DE102017122807A1 - Oral thyroid therapy - Google Patents

Abstract

Let us describe an oral thyroid therapeutic containing levothyroxine or its pharmaceutically acceptable salts as the active ingredient, in combination with at least one antioxidant and at least one adsorbent, the ratio in wt% of active ingredient: antioxidant: adsorbent 1: 1: 5 to 1:50 : 100 is.

Description

The present invention relates to an oral thyroid therapeutic containing levothyroxine and / or liothyronine as the active ingredient having improved drug stability.

Levothyroxine (C ₁₅ H ₁₁ I ₄ NO ₄ , M _r = 776.9 g / mol) corresponds to the endogenous thyroid hormone known as thyroxine or T4 and is a generic name (INN). Levothyroxine is the tetraiodinated derivative of the amino acid tyrosine. In medicines, the sodium salt of levothyroxine, which is referred to as L-thyroxine Na or levothyroxine sodium, is predominantly used. Levothyroxine is also a precursor of triiodothyronine or T3, which is also referred to as liothyronine.

The active substance thyroxine and also its enantiomers in pure form, do not have sufficient stability to store them containing oral pharmaceuticals for a long period of time. It is therefore necessary to provide galenic preparations which ensure sufficient stability of the active ingredient and the entire preparation, in as many climates as possible.

One approach to this end is the use of special packaging which binds atmospheric oxygen or keeps it away from the preparation containing the active ingredient levothyroxine. Such devices are for example in the US 2009/0297566 A1 or the EP 1 772 395 A1 described.

The prior art discloses a number of levothyroxine preparations which have improved stability. For this purpose, stabilizers are added to the preparations. In the WO 2003/041699 A1 and the US 8,779,000 B1 the addition of antioxidants is proposed.

However, there are also compositions which do not contain certain usual ingredients because they negatively affect the stability of levothyroxine. These compositions are described in, for example US 8,779,000 B1 or the DE 198 30 246 A1 , In the DE 198 30 246 A1 The exclusion of antioxidants is explicitly suggested.

Also known are preparations in which the active ingredient levothyroxine is encapsulated or embedded by means of certain excipients. Such preparations are in the WO 1998/18610 A1 described.

Also known is the addition of iodine-containing compounds such as potassium iodide to stabilize the composition.

However, the problem of the stability of oral thyroid therapeutics has not yet been satisfactorily resolved. Thus, there is a continuing need for stable oral formulations of thyroid therapeutics containing the drug levothyroxine and also liothyronine.

The object of the present invention is therefore to improve the stability of levothyroxine and / or liothyronine-containing oral dosage forms. It is in particular an object of the present invention to provide an oral dosage form which meets the stability requirements for finished medicinal products in climate zone II (25 ° C., 60% relative humidity) and climate zone IVB (30 ° C., 75% relative humidity).

The object is achieved by providing an oral thyroid therapy with the features of the main claim. Advantageous embodiments of the oral thyroid therapeutic according to the invention are characterized in the appended subclaims.

The present invention is an oral thyroid therapeutic agent containing at least one active ingredient in the form of a thyroid hormone or its pharmaceutically acceptable salts as active ingredient, in combination with at least one antioxidant and at least one adsorbent, wherein the ratio in wt .-% of active ingredient: antioxidant: adsorbent 1: 1: 5 to 1: 50: 100.
When calculating the ratio, it can be assumed that the oral thyroid therapeutic according to the invention, in addition to the active ingredient, the antioxidant and the adsorbent, together with other pharmaceutically acceptable carriers and excipients, comprises a total of 100% by weight.

A further advantageous embodiment of the oral thyroid therapeutic according to the invention is characterized in that the active ingredient in the form of a thyroid hormone levothyroxine or its pharmaceutically acceptable salts or Liothyronin or its pharmaceutically acceptable salts or that mixtures of said active ingredients are included.

Further preferred is an oral thyroid therapeutic in which a further active ingredient is contained, wherein the further active ingredient is preferably at least one iodine salt selected from iodides or iodates of the alkali metals, in particular potassium iodide or potassium iodate, and mixtures of said iodine salts.

According to the invention, preference is given to an oral thyroid therapeutic, in which case pharmaceutically acceptable excipients, carriers and / or diluents are also included.

Also preferred according to the invention is an oral thyroid therapeutic, wherein the antioxidant is selected from sulfur-containing organic antioxidants.
It is particularly preferred that the sulfur-containing, organic antioxidants are selected from cysteine, cystine, glutathione, Dimercaptopropansulfonsäure and their salts and derivatives and from mixtures of the aforementioned means.
Most preferably, the sulfur-containing organic antioxidant is cysteine.

Also preferred according to the invention is an oral thyroid therapeutic, wherein the adsorbent is selected from inorganic adsorbents. Preferred are inorganic adsorbents which are basic or oxydic.
It is particularly preferred that the inorganic adsorbents are selected from silica gels, zeolites, alkaline earth metal oxides, alkali metal carbonates, Alkalihydrogencarbonaten, alkaline earth carbonates, Erdalkalihydrogencarbonaten, alkaline earth silicates and mixtures of the aforementioned adsorbents.
It is very particularly preferred that the alkaline earth metal oxide is magnesium oxide and / or the alkaline earth silicate is magnesium silicate hydrate (talc) and / or the alkali carbonate is sodium carbonate.

Also preferred is an oral thyroid therapeutic, wherein the ratio in wt .-% of active ingredient: antioxidant: adsorbent 1: 5: 5 to 1: 10: 40.

Also preferred according to the invention is an oral thyroid therapeutic, the active ingredient content being from 0.01 to 0.5% by weight.

Also preferred is an oral thyroid therapeutic, wherein the active ingredient content of a single dosage is 25 μg to 300 μg. Very particular preference is given to an active ingredient content of from 25 μg to 150 μg.

According to the invention, it is furthermore preferred that the content of cysteine is 0.1-5% by weight.

According to the invention, it is preferable that the content of MgO is 0.5-10% by weight. Magnesium oxide can adsorb volatile compounds by forming Van der Waals bonds.

According to the invention it is preferred that the preparation additionally contains pregelatinized starch. In this case, particular preference is given to fractions of 30-60% by weight.

Furthermore, it is preferred according to the invention that microcrystalline cellulose is contained. In this case, proportions of 10 to 30% by weight are particularly preferred.

In addition, it is preferred according to the invention that corn starch is contained. In this case, proportions of 10 to 50% by weight are particularly preferred.

Preferred oral thyroid therapeutics are characterized in that the active ingredient content is 0.01-1% by weight. It is particularly preferred that the active ingredient content is 0.1-0.5% by weight.

This means that an oral thyroid therapeutic according to the invention has the following composition in% by weight: Levothyroxine sodium 0.01 -1% other active ingredients 0 - 10% Antioxidant 0.01 - 50% adsorbent 0.05 - 99% Tableting aids ad 100%

Particular preference is given to oral thyroid therapeutics according to the invention which have the following composition in% by weight: Levothyroxine sodium 0.1 - 0.5% other active ingredients 0 - 10% Antioxidant 0,5 - 5% adsorbent 0,5 - 40% Tableting aids ad 100%

Further preferred are oral thyroid therapeutics according to the invention which have the following composition in% by weight: Liothyronine sodium 0.01 - 1% other active ingredients 0 - 10% Antioxidant 0.01 - 50% adsorbent 0.05 - 99% Tableting aids ad 100%

Also preferred are oral thyroid therapeutics according to the invention which have the following composition in% by weight: Levothyroxine sodium 0.1 - 0.5% Liothyronine sodium 0.01 - 0.5% Antioxidant 0,5 - 5% adsorbent 0,5 - 40% Tableting aids ad 100%

Also preferred according to the invention are oral thyroid therapeutics which have the following composition in% by weight: Levothyroxine sodium 0.1 - 0.5% lodsalze 0.01 - 5% Antioxidant 0,5 - 5% adsorbent 0,5 - 40% Tableting aids ad 100%

Surprisingly, it has been found that the antioxidant and the adsorbent must be present in a high stoichiometric excess based on the active ingredient in the preparation according to the invention in order to achieve the desired stability of the active ingredient. It has been found that advantageously a 10 to 50-fold stoichiometric excess of antioxidant, based on the active ingredient, is to be selected. The same applies to the adsorbent. Again, a 10 to 50-fold stoichiometric excess, based on the active ingredient, is advantageous.

According to the invention, it is also preferred that the oral thyroid therapeutic be in the form of a base preparation with tablets which can be divided once or several times. Particular preference is given here divisible tablets having a break line, a plurality of mutually parallel break grooves or a cross-hatch notch. This makes it possible to achieve individual doses in patients without having to prepare or prepare a separate drug for each dosage.

The present invention thus relates to a concept and method for the preparation of a thyroid therapeutic in different dosage strengths from a base granule prepared from the base preparation to provide a linear pharmacokinetics for the thyroid hormone contained after its oral administration, depending on the given dose receive.

The medicaments of the invention are prepared in a known manner with the customary solid or liquid auxiliaries, carriers and / or diluents and the auxiliaries customarily used in accordance with the desired mode of administration with a suitable dosage. The preferred formulations consist of a dosage form which is suitable for oral administration. Such dosage forms are, for example, solutions, suspensions, tablets, film-coated tablets, capsules, solutions or special sustained-release dosage forms.

Corresponding sustained-release forms can be prepared by mixing the active ingredient, together with the antioxidant and the adsorbent in the combination according to the invention, with known excipients or agents for achieving a depot effect. The tablets can also consist of several layers.

Accordingly, microtablets can also be produced, which can then be filled into capsules. But also the powder / granules of the base recipe can be filled directly into capsules. With the help of conventional capsule filling machines, it is therefore possible to produce differently dosed preparations without long changeover times, since the same basic formulation is always used. It is only an adjustment of the amount required to produce differently dosed forms.

Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. In this case, the dragee wrapper may consist of several layers, wherein the auxiliaries known to those skilled in the art may be used.

The preparation of the oral pharmaceutical preparations according to the invention is known per se and described in the handbooks known to the person skilled in the art (eg Hager, Hager's Handbook of Pharmaceutical Practice, 5th edition, Springer Verlag, 1999 . List et al., Dosage Formation, 2nd Edition, Scientific Publishing Company 1985 . Bauer et al., Pharmaceutical Technology, 9th Edition, Wissenschaftliche Verlagsgesellschaft mbH, 2012 ).

The oral thyroid therapeutic according to the invention has a high stability in all climates. The storage stability over conventional preparations is significantly improved. This makes it possible to provide a preparation for all climates. In addition, it is possible to provide various dosage forms by means of a single base preparation. This simplifies the preparation and storage of the preparations and reduces costs.

The following examples illustrate the invention in more detail without limiting the scope of the invention.

example 1

In the Table I gives a formulation for a composition according to the invention of an oral thyroid therapeutic. The ratio in wt .-% of
Active ingredient: Antioxidant: Adsorbent 1: 7: 32. Table I component Wt .-% L-thyroxine Na × 5 H ₂ O 0.1 Microcrystalline cellulose 19.2 Pregelatinized starch 44.8 corn starch 30.0 L-cysteine × HCl × H ₂ O 0.7 magnesia 3.2 sodium 2.0 100.0

Example 2

Table II gives a formulation for a composition according to the invention of an oral thyroid therapeutic. The ratio in wt .-% of
Active ingredient: Antioxidant: Adsorbent 1: 5: 47. Table II component Wt .-% L-thyroxine Na × 5 H ₂ O 0.1 Microcrystalline cellulose 58.5 corn starch 34.2 L-cysteine × HCl × H ₂ O 0.5 magnesia 4.7 talc 2.0 100.0

Example 3

Table III gives a formulation for a composition according to the invention of an oral thyroid therapeutic. The ratio in wt .-% of
Active ingredient: Antioxidant: Adsorbent 1: 5: 32. Table III component Wt .-% L-thyroxine Na × 5 H ₂ O 0.1 Microcrystalline cellulose 19.2 Pregelatinized starch 45.0 corn starch 30.0 L-cysteine × HCl × H ₂ O 0.5 magnesia 3.2 talc 2.0 100.0

Example 4

Stability of the oral thyroid therapeutics of the invention

Using the formulation according to Example 3 tablets were prepared with an amount of active ingredient of 100 ug levothyroxine-Na. In addition, such tablets were prepared without the antioxidant (cysteine) and without the adsorbent (magnesium dioxide). These two preparations were then subjected to a stress test together with a commercial product (Letrox® 100). Here, a storage of the preparations was carried out for 12 days at a temperature of 70 ° C and a relative humidity of 100%. The content of active ingredient was determined before storage and after storage for 3, 6, 9 and 12 days. The test results are in the 1 shown. It turns out that the formulation according to Example 3 (with antioxidant and adsorbent) had only a very small reduction in the active ingredient content after 12 days.

Example 5

Preparation of different dose levothyroxine sodium tablets

Using the formulation of Example 1, it is possible to produce tablets of different dosages solely by varying the tablet mass. Here, the percentage composition and thus also the ratio between active ingredient (levothyroxine), antioxidant and adsorbent and excipients remains unchanged.

Starting from the composition of the individual components given in Table I of Example 1, a tableting mixture is prepared which contains 100 μg of active substance in a 104 mg mixture. The dosage of active ingredient can then be adjusted according to the tablet mass chosen during pressing. This is shown in the following overview. Dosage 25 μg Tablet mass: 26.0 mg Dosage 50 μg Tablet mass: 52.0 mg Dosage 75 μg Tablet mass: 78.0 mg Dosage 100 μg Tablet mass: 104.0 mg Dosage 125 μg Tablet mass: 130.0 mg Dosage 150 μg Tablet mass: 156.0 mg Dosage 175 μg Tablet mass 182 mg Dosage 200 μg Tablet mass 208 mg Dosage 300 μg Tablet mass 312 mg

However, it may be necessary to use the

Increase tablet size for better breakability. In this case, the tablet mass is doubled for the 100 μg dosage and is then 208 mg. It should be noted that the ratio of active ingredient to antioxidant to adsorbent is not changed. For this purpose, it is necessary to increase the amounts of other Tablettierhilfsstoffe accordingly, without changing the ratio of active ingredient, antioxidant and adsorbent according to the invention. The tablet mass to be chosen when pressing the tablets is shown in the following overview. Dosage 25 μg Tablet mass: 52.0 mg Dosage 50 μg Tablet mass: 104.0 mg Dosage 75 μg Tablet mass: 156.0 mg Dosage 100 μg Tablet mass: 208.0 mg Dosage 125 μg Tablet mass: 260.0 mg Dosage 150 μg Tablet mass: 312.0 mg

Example 6

Determination of the release rate

In the 2 the release profile of the preparation according to the invention according to Example 3 is shown. The tablets have an active substance content of 100 μg with a mass of 104 mg. The investigations were carried out in a paddle apparatus at 100 min ^-1 . The volume of the release medium is 500 ml, the release medium is phosphate buffer with a pH of 7.4.
After 15 minutes, 80% of the drug is already released, after 60 minutes more than 90%.
This shows that the substances used to stabilize the active substance, namely antioxidants and adsorbents, do not adversely affect the release and thus also the bioavailability.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• US 2009/0297566 A1 [0004]
• EP 1772395 A1 [0004]
• WO 2003/041699 A1 [0005]
• US 8779000 B1 [0005, 0006]
• DE 19830246 A1 [0006]
• WO 1998/18610 A1 [0007]

Cited non-patent literature

• Hager, Hager's Handbook of Pharmaceutical Practice, 5th Ed., Springer Verlag, 1999 [0039]
• List et al., Pharmaceutical Theory, 2nd Edition, Scientific Publishing Company 1985 [0039]
• Bauer et al., Pharmaceutical Technology, 9th Edition, Wissenschaftliche Verlagsgesellschaft mbH, 2012 [0039]

Claims (15)

Oral thyroid therapeutic, comprising at least one active ingredient in the form of a thyroid hormone or its pharmaceutically acceptable salts, in combination with at least one antioxidant and at least one adsorbent, wherein the ratio in wt .-% of active ingredient: antioxidant: adsorbent 1: 1: 5 to 1: 50: 100. Oral thyroid therapy, according to Claim 1 Characterized in that the active ingredient in the form of a thyroid hormone levothyroxine or its pharmaceutically acceptable salts or liothyronine or pharmaceutically acceptable salts, or that mixtures of the active substances are included. Oral thyroid therapy, according to Claim 1 or 2 , characterized in that a further active ingredient is contained, wherein the further active ingredient is preferably at least one iodine salt selected from iodides or iodates of the alkali metals, in particular potassium iodide or potassium iodate, and mixtures of said iodine salts. Oral thyroid therapeutic, according to at least one of the preceding claims, characterized in that further pharmaceutically acceptable excipients, carriers and / or diluents are included. Oral thyroid therapeutic, according to at least one of the preceding claims, characterized in that the antioxidant is selected from sulfur-containing, organic antioxidants. Oral thyroid therapy, according to Claim 5 , characterized in that the sulfur-containing, organic antioxidants are selected from cysteine, cystine, glutathione, Dimercaptopropansulfonsäure and their salts and derivatives and mixtures of the aforementioned agents. Oral thyroid therapy, according to Claim 6 , characterized in that the sulfur-containing organic antioxidant is cysteine. Oral thyroid therapeutic, according to at least one of the preceding claims, characterized in that the adsorbent is selected from inorganic adsorbents. Oral thyroid therapy, according to Claim 8 , characterized in that the inorganic basic or oxidic adsorbents are selected from silica gels, zeolites, alkaline earth metal oxides, alkali metal carbonates, Alkalihydrogencarbonaten, alkaline earth metal carbonates, Erdalkalihydrogencarbonaten and mixtures of the aforementioned adsorbents. Oral thyroid therapy, according to Claim 9 , characterized in that the alkaline earth metal oxide is magnesium oxide and / or the alkaline earth silicate is talc and / or the alkali metal carbonate is sodium carbonate. Oral thyroid therapeutic, according to at least one of the preceding claims, characterized in that the ratio in wt .-% of active ingredient: antioxidant: adsorbent 1: 5: 5 to 1: 10: 40. Oral thyroid therapeutic, according to at least one of the preceding claims, characterized in that the active ingredient content is 0.01 to 0.5 wt .-%. Oral thyroid therapeutic, according to at least one of the preceding claims, characterized in that the active ingredient content of a single dosage is 25 micrograms to 150 micrograms. Oral thyroid therapeutic, according to one of the preceding claims, in the form of a single or multiple divisible tablet. Oral thyroid therapy, according to Claim 14 , characterized in that the divisible tablet has a breaking groove, a plurality of mutually parallel breaking grooves or a Kreuzbruchrille.

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