SOLID PHARMACEUTICAL PREPARATION CONTAINING LEVOTHYROXINE

Abstract

The invention relates to a solid pharmaceutical preparation comprising levothyroxine sodium, gelatine, citric acid and a filler. The solid pharmaceutical preparation has an improved stability.

Claims

1. Solid pharmaceutical preparation comprising levothyroxine sodium, gelatine, citric acid and a filler.

2. Solid pharmaceutical preparation according to claim 1, characterized in that it comprises liothyronine sodium.

3. Solid pharmaceutical preparation according to claim 1, characterized in that the filler is a sugar alcohol such as sorbitol or mannitol dulcitol, xylitol or ribitol, preferably sorbitol or mannitol, particular preferably mannitol, a sugar such as glucose, fructose, mannose, lactose, saccharose or maltose, preferably lactose, saccharose or maltose, particular preferably lactose, a starch such as potato starch, rice starch, maize starch or pregelatinized starch, preferably maize starch or pregelatinized starch, particular preferably maize starch, a cellulose such as powdered cellulose or microcrystalline cellulose, preferably microcrystalline cellulose, or a mixture thereof.

4. Solid pharmaceutical preparation according to claim 3, characterised in that the filler is mannitol and/or maize starch.

5. Solid pharmaceutical preparation according to claim 1, characterized in that it further comprises an antioxidant selected from the group consisting of tocopherol, propyl gallate, tertiary butylhydroquinone, butylated hydroxyanisole and butylated hydroxytoluene, preferably hydroxyanisole or butylated hydroxytoluene, particular preferably butylated hydroxytoluene.

6. Solid pharmaceutical preparation according to claim 1, characterised in that it is in granule, pellet, capsule or tablet form.

7. Solid pharmaceutical preparation according to claim 6, characterised in that it is a tablet.

8. Solid pharmaceutical preparation according to claim 1, characterised in that at least one disintegrating agent is present.

9. Solid pharmaceutical preparation according to claim 8, characterized in that the disintegrating agent is sodium starch glycolate, or carboxymethylcellulose sodium or a mixture thereof.

10. Solid pharmaceutical preparation according to claim 9, characterized in that the disintegrating agent present is carboxymethylcellulose sodium.

11. Solid pharmaceutical preparation according to claim 1, characterised in that it comprises 1 to 10% by weight of gelatine, 0.1 to 3% by weight citric acid, 50 to 80% by weight of mannitol or lactose, 10 to 30% by weight maize starch.

12. Solid pharmaceutical preparation according to claim 11, characterised in that it comprises 0,05 to 0,5% by weight butylated hydroxytoluene.

13. Process for the production of a solid pharmaceutical preparation according to claim 7, characterized in that (a) levothyroxine sodium and optionally liothyronine sodium is/are suspended in an aqueous gelatine solution, (b) the suspension obtained by step (a) is sprayed onto the filler in a fluidized bed granulation and dried to form granules, (c) the granules obtained by step (b) is collected and optionally, (d) a disintegrant and optionally a lubricant is/are mixed with the granules obtained by step (c), and (e) the mixture obtained by step (d) is compressed to give tablets.

14. Process for the production of a solid pharmaceutical preparation according to

13. , characterized in that citric acid and, if present, the antioxidant is dissolved in the aqueous gelatine solution used in step (a) or is admixed with the granules in step (d).

15. Process for the preparation of a solid pharmaceutical preparation according to claim 13, characterised in that the granules or the tablets are provided with a coating.

16. A process for the stabilization of levothyroxine sodium, comprising adding to said levothyroxine sodium a stabilizing-effective amount of gelatine, citric acid and a filler.

17. The process according to claim 16, wherein the filler is dulcitol, xylitol, ribitol, sorbitol, mannitol, glucose, fructose, mannose, lactose, saccharose, maltose, potato starch, rice starch, maize starch, pregelatinized starch, powdered cellulose, microcrystalline cellulose or a mixture thereof.

Description

EXAMPLE 1

[0050] Tablet (batch 015093) comprising

[0051] 0.075 mg of levothyroxine sodium

[0052] 68.525 mg of mannitol

[0053] 20.00 mg of maize starch

[0054] 5.00 mg of sodium starch glycolate

[0055] 5.00 mg of gelatine

[0056] 0.40 mg of citric acid

[0057] 1.00 mg of magnesium stearate

[0058] The gelatin is diluted in hot water (ca. 90% of total amount of water, temperature 90° C.±10° C.) under stirring. The levothyroxine sodium is suspended in cold water (10% of total amount of water) with Ultraturrax. When the gelatin solution has cooled down to 50° C.±5° C., the levothyroxine sodium suspension is given to it, while the final temperature of the granulation fluid is 40-45° C.

[0059] The granulation fluid containing gelatin and active compound is sprayed onto the mannitol and maize starch in the fluidised bed. The temperature of the granulation fluid is kept at around 40° C. The granules are finalized as soon a outlet air temperature has raised up to 40° C.

[0060] Citric acid, sodium starch glycolate and magnesium stearate are admixed with the granules, the resultant mixture is pressed to give tablets. Instead of admixing with the granules citric acid can also be added by dissolving it during preparation of the levothyroxine sodium containing gelatine solution.

EXAMPLE 2

[0061] Tablet (batch 015099) comprising

[0062] 0.30 mg of levothyroxine sodium

[0063] 68.20 mg of mannitol

[0064] 20.00 mg of maize starch

[0065] 3.50 mg of croscarmellose sodium

[0066] 5.00 mg of gelatine

[0067] 2.00 mg of citric acid

[0068] 1.00 mg of magnesium stearate

[0069] The tablets are produced analogous to Example 1.

EXAMPLE 3

[0070] Tablet (batch 014916) comprising

[0071] 0.105 mg of levothyroxine sodium

[0072] 70.295 mg of mannitol

[0073] 20.00 mg of maize starch

[0074] 3.50 mg of croscarmellose sodium

[0075] 5.00 mg of gelatine

[0076] 0.10 mg of butylated hydroxytoluene

[0077] 0.80 mg of citric acid

[0078] 1.00 mg of magnesium stearate

[0079] The tablets are produced analogous to Example 1. The butylated hydroxytoluene is diluted in hot water (ca. 90% of total amount of water, temperature 90° C.±10° C.) under stirring. Afterwards the gelatin is given to this solution under stirring. The Levothyroxine sodium is suspended in cold water (10% of total amount of water) with Ultraturrax. As soon the BHT-gelatin solution has cooled down to 50° C.±5° C., the levothyroxine sodium suspension is given to it, while the final temperature of the granulation fluid now is 40-45° C.

EXAMPLE 4

[0080] Tablet comprising

[0081] 0.300 mg of levothyroxine sodium

[0082] 73.100 mg of mannitol

[0083] 20.00 mg of maize starch

[0084] 3.50 mg of croscarmellose sodium

[0085] 2.00 mg of gelatine

[0086] 0.10 mg of butylated hydroxytoluene

[0087] 0.80 mg of citric acid

[0088] 1.00 mg of magnesium stearate

[0089] The tablets are produced analogous to Example 3.

EXAMPLE 5

[0090] Tablet comprising

[0091] 0.025 mg of levothyroxine sodium

[0092] 65.375 mg of mannitol

[0093] 20.00 mg of maize starch

[0094] 3.50 mg of croscarmellose sodium

[0095] 10.00 mg of gelatine

[0096] 0.10 mg of butylated hydroxytoluene

[0097] 0.80 mg of citric acid

[0098] 1.00 mg of magnesium stearate

[0099] The tablets are produced analogous to Example 3.

EXAMPLE 6

[0100] Tablet comprising

[0101] 0.105 mg of levothyroxine sodium

[0102] 70.395 mg of isomalt

[0103] 20.00 mg of maize starch

[0104] 3.50 mg of croscarmellose sodium

[0105] 5.00 mg of gelatine

[0106] 0.40 mg of citric acid

[0107] 1.00 mg of magnesium stearate

[0108] The tablets are produced analogous to Example 1.

EXAMPLE 7

[0109] Tablet comprising

[0110] 0.105 mg of levothyroxine sodium

[0111] 81.645 mg of cellulose microcrystalline

[0112] 3.50 mg of croscarmellose sodium

[0113] 4.50 mg of gelatine

[0114] 1.50 mg of citric acid

[0115] 0.25 mg of magnesium stearate

[0116] The tablets are produced analogous to Example 1.

EXAMPLE 8

[0117] Tablet comprising

[0118] 0.105 mg of levothyroxine sodium

[0119] 70.295 mg of sorbitol

[0120] 20.00 mg of maize starch

[0121] 3.50 mg of croscarmellose sodium

[0122] 5.00 mg of gelatine

[0123] 0.10 mg of butylated hydroxytoluene

[0124] 0.80 mg of citric acid

[0125] 1.00 mg of magnesium stearate

[0126] The tablets are produced analogous to Example 3.

EXAMPLE 9

[0127] Tablet comprising

[0128] 0.105 mg of levothyroxine sodium

[0129] 70.295 mg of sucrose

[0130] 20.00 mg of maize starch

[0131] 3.50 mg of croscarmellose sodium

[0132] 5.00 mg of gelatine

[0133] 0.10 mg of butylated hydroxytoluene

[0134] 0.80 mg of citric acid

[0135] 1.00 mg of magnesium stearate

[0136] The tablets are produced analogous to Example 3.

EXAMPLE 10

[0137] Tablet comprising

[0138] 0.105 mg of levothyroxine sodium

[0139] 70.395 mg of mannitol

[0140] 20.00 mg of maize starch

[0141] 3.50 mg of croscarmellose sodium

[0142] 5.00 mg of gelatine

[0143] 2.00 mg of citric acid

[0144] 0.10 mg of sodium ascorbate

[0145] 1.00 mg of magnesium stearate

[0146] The tablets are produced analogous to Example 1.

EXAMPLE 11

[0147] Granules comprising

[0148] 0.105 mg of levothyroxine sodium

[0149] 70.295 mg of mannitol

[0150] 20.00 mg of maize starch

[0151] 5.00 mg of gelatine

[0152] 0.10 mg of butylated hydroxytoluene

[0153] 0.80 mg of citric acid

[0154] The citric acid and the gelatin are diluted in hot water (ca. 90% of total amount of water, temperature 90° C.±10° C.) under stirring. The levothyroxine sodium is suspended in cold water (10% of total amount of water) with Ultraturrax. When the gelatin solution with the citric acid has cooled down to 50° C.±5° C., the levothyroxine sodium suspension is given to it, while the final temperature of the granulation fluid is 40-45° C.

[0155] The granulation fluid containing gelatin and active compound is sprayed onto the mannitol and maize starch in the fluidised bed. The temperature of the granulation fluid is kept at around 40° C. The granules are finalized as soon a outlet air temperature has raised up to 40° C.

EXAMPLE 12

[0156] Capsules comprising granules

[0157] Granules of example 11 filled into capsules (gelatine or HPMC)

COMPARISON EXAMPLE 1

[0158] Tablet (batch 127494) comprising

[0159] 0.105 mg of levothyroxine sodium

[0160] 65.895 mg of lactose

[0161] 25.00 mg of maize starch

[0162] 3.50 mg of crosscarmellose sodium

[0163] 5.00 mg of gelatine

[0164] 0.50 mg of magnesium stearate

[0165] The tablets are produced analogous to Example 1.

COMPARISON EXAMPLE 2

[0166] Tablet (batch 014698) comprising

[0167] 0.105 mg of levothyroxine sodium

[0168] 70.395 mg of mannitol

[0169] 20.00 mg of maize starch

[0170] 3.50 mg of crosscarmellose sodium

[0171] 5.00 mg of gelatine

[0172] 0.50 mg of magnesium stearate

[0173] The tablets are produced analogous to Example 1.

COMPARISON EXAMPLE 3

[0174] Tablet (batch 014842) comprising

[0175] 0.105 mg of levothyroxine sodium

[0176] 70.295 mg of mannitol

[0177] 20.00 mg of maize starch

[0178] 3.50 mg of crosscarmellose sodium

[0179] 5.00 mg of gelatine

[0180] 0.10 mg of butylated hydroxytoluene

[0181] 1.00 mg of magnesium stearate

[0182] The tablets are produced analogous to Example 1. Butylated hydroxytoluene was admixed as described in Example 3.

Stability Testing

[0183] To assess the influence of the ingredients, especially citric acid and/or antioxidant on storage stability the pharmaceutical preparations of Examples 1 to 4 and the Comparison Examples 1 and 2 were transferred into glass bottles without closure and stored under elevated temperature and humidity (60 degree Celsius and 75% relative humidity (r.h.)). Storage times and the amounts of active compound measured in each case are shown in Table 1.

TABLE-US-00001 TABLE 1 Levothyroxine Levothyroxine Example Day Sodium [μg] Sodium [%] Preparation with citric acid Ex. 1 0 99.4 100 Ex. 1 14 90.2 90.7 Preparation with citric acid Ex. 2 0 103.5 100 Ex. 2 14 94.8 91.6 Preparation with citric acid and butylated hydroxytoluene Ex. 3 0 103.7 100 Ex. 3 14 96.4 93.0 Preparation without citric acid and butylated hydroxytoluene Comp. Ex. 1 0 105.2 100 Comp. Ex. 1 14 70 66.5 Preparation without citric acid and butylated hydroxytoluene Comp. Ex. 2 0 106.8 100 Comp. Ex. 2 14 93.9 87.9 Preparation without citric acid but with butylated hydroxytoluene Comp. Ex. 3 0 105.5 100 Comp. Ex. 3 14 93.6 88.7

[0184] As demonstrated by the data in table 1 the presence of citric acid leads to an improvement of stability which is further improved by the antioxidant. As no improvement of stability is obtained if the antioxidant is present without citric acid the antioxidant exhibits an antioxidant unexpectedly exhibits a synergistic stabilization effect in combination with citric acid.

[0185] The pharmaceutical preparations of Examples 3 and 4 and Comparison Examples were transferred into HDPE bottles, closed and stored at 40° C. and 75% r.h. Storage times and the amounts of active compound measured in each case are shown in Table 2.

TABLE-US-00002 TABLE 2 Levothyroxine Levothyroxine Example Weeks Sodium [μg] Sodium [%] Preparation with citric acid and butylated hydroxytoluene Ex. 4 0 103.7 100 Ex. 4 13 103.7 100 Ex. 4 26 103.6 99.9 Preparation without citric acid and butylated hydroxytoluene Comp. Ex. 1 0 104.5 100 Comp. Ex. 1 13 102.2 97.8 Comp. Ex. 1 26 101.4 97.0 Preparation without citric acid and butylated hydroxytoluene Comp. Ex. 2 0 105.5 100 Comp. Ex. 2 13 102.9 97.5 Comp. Ex. 2 26 101.1 95.8 Preparation without citric acid but with butylated hydroxytoluene Comp. Ex. 3 0 105.5 100 Comp. Ex. 3 13 102.0 96.7 Comp. Ex. 3 26 101.8 96.5

[0186] As apparent from table 2 the presence of an antioxidant does not exhibit a significant stabilisation effect without the presence of citric acid. Further and surprisingly the combination of citric acid with the antioxidant leads to such a good stabilization effect that after half year storage at elevated temperature and humidity (40° C. and 75% r.h.) the content of levothyroxine sodium in the preparation decreased only 0.1% by weight.

Analytical Test Methods:

[0187] Identity, purity and assay of the solid pharmaceutical preparation comprising levothyroxine sodium are tested by high-performance liquid chromatography or ultra high performance liquid chromatography with UV detection using an reversed phase column and a gradient system after preparation and during the stability studies. The extraction medium and mobile phase used are mixtures of acetonitrile, water and phosphoric acid.