MXPA00011182A - Pharmaceutical preparation containing levothyroxine sodium - Google Patents

Abstract

The invention relates to a pharmaceutical preparation containing levothyroxine sodium, gelatin, and fillers which is free of organic solvent residues. The invention also relates to a method for the production of said preparation.

Description

PHARMACEUTICAL PREPARATION CONTAINING SODIUM LEVOTIROXIN DESCRIPTION OF THE INVENTION The object of the invention is a new stable pharmaceutical preparation containing sodium levothyroxine, gelatin and fillers, and which is free of traces of organic solvents. This new preparation has an improved stability and can be used as a thyroid hormone preparation. This new preparation also offers a better release in vi tro of the active substance. The aim of the invention was to provide new drugs in the form of pharmaceutical preparations, whose properties were better than those of the known drugs and used for the same purposes. The "Department of Health and Human Services, Food and Drug Administration" published in Federal Register Vol. 62, No. 15, of August 14, 1997; p. 43535, that the products available in the US market that contain sodium levothyroxine and that are administered orally present stability problems, for which reason they are Ref: 123300 exceeded in the dose in an amount of up to 20%, and that the Manufacturers must develop new and appropriate forms of employment. The requirements for in vitro release for sodium levothyroxine tablets have also increased. In the monograph-project of the Pharmacopeial Foru (Pharm. Preview, 1995, 21, pp. 1459 to 1461) it is foreseen to perform test 2 (water in 45 minutes> 70%) in addition to test 1 valid until now (buffer phosphate pH 7.4 in 80 minutes> 55%). This objective was achieved through the discovery of this new preparation. In World Patent No. 97 17 951, preparations containing thyroxine and other additives such as glycine, a carbohydrate and an inorganic salt are disclosed. German patent no. 195 41 128 describes another thyroxine preparation stabilized with thiosulfate. US Patent No. 5,635,209 discloses a combined preparation containing sodium levothyroxine and potassium iodide. Another thyroxine-based formulation containing thyroxine / cyclodextrin complexes is described in World Patent No. 97 19 703.

In addition to sodium levothyroxine, the pharmaceutical formulation of the invention may also contain sodium liothyronine. The object of the invention is preferably a pharmaceutical preparation as described, which is characterized by containing from 5 to 400 μg, preferably from 10 to 300 μg, and in particular from 25 to 300 μg of sodium levothyroxine. Another preferred object of the invention is a pharmaceutical preparation as described, which is characterized by containing micronized sodium levothyroxine with a granule size comprised between μg and 25 μm. Another preferred object of the invention is, moreover, a pharmaceutical preparation as described, characterized in that it contains charges selected from the group consisting of lactose and / or corn starch and / or microcrystalline cellulose. A pharmaceutical preparation characterized in that it is a solid preparation in the form of tablets is particularly preferred. Particularly preferred embodiments contain 25, 50, 75, 100, 125, 150, 175 or 200 μg of sodium levothyroxine.

The active substance (s) is / are sensitive to light, heat and oxygen. Due to this known instability an overdose of 50% active substance is added to the formulation. The preparation of the invention has surprising stability when gelatin is used as the binder. When the latter is replaced by another usual binder such as Methocel, a decrease in the content of the active substance can be observed at the beginning of the stability tests, then the increase in the sum of the byproducts is checked. If the initial value of the active substance is determined, for example, in a load of 100 μg in which the gelatin was replaced by Methocel, only the value of 100% will be obtained instead of the expected value of 105%. 100. 48% The stability tests show that the tablets of the invention containing sodium levothyroxine are stable for at least two years, provided they are stored at temperatures below 30 ° C. In addition, the release of the active substance levothyroxine sodium benefits surprisingly when the active substance is introduced in micronized form. Sodium levothyroxine is usually very poorly soluble in both water and ethanol. However, with a particle size between 5 μm and 25 μm (95%), the release of the active substance is in the 1 > 90% (phosphate buffer solution) and in the 2 > 80% (water). The composition of the invention can also be prepared surprisingly without using organic solvents. If the water used in the process of the invention is replaced by an organic solvent, for example methanol, then after one year, a decrease in the content is observed in test loads stored at 25 ° C and a relative humidity of 60%. of sodium levothyroxine 10%. As fillers for the pharmaceutical preparation of the invention, lactose, corn starch and / or microcrystalline cellulose are preferred, both in the form of single fillers and combinations of these compounds. Particularly preferred pharmaceutical preparations described above contain corn starch and lactose. Another object of the invention is also a process for preparing a pharmaceutical preparation containing sodium levothyroxine and, possibly, sodium liotironin, a process characterized in that sodium levothyroxine and, possibly, sodium liothyronine are sprayed through a fluidized bed granulation. suspended in an aqueous gelatin solution, on the charge (s), then a dispersing agent and a lubricant are added, the mixture is mixed and compressed in the form of tablets. Another object of the invention is a process as described, characterized in that sodium croscarmellose is used as the dispersing agent and magnesium stearate is used as a lubricant. Other vehicles or auxiliary substances may be added such as, for example, binding agents, antioxidants, colorants, lubricants, sweeteners and / or flavors. As lubricants and glidants, for example, talc, starch, calcium or magnesium stearate, boric acid, paraffin, cocoa butter, macrogol, leucine or sodium benzoate are preferred, particularly preferred. magnesium stearate. The examples shown below illustrate the. processing and composition of the pharmaceutical preparation of the invention.

Example 1 The amounts indicated below are those needed to prepare, for example, 2 million tablets: * An overdose of 5% was included in the calculation for sodium levothyroxine. ** The water is removed again by drying. preparation: 1. The gelatin is dissolved in approximately 90% of the water at a temperature of 80 to 100 ° C.

At room temperature sodium levothyroxine is suspended in approximately 10% of the water. The suspension is then added to the gelatin solution at 50 ° C (± 5 ° C). The temperature of the suspension obtained (= granulation liquid) is 45 to 50 ° C. 2. Lactose and corn starch are placed in a fluidized bed granulator. The granulation liquid is sprayed onto the powder. The temperature of the granulation liquid is maintained between 40 and 50 ° C during the spraying process. During granulation the inlet temperature is maintained at approximately 70 ° C (± 5 ° C) and that of the outlet between 20 and 40 ° C. The spray pressure is between 3 and 5 bar. After the spray, the granulate is dried until reaching a temperature of approximately 40 ° C at the outlet. The dry granulate is then sieved using known methods (1 mm) (= mixture a). The croscarmellose sodium and the magnesium stearate are sieved. The components are then mixed together with the mixture a for 10 minutes in a drum mixer. The mixture ready to be compressed is compressed into tablets.

Example 2 Composition of a 100 mg tablet (± 3 mg) containing 100 μg of sodium levothyroxine: Levothyroxine sodium 0.100 mg Lactose monohydrate 65.90 mg Corn starch 25.00 mg Gelatin 5.00 mg Croscarmellose sodium 3.50 mg Magnesium stearate 0.50 mg 100.00 mg Sodium levothyroxine must be overdosed by 5%.

Example 3 Composition of a 100 mg tablet (± 3 mg) containing 100 μg of sodium levothyroxine: Levothyroxine sodium 0.100 mg Liothyronine sodium 0.020 mg Lactose monohydrate 65.88 mg Corn starch 25.00 mg Gelatin 5.00 mg Croscarmellose sodium 3.50 mg Magnesium stearate 0.50 mg '100.00 mg Sodium levothyroxine should be overdosed by 5%. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (8)

1. Having described the invention as above, the content of the following claims is claimed as property: 1. Pharmaceutical preparation, characterized in that it contains sodium levothyroxine, gelatin and fillers, and is free of traces of organic solvents.
2. 2. Pharmaceutical preparation according to claim 1, characterized in that it also optionally contains sodium liothyronine.
3. 3. Pharmaceutical preparation according to claim 1, characterized in that it contains from 5 to 400 μg of sodium levothyroxine,
4. 4. Pharmaceutical preparation according to claim 1, characterized in that it contains micronized sodium levothyroxine with a particle size comprised between 5 μm and 25 μm.
5. 5. Pharmaceutical preparation according to claim 1, characterized in that it contains charges selected from the group consisting of lactose and / or corn starch and / or microcrystalline cellulose.
6. 6. Pharmaceutical preparation according to claim 1, 2 or 3, characterized in that it is a solid preparation in the form of tablets.
7. 7. Process for preparing a pharmaceutical preparation, characterized in that by means of a fluidized bed granulation, sodium levothyroxine and, possibly, sodium liothyronine are sprayed, which is / are suspended in aqueous gelatin solution, on the load (s) / s, then a dispersing agent and a lubricant are added, the mixture is mixed and compressed in the form of tablets.
8. 8. Process according to claim 1, characterized in that croscarmellose sodium is used as a dispersant and magnesium stearate as a lubricant.