Stable pharmaceutical dosage forms comprising Levothyroxine sodium

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The present invention relates to a novel and stable levothyroxine sodium pharmaceutical composition and belongs to the technical field of pharmaceutical preparation and in particular to a levothyroxine sodium tablets. In the current invention, the levothyroxine sodium dosage forms comprise as active ingredient levothyroxine sodium in an amount of about 0.01% w/w to about 1% w/w and as excipients Microcrystalline cellulose in an amount of 80% w/w to 95% w/w , disintegrant in an amount of 5% w/w to 10% w/w , glidant in an amount of 0.5% w/w to 3% w/w , and lubricant in an amount of 0.5% w/w to 2% w/w .

The proposed composition by improving the stability and the dissolution of the preparation can benefit the clinical application.

Finally, the present invention is directed to therapeutic agents for treatment of hormone disorders and relates to stable pharmaceutical dosage forms of Levothyroxine sodium.

Evaluation of stability results

The results show excellent initial assay, uniformity and dissolution for Example 2. For this formulation, an approximately 8% decrease in levothyroxine sodium assay was observed after six (6) months accelerated stability studies in all the primary packaging containers. As shown from the stability studies the use of the specific excipients combinations do not affect levothyroxine sodium, thus the stability of levothyroxine sodium is maintained during the shelf life of the tablets. The results of the 6 months stability studies under high temperature, humidity and light conditions indicate that the use of the specific excipients at the used amounts can significantly improve the stability of the levothyroxine sodium tablets.

An additional advantage of the preparations according to the invention is that this stability behavior represents an improvement over the lactose-based formula, where a 13.1-22 % decrease in levothyroxine sodium assay is observed under the same conditions and with the use of different types of excipients from these that are used in the current invention and are referred in the claim section.

A further advantage is that the dissolution profile met currents U. S. P. requirements as shown in Tables 4-5.

In case of Aluminum blister-PVDC packaging, the loss of potency of inventive compositions ranges between 7.5% and 8.2% whereas the loss of potency of the other compositions is larger than 10%. Furthermore, the relative difference of the loss of potency between inventive compositions and lactose based compositions is in the range of 16%-64%. Similarly, in case of PCTFE aluminum (ACLAR) packaging, the superiority of inventive compositions is declared. Specifically, the potency of the innovative compositions is significantly (p<0.05) less reduced than the corresponding value of the lactose based compositions . Finally, in case of cold form Alu-Alu Blister PVC/Alh45/OPA25 packaging, the potency of the innovative compositions is reduced only by 6% at maximum. On the other hand the potency of lactose based compositions is reduced by 12% at maximum.

The stability studies showed that the inclusion of lactose in levothyroxine sodium compositions increases the instability of the compositions probably because of the Maillard reaction, and the packing is not always adequate. Although lactose monohydrate has a very low tendency to adsorb moisture, the fact that the levothyroxine sodium as a raw material contains significant amount of water may contribute to the reduced stability of the lactose based formulations, especially when a drying step is not included in the manufacturing process, e.g. in direct compression. Moreover, the momentarily increased temperatures due to the high compression forces during tableting may offer the sufficient activation energy for the Maillard reaction.

It should be also noted that the compositions containing sodium starch glycolate (SSG) were not as stable as the innovative compositions containing croscarmellose sodium (CCS). Both superdisintegrants are synthesized from polymers of glucose, i.e. starch (SSG) and cellulose (CCS). Although the chemical modifications in both cases are introduction of carboxymethyl sodium groups and cross-linking of the polymer backbone, there are differences in the chemistry/manufacturing process of these modifications that may affect the stability of the levothyroxine sodium compositions. In detail, the backbone of SSG and CCS consists of two polymers of α-glucose (amylose and amylopectin) and β-glucose, respectively. Furthermore, the degree of substitution of CCS is higher than that of SSG, and the mechanism of cross-linking is different. In both cases the substitution is performed using Williamson's ether synthesis to give the sodium salt of carboxymethylcellulose. However, in case of CCS the degree of substitution is such that approximately 3 anhydroglucose units out of 4 are substituted. A major difference from the chemistry/manufacturing process of SSG is that some of the carboxymethyl groups are used to cross-link the cellulose chains via dehydration. Thus the cross-links are carboxyl ester links rather than phosphate ester links as in SSG. It has been found that the combination of excipients (microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate) and levothyroxine sodium provides a stable, uniform pharmaceutical preparation with excellent characteristics during its shelf life. This stabilizing mixture protects the levothyroxine sodium and provides excellent flow characteristics to the blend resulting in direct compression manufacturing (low cost and low humidity process) and in greater uniformity of the final product with dissolution characteristics that maintain during the shelf life ensuring its reliable bioperformance during the shelf life of the product.