUMMARY OF THE INVENTION
The present invention relates to methods and compositions which increase the stability of levothyroxine sodium and other thyroxine active drugs. This invention prevents the decreases in effective dosage which plague prior art thyroxine active drug formulations and substantially increases shelf life. The compositions include an active thyroxine drug with an alditol and a saccharide. Other optional ingredients in the composition include but are not limited to pharmaceutically acceptable excipients such as cellulose polymers or carbohydrates, disintegrants, lubricants and glidants.
Accordingly, the present invention provides a storage stable oral pharmaceutical composition which comprises a therapeutically effective amount of a thyroxine active drug and stabilizing amounts of an alditol and a saccharide. In a preferred embodiment, the thyroxine active drug is levothyroxine sodium, the alditol is mannitol, and the saccharide is sucrose. In yet another embodiment, compositions of the invention comprise at least one further pharmaceutical excipient, such as a carbohydrate, a starch or a modified starch, for example microcrystalline cellulose. In yet a further embodiment, this invention provides storage stable oral pharmaceutical compositions in unit dosage form comprising the compositions discussed above, and particularly a storage stable oral dosage form composition which comprises levothyroxine sodium, mannitol, sucrose, and optionally further comprises microcrystalline cellulose, polyvinylpyrrolidone, crospovidone, magnesium stearate, sodium lauryl sulfate, and colloidal silicon dioxide. The invention preferably provides such storage stable oral dosage forms in the form of tablets.
A preferred embodiment of the invention encompasses a storage stable oral pharmaceutical composition which comprises a therapeutically effective amount of levothyroxine sodium; about 58% by weight mannitol; about 14% by weight sucrose; about 25% by weight microcrystalline cellulose; about 1.5% by weight polyvinylpyrrolidone; about 1.4% by weight magnesium stearate; about 0.3% by weight colloidal silicon dioxide; and about 0.1% by weight sodium lauryl sulfate.
Another preferred embodiment of the invention encompasses a storage stable oral pharmaceutical composition which comprises a therapeutically effective amount of levothyroxine sodium; about 39% by weight mannitol; about 23% by weight sucrose; about 28% by weight microcrystalline cellulose; about 1.5% by weight polyvinylpyrrolidone; about 6% by weight crospovidone; about 2% by weight magnesium stearate; about 0.3% by weight colloidal silicon dioxide; and about 0.1% by weight sodium lauryl sulfate.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to storage stable granulation intermediates and oral pharmaceutical compositions in unit dosage form of a thyroxine active drug and methods by which they are produced. The methods involve a granulation intermediate containing the thyroxine active drug substance, an alditol, and a monosaccharide or disaccharide to provide a formulation with an increase of stability of both the granulation intermediates and the final oral dosage forms prepared from these granulation intermediates. Thus, the present invention provides a stable dosage form in which the dosage of thyroxine active drug is maintained at a predictable level for a longer period of time.
Formulations of levothyroxine with greatly increased resistance to degradation can be produced by providing excipients which reduce or eliminate degradation of the active substance. Although the prior art indicates that reaction between levothyroxine sodium and certain carbohydrate, monosaccharide or disaccharide excipients is responsible for the poor stability of the drug, the present inventive formulation achieves surprisingly stable levothyroxine dosage forms using these previously disfavored excipients. Additionally, preferred formulations are maintained at a pH of less than about 10.
The methods and formulations of this invention take advantage of the
Hanshew, Jr. Dwight D.
Wargo David John
Mylan Pharmaceuticals Inc.
Oh Simon
Page Thurman K.
Rothwell Figg Ernst & Manbeck
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