Stabilized thyroxine medications

Details Stabilized thyroxine medications Stabilized thyroxine medications

1999-06-07

2001-02-20

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S465000, C424S475000, C514S005200

Reexamination Certificate

active

06190696

ABSTRACT:

Thyroxine and Liothyronine containing medications are and have been used for many years to treat thyroid deficiency and related illnesses. In administering thyroxine and or liothyronine products it is important to assure that the patient is receiving the correct dose, customized to his or her particular needs.
Many individual tablet strengths are available to allow the physician to titrate their patients accurately.
An example is Levothyroxine Sodium that is available in 10 individual strengths ranging from 25-300 mcg per tablet.
This group of compounds can be extracted from glands or made synthetically. A well known problem encountered by many manufacturers of these products is their inherent thermo-labile nature. These compounds degrade rapidly during their shelf life causing sub-potency that can potentially lead to under-medicated patients.
In order to compensate for this rapid degradation, manufacturers customarily add an excess of the active ingredient.
This in turn has led to super potent product being released to the market that lose a significant percentage of their potency over their claimed shelf life.
Most if not all products currently available have potency inconsistencies over their shelf life.
The use of super potent products is of course as undesirable as the use of sub potent products.
Although these products have been offered for many years without FDA approval (thyroxine products are “grand fathered”), the FDA has stated that it requires manufacturers to file a New Drug Application with the agency.
As reason FDA stated in a Federal Register notice in August 1997 that “no currently marketed orally administered levothyroxine sodium product has been shown to demonstrate consistent potency and stability and, thus, no currently marketed levothyroxine is generally recognized as safe and effective” FDA noted that “almost every manufacturer of orally administered levothyroxine sodium products, including the market leader, has reported recalls that were the result of potency or stability problems.”
Since 1991, the agency reported, “there have been no less than 10 firm-initiated recalls of levothyroxine sodium tablets involving 150 lots and more than 100 mil. tablets. In all but one case, the recalls were initiated because tablets were found to be subpotent or potency could not be assured through the expiration date.”
Stability problems with levothyroxine products have been the subject of two warning letters since 1991. FDA said “this pattern of stability problems suggests that the customary two-year shelf life may not be appropriate for these products because they are prone to experience accelerated degradation in response to a variety of factors.”
To further increase the quality of care provided to patients with insufficient thyroid function it is important to provide access to medication that has a consistent potency over its claimed shelf life. This will allow the endocrinologist to accurately titrate their patients without the potential that variation in thyroxine batches will cause clinical changes and considerable discomfort to the patient that can even result in hospitalization.
DESCRIPTION OF THE PRIOR ART
Various prior art formulations are disclosed in the U.S. Patents to Kummer, et al., U.S. Pat. No. 4,110,470; Miller, et al., U.S. Pat. No. 4,585,652; Anderson, et al., U.S. Pat. No. 4,818,531; Sloan, U.S. Pat. No. 5,001,115; Ginger, et al., U.S. Pat. No. 2,889,363;Ginger, et al., U.S. Pat. No. 2,889,364; Chen, et al. U.S. Pat. No. 5,225,204; and Groenewoud, et al., U.S. Pat. No. 5,635,209.
In the U.S. Pat. No. 2,889,364; Chen et al., methods are described using poloxamer and other compounds as a stabilizing complex former in combination with levothyroxine and cellulose compounds. It also describes the use of cellulose compounds alone as the stabilizer in both dry and solvent based processes. A major disadvantage of a wet granulation process in particular when water and heat is used as stated in this patent is that one will have to compensate in advance for the degradation that will occur during the process leaving unknown degradation products in the finished stabilized product. The use of cellulose compound to achieve stabilization in dry processes will circumvent this, however the stabilizing effect of cellulose compounds is limited and much less effective than for example Sodium Iodide.
Chen, et al. also teach to avoid the use of lactose and other saccharides since these compounds are known to degrade thyroxine medications more rapidly. Some of these well accepted excipients have very desirable tableting characteristics and can be used in my invention after careful isolation of thyroxine in granules composed of a stabilizing matrix and the active compound. Yet another disadvantage is the use of some of the solvents that are suggested such as methylene dichloride and methanol that are quite toxic and for which the United States Pharmacopoeia XXIII (USP), has extremely low acceptance limits for residues of these substances in the finished product. Current chemical processes mostly avoid chlorinated and other toxic solvents altogether wherever possible. In my new invention only purified water or ethanol is used before contact with thyroxine to avoid initial degradation. In my new invention heat is only used in a process step before the thyroxine or liothyronine is added for the same reason not to cause any initial degradation. Water of course is non-toxic and ethanol has very limited toxicity, if any, at the level used in my invention. Chen et al. also suggests the use of calcium phosphate, calcium carbonate and calcium sulfate. However in a letter (Letters—Mar. 11, 1998) to the Journal of the American Medical Association, researchers report reduction of levothyroxine efficacy if used simultaneously with calcium carbonate. The report furthers states “Calcium carbonate itself or, alternatively excipients or contaminants in the preparation could form insoluble chelates with levothyroxine.”
In my new invention the use of calcium and other multivalent ions is avoided to further improve the stability and efficacy of the medication.
In my prior U.S. Pat. No. 5,635,209 a method is described wherein levothyroxine sodium titration is physically combined with potassium iodide and other ingredients to form a more stable formulation.
While the composition described in U.S. Pat. No. 5,635,209 is suitable for its intended use it has several limitations and disadvantages. For example potassium iodide is used in varying levels ranging from 0.1% to 0.7%. Although the levels suggested for the lower strengths do not exceed recommended daily allowances (RDA) the higher levels do exceed this level. This can potentially lead to undesirable effects caused by excess iodine intake especially when these medications are taken in combination with multivitamin and mineral combinations. For example Flintstones® multi vitamin tablets for children and other brands contain 150 mcg of iodine which is equivalent to the RDA.
A carefully selected level of iodine compounds in my new invention is less than the daily recommended allowance.
In my new invention only one level is used for the lower as well as the higher strengths and in one particular process described in my new invention far less than the normal daily intake. Yet the stabilizing effect is sufficient to provide significantly improved stability without any concern about the high iodide levels, especially for the pediatric patient population.
Another disadvantage of the use of potassium iodide is the potential of metathesis with Levothyroxine sodium. The potassium from the potassium iodide can potentially take the place of the sodium on the thyroxine molecule and vice versa. This can potentially lead to a change in the dissolution rate and essentially change the compound from the identity claimed on the label of the medication. My new invention describes the use of sodium iodide which does not present this undesirable potential reaction.
Also U.S. Pat. No. 5,635,209 does not include the combination products of levothyroxine sodium and

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