Title:  Stabilized thyroxine medications

United States Patent:  6,190,696

Appl. No.:  327256

Thyroxine medications which include combinations of levothyroxine, and/or liothronine, or dextrothyroxine, or thyroid, and one or more iodine salts, or iodine donor compounds are described, which produce a stable thyroxine medication, with a long shelf life. A method for manufacturing the medications is also described.

DESCRIPTION OF THE PRIOR AND INVENTION

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.RTM. 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 liothryronine sodium or thyroid gland preparation furthermore it only describes the process of stabilizing levothyroxine sodium in the finished product.

My new invention describes a way to stabilize the raw materials itself to increase the flexibility in which the invention can be used as described in the examples of the invention. In addition to the increased flexibility of the use of this stabilized levothyroxine or liothyronine concentrate it brings the level of the suitable iodine salts down to levels that are far less than the RDA and therefore do not add significantly to normal dietary and/or supplemental intake.

Also neither one of the two inventions describe the use of antioxidants. This new invention will show how an antioxidant can be effectively used to further aid in the stabilization if the said medications.

Levothyroxine Sodium and Liothyronine Sodium Stability

The instability of levothyroxine and liothyronine has been known for a long time. Levothyroxine and liothyronine are degrade through oxidation and or de-iodination and other excipient/active interactions in which de-iodination appears to be the predominant degradation pathway.

Of interest is the article by Rapaka et al. that describes the difference between the stability of liothyronine and levothyroxine. The two co-valently bound iodine atoms in the 1 and 5 position are the least stable, once 1 iodine atom becomes detached the resulting compound is even less stable and more likely to lose the second iodine atom.

The inventions demonstrates that levothyroxine and liothyronine can be stabilized by embedding the active particles in a matrix that contains an effective stabilizer in the form of an iodide salt of for example sodium. The resulting action is stabilization of the levothyroxine particle without it being necessary that the stabilizing agents interact by surrounding the individual thyroxine molecules.

One would expect to see better stabilizing action the more iodide is used however an optimum concentration is reached around 0.1% iodide and above approximately 0.3% iodide in a 100 mg tablet containing 100 mcg levothyroxine sodium it starts to interfere with the stability of the active compound.

Since another degradation pathway is oxidation the addition of a specially prepared antioxidant will further aid in the stabilization of levothyroxine sodium and liothyronine sodium.

Further degradation can be prevented through careful selection of excipients that have proper tableting or encapsulation characteristics without exerting destabilizing effects on the active compounds.

Such compounds are for example but not limited to:

Microcrystalline cellulose, especially newly introduced grades by FMC: Avicel.RTM. (brand name of microcrystalline cellulose) PH-112, and low moisture grade specifically developed for moisture sensitive products with a mean particle size of 90 micron this grade is free flowing to facilitate tableting with good weight control. Avicel PH-113, also low moisture but with a smaller particle size to better facilitate wet granulations with for example alcohol. Avicel.RTM. PH-200 is a large particle grade specifically used as a tableting binder with superior flow characteristics. Avicel.RTM. PH-301, PH302 and the older products PH-101, PH-102 can also be used in a satisfactory manner although the older grades may have some minor disadvantages as it relates to product flow and moisture content. The most recent innovation in the microcrystalline cellulose product line is Ceolus.RTM., also introduced by FMC. Ceolus.RTM. can be used to produce hard tablets because of its flatter structure than regular microcrystalline cellulose; it is prepared from wood pulp from specially selected grades of wood.

Mendel offers a similar product line for microcrystalline cellulose, as Emcocel.RTM. and generic equivalents for the older types are also available. Grades of microcrystalline are typically used as dry binders in tableting, in wet granulations since they can absorb significant quantities of liquids because of their porous structure, as diluents in powders for encapsulation and as carriers for actives and or excipients.

Grades of microcrystalline cellulose also exert some disintegration properties and are considered chemically inert towards most active ingredients.

A newly introduced innovation by Mendel is Prosolv.TM. or silicified microcrystalline cellulose, which is a highly compressible co-processed combination of microcrystalline cellulose with colloidal silicon dioxide.

It has superior tableting characteristics and is offered in two grades, one for wet granulations (Prosolv SMCC.TM.50) and one as a dry binder/diluent (Prosolv SMCC.TM.90). Although it has different characteristics compared to regular microcrystalline cellulose it has retained all desired properties of these compounds.

As disintegrant several compounds can be used such as sodium starch glycolate especially Explotab.RTM. CLV, that through high cross linking has a lower viscosity than the regular grade and has a more robust disintegration action compared to regular sodium starch glycolate.

Another suitable disintegrant is Emcosoy.RTM. offered by Mendel as a kosher product. Encosoy.RTM. consists of soy polysaccharides and a non-ionic effective disintegrant. Alginic acid is another disintegrant that may be used. Mendel offers alginic acid under the trade name Satialgine.TM. H8.

As lubricant magnesium stearate or other stearates may be used however the preferred lubricant is Sodium Stearyl Fumarate since it does not have the potential to chelate the levothyroxine sodium by donating multi valent alkali or other metal ions.

Mendel offers Stearyl Fumarate sodium under the trade name Pruv.TM.. Another useful lubricant is hydrogenated vegetable oil, offered by Mendel under the name Lubritab.RTM.. Lubritab.RTM. is chemically less reactive than other commonly used lubricants and therefore has excellent formulation compatibility.

Claim 1 of 8 Claims

I claim:

1. A method of making stabilized thyronine medications by combining together

(a) Liothyronine Sodium

(b) at least one iodine salt mixed with a carrier

(c) a disintegrant

(d) a lubricant

(e) a binder, and

(f) a filler.

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