Stabilized composition of levothyroxine sodium medication and method for its production

The invention discloses a medication which requires the combination of levothyroxine sodium and potassium iodide, with the potassium iodide acting as a stabilizing excipient, the presence of which results in a more stable levothyroxine sodium medication and provides for longer shelf life of the medication. A method for manufacturing the disclosed medication is also provided.

INTRODUCTION 
Levothyroxine sodium is prescribed in thyroid replacement therapy. It is 
often prescribed in tablet form. Clinically, levothyroxine sodium serves 
as specific replacement therapy for reduced or absent thyroid function of 
any etiology, including human ailments such as myxedema, cretinism and 
obesity, in non-exclusive particular. The levothyroxine sodium is normally 
expressed chemically as C.sub.15 H.sub.10 I.sub.4 NaO.sub.4 XH.sub.2 O. 
Levothyroxine sodium is not a very stable compound. It is well known that 
the stability of the levothyroxine sodium hormone is quite poor, since it 
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, especially in the presence of other pharmaceutical 
excipients such as carbohydrates, including lactose, sucrose, dextrose and 
starch, as well as certain dyes. Due to this inherent instability, tablet 
formulations of levothyroxine sodium tend to degrade rapidly, particularly 
under conditions of high humidity and temperature. Gupts, et al, have 
reported that some tablets decompose by approximately 1% per month, while 
others decompose by up to 40% in 30 days once the bottles containing the 
tablets are opened. It is not uncommon for levothyroxine sodium tablets to 
be dispensed in quantities for up to 100 days' supply at a time. "Effect 
of Excipients on the Stability of Levothyroxine Sodium Tablets," Journal 
of Clinical Pharmacy and Therapeutics, (1990) 15, 331-336. It is, 
therefore, desirable to manufacture levothyroxine sodium tablets which are 
more stable than those known in the prior art, so that the percentage of 
the active ingredient of levothyroxine sodium will not diminish over time 
as quickly as with the more unstable tablets. 
Various dry dosage formulations containing levothyroxine sodium, as well as 
processes of manufacture, are known in the art. U.S. Pat. No. 2,889,363, 
issued Jun. 2, 1959, to Ginger, et al and U.S. Pat. No. 2,889,364, dated 
Jun. 2, 1959, also to Ginger, et al., detail processes for producing 
thyroxine sodium. These prior art formulations experience stability 
problems. 
One disclosure of a claimed stable dosage of levothyroxine sodium is found 
in U.S. Pat. No. 5,225,204, issued Jul. 6, 1993, to Chen, et. al., which 
details the use of polyvinylpyrrolidone or Poloxamer as a stabilizing 
complexing agent. The present invention differs from Chen's in several 
respects, not the least of which is in the use of potassium iodide as the 
stabilizing excipient. 
The present invention discloses the use of potassium iodide as an excipient 
used in the manufacture of levothyroxine sodium medication, resulting in a 
more stable end product. It is an object of the invention to obtain a 
levothyroxine sodium tablet which retains its potency longer and, 
therefore, has a greater shelf life. It is a further object of this 
invention to develop a process by which to manufacture the more stable 
levothyroxine sodium medication and tablets. 
THE INVENTION 
In a preferred embodiment of the invention, a levothyroxine sodium 
trituration of 1.05% is obtained, with the other 98.95% of the trituration 
being composed of microcrystalline cellulose, NF PH101. The preferred 
embodiment also includes combining granulated potassium iodide with 
microcrystalline cellulose to form a potassium iodide granulation, such 
that the potassium iodide portion ranges from 0.1% to 0.7% of the 
granulation with the rest of the granulation being microcrystalline 
cellulose. 
The more stable levothyroxine medication of the present invention is 
manufactured by physically combining the levothyroxine trituration with 
the potassium iodide granulation, and also adding croscarmellose sodium, 
which acts as a disintegrant, and magnesium stearate, which acts as a 
lubricant. A colored dye may also be used. The resulting combination may 
then be formed into tablets. By varying the concentration of the potassium 
iodide with respect to the microcrystalline cellulose in the potassium 
iodide granulation, the percentage of the levothyroxine sodium in the end 
product active ingredient is thereby varied. This allows for increasing or 
decreasing the strength of the active ingredient in tablets formed. 
It is therefore an object of this invention to provide a stabilized 
formulation of levothyroxin sodium which resists degredation by light, 
heat, humidity or association with commonly used excipients. 
Another object of this invention is to provide a stabilized dosage 
formulation complex of levothyroxine sodium and potassium iodide. 
A still further object of this invention is to provide a stabilized complex 
of levothyroxine sodium which is capable of being mixed with suitable 
excipients and compressed into tablets or placed in capsules as dosage 
structures characterized by uniform distribution of levothyroxine sodium 
in the tablet matrix or capsule. 
Another object of this invention is to provide a process for producing a 
stabilized dosage formulation containing levothyroxine sodium using 
potassium iodide as a stabilizing excipient. 
Yet another object of this invention is to provide a method for producing 
stabilized levothyroxine sodium dosage formulations which are suitable for 
mixing with various pharmaceutically acceptable excipients and compression 
into tablets or filling capsules.

DETAILED DESCRIPTION OF THE INVENTION 
The present invention discloses a new composition for levothyroxine sodium 
medication which provides for greater shelf life of levothyroxine sodium 
tablets, because the composition is more stable and less susceptible to 
degradation over time. The present invention also discloses a method for 
manufacturing the more stable composition. 
In one embodiment of the invention, the levothyroxine sodium medication is 
prepared by combining the following components to create the final 
product: 
Levothyroxine Sodium Trituration 
Potassium Iodide Granulation 
FD&C Yellow #6 Lake 38% Dye 
D&C Yellow #10 Lake 15% Dye 
Croscarmellose Sodium, NF 
Magnesium Stearate, NF 
Levothyroxine Sodium Trituration 
The levothyroxine sodium trituration is made up of 1.05% levothyroxine 
sodium and 98.95% microcrystalline cellulose. In one embodiment of the 
invention, the microcrystalline cellulose is NF PH101, while the 
levothyroxine sodium is USP. 
Potassium Iodide Granulation 
The potassium iodide granulation component of the present invention is 
composed of potassium iodide and microcrystalline cellulose. The 
percentage of potassium iodide varies from 0.1% to 0.7% while the 
percentage of microcrystalline cellulose varies from 99.9% to 99.3%, 
respectively. In one embodiment of the invention, potassium iodide is 
dissolved in deionized water to make a potassium iodide solution. 
Microcrystalline cellulose is placed in a blender and the potassium iodide 
solution is slowly added to the blender to create a wet potassium iodide 
granulation. The microcrystalline cellulose is used as a carrier. 
Alternative carrier materials, known in the prior art, may also be used. 
The wet granulation is transferred to a drying apparatus. The drying 
process is continued until the granulation is dried to .+-.1.0% units of 
initial moisture. The granulation is then screened to provide a potassium 
iodide granulation of uniform particle size. 
One embodiment of the invention uses a potassium iodide granulation 
consisting of 0.1% potassium iodide and 99.9% microcrystalline cellulose. 
In that embodiment, to prepare the potassium iodide granulation for an 
ultimate batch size of 3 million tablets, with each tablet containing 0.10 
mg of potassium iodide, the potassium iodide granulation is prepared by 
dissolving 300.000 grams of potassium iodide into 60.00 kg of deionized 
water and adding to that solution 299.700 kg of microcrystalline 
cellulose. 
In another embodiment of the invention wherein the potassium iodide 
granulation component is comprised of 0.70 mg of potassium iodide per 
tablet, to prepare a batch size of 3 million tablets, the potassium iodide 
granulation is prepared by dissolving 2100.000 grams of potassium iodide 
into 60.00 kg of deionized water, and thereafter adding to that solution 
297.90 kg of microcrystalline cellulose. 
Stabilized Levothyroxine Sodium Medication 
The stabilized levothyroxine sodium medication is manufactured by combining 
the levothyroxine sodium trituration with the potassium iodide 
granulation, and other components. In one embodiment of the invention, a 
batch size of 1 million tablets is prepared with each tablet size being 
100 mg. The relative strength of the levothyroxine sodium active 
ingredient in each 100 mg tablet is varied by varying the percentage of 
potassium iodide in the potassium iodide granulation used in the process. 
The dosage of the levothyroxine sodium per tablet typically varies from 25 
.mu.g per tablet, to 300 .mu.g per tablet, and includes various dosages in 
between. 
As an example, to create a batch of 1 million tablets of tablet size 100 mg 
each, with dosage of 100 .mu.g of levothyroxine sodium per tablet, the 
following components and amounts are added together in a blender: 
10.000 kg of Levothyroxine Sodium Trituration 1.05% 
1,000.000 gm of Croscarmellose Sodium MF 
20.000 gm of FD&C Yellow #6 Lake 38% Dye 
310.000 gm of D & C Yellow #10 Lake 15% Dye 
52.86 kg of microcrystalline cellulose with the KI granulation of 0.1% 
35.31 kg of microcrystalline cellulose with the KI granulation of 0.7% 
Varying the amount of potassium iodide will cause a variation in the 
dosages of levothyroxine sodium per tablet. The amount of potassium iodide 
required for a stabilized tablet with a levothyroxine sodium dosage of 25 
.mu.g, is four times the amount of levothyroxine sodium used. To obtain a 
more stable dosage of 300 .mu.g of levothyroxine sodium, the ratio of 
potassium iodide to levothyroxine sodium is 1.5 to 1. 
The components mentioned above are blended to ensure maximum physical 
mixing. Then 500.000 gm of magnesium stearate, NF, are added to the 
blended mixture, and the resulting combination is again blended to ensure 
maximum physical mixing. The resulting levothyroxine sodium medication is 
then compressed into tablets using known, prior art procedures. In one 
embodiment of the invention, the tablets are yellow, biconvex, round, and 
debossed, and the tablets weigh 100 mg, .+-.3%. 
Testing Conducted to Show Stabilized Nature of New Medication 
The medication disclosed herein was subjected to testing to determine the 
increased level of stability obtained by the addition of potassium iodide 
in the manner disclosed. What was desired was to determine the increased 
stabilization of the levothyroxine sodium 100 .mu.g tablets over time, 
when subjected to the influence of a variety of environmental factors such 
as temperature and humidity. The length of the studies and the storage 
conditions were sufficient to cover the environment during normal storage, 
shipment, and subsequent use of levothyroxine sodium tablets. A short-term 
three month accelerated testing was carried out at a temperature of 
40.degree. C. and 75% relative humidity (RH) conditions for that 
temperature. The data obtained from the accelerated testing was used to 
evaluate the stability of the products. 
Two batches of levothyroxine sodium tablets were subjected to the 
environmental testing. The first batch consisted of 100 .mu.g tablets 
obtained from a current commercially available source. The second batch 
subjected to the identical testing was of the composition of the 
stabilized levothyroxine sodium medication as disclosed herein. Both 
batches were tested for the potency of the levothyroxine sodium active 
ingredients over time. The potency was tested at the following points in 
time: before being subjected to the environmental testing, and then every 
month thereafter over the three-month testing period. 
Table 1 discloses the results of the test and indicates that the disclosed 
formulation of levothyroxine sodium medication in the present invention 
retains greater potency over time than other known formulations, and is 
therefore more stabilized. 
TABLE 1 
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Percent Potency of Levothyroxine Sodium 
Commercial New Stabilized 
Time Formulation 
Formulation 
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Initial 100% 98.2% 
1 month 95.4% 98.6% 
2 month 92.8% 96.1% 
3 month 86.2% 95.7% 
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