DE102017122807B4 - Oral thyroid therapeutic - Google Patents

Abstract

Oral thyroid therapeutic agent, containing 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, the ratio in % by weight of active ingredient: antioxidant: adsorbent being 1: 1: 5 to 1: 50:100, characterized in that the antioxidant is selected from sulphur-containing, organic antioxidants selected from cysteine, cystine, glutathione, dimercaptopropanesulfonic acid and their salts and derivatives and from mixtures of the aforementioned agents.

Description

The present invention relates to an oral thyroid therapeutic containing levothyroxine and/or liothyronine as active ingredient with improved active ingredient 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 non-proprietary name (INN). Levothyroxine is the tetraiodinated derivative of the amino acid tyrosine. The sodium salt of levothyroxine, which is known as L-thyroxine Na or levothyroxine sodium, is predominantly used in medicinal products. Levothyroxine is also a precursor of triiodothyronine or T3, which is also known as liothyronine.

The active ingredient thyroxine and its enantiomers in pure form do not have sufficient stability to store oral pharmaceuticals containing them over a longer period of time. It is therefore necessary to create galenic preparations which ensure adequate stability of the active ingredient and of the preparation as a whole in as many climatic zones as possible.

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

A number of levothyroxine preparations which have improved stability are known in the prior art. For this purpose, stabilizers are added to the preparations. In the WO 2003/041699 A1 , the DE 195 41 128 C2 and the U.S. 8,779,000 B1 the addition of antioxidants is suggested.

However, there are also compositions which do not contain certain, otherwise customary components, because these have a negative effect on the stability of the levothyroxine. These compositions are described, for example, in U.S. 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 substance 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.

It is also known in the prior art that stabilizers containing sulfur are used in many solid and liquid pharmaceutical preparations. This is described, for example, in Celestino M.T. [et al.] (Rational use of antioxidants in solid oral pharmaceutical preparations. Brazilian Journal of Pharmaceutical Sciences, Vol. 48, Sep 2012, No. 3, pages 405-415. DOI: 10.1590/S1984-82502012000300007) in Abdelnabi R. [et al.](Glutathione is a highly efficient thermostabilizer of poliovirus Sabin strains. Vaccine, Vo. 35, Mar 2017, No. 10, pages 1370-1372. DOI: doi: 10.1016/j.vaccine.2017.01.070) or Pramanick S. [et al.] (Excipient Selection In Parenteral Formulation Development. Pharma Times, Vol. 45, March 2013, No.3, pages 65-77. URL: https://www.pharmaexcipients.com/wpcontent/uploads /attachments/257115883-Excipient for parenteral.pdf?t=1425059372). The use of antioxidants in certain medicinal products is also described, such as for Mysimba® (8 mg/90 mg prolonged-release tablets: Summary of Product characteristics. URL: https://www.ema.europa.eu/en/documents/ productinformation/mysimba-epar-productinformation_en.pdf) or ADVATE® (250 IU powder and solvent for solution for injection: Summary of product characteristics. URL: https://www.ema.europa.eu/en/documents/productinformation/advateepar -product-information_en.pdf).

However, the problem of the stability of oral thyroid therapeutics has not yet been satisfactorily solved. There is therefore a continuing need for stable oral preparation forms of thyroid therapeutics with the active ingredient levothyroxine and also liothyronine.

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

The object is achieved by providing an oral thyroid therapeutic with the features of the main claim. Advantageous configurations of the oral thyroid therapeutic agent according to the invention are characterized in the dependent claims.

The present invention relates to an oral thyroid therapeutic agent containing at least one active ingredient in the form of a thyroid hormone or its pharmaceutically acceptable salts as the active ingredient, in combination with at least one antioxidant and at least one adsorbent, the ratio in % by weight of active ingredient: antioxidant: adsorbent 1:1:5 to 1:50:100, the antioxidant being selected from sulphur-containing, organic antioxidants selected from cysteine, cystine, glutathione, dimercaptopropanesulfonic acid and their salts and derivatives and from mixtures of the aforementioned agents.

When calculating the ratio, it is to be assumed that the oral thyroid therapeutic agent according to the invention comprises a total of 100% by weight in addition to the active ingredient, the antioxidant and the adsorbent together with other pharmaceutically compatible carriers and excipients.

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

Also preferred is an oral thyroid therapeutic containing a further active substance, the further active substance preferably being at least one iodine salt selected from iodides or iodates of the alkali metals, in particular potassium iodide or potassium iodate, and mixtures of the iodine salts mentioned.

According to the invention, an oral thyroid therapeutic agent is preferred, with pharmaceutically acceptable excipients, carriers and/or diluents also being present.

It is most preferred that the sulphur-containing organic antioxidant is cysteine.

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

Preference is also given to an oral thyroid therapeutic agent, the ratio in % by weight of active substance:antioxidant:adsorbent being from 1:5:5 to 1:10:40.

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

An oral thyroid therapeutic agent is also preferred, the active substance content of a single dosage being 25 μg to 300 μg. An active substance content of 25 μg to 150 μg is very particularly preferred.

It is also preferred according to the invention that the cysteine content is 0.1-5% by weight.

It is preferred according to the invention that the MgO content is 0.5-10% by weight. Magnesium oxide can adsorb volatile compounds by forming van der Waals bonds.

It is preferred according to the invention that the preparation additionally contains pregelatinized starch. Proportions of 30-60% by weight are particularly preferred here.

Furthermore, it is preferred according to the invention that microcrystalline cellulose is contained. Proportions of 10-30% by weight are particularly preferred here.

In addition, it is preferred according to the invention that corn starch is present. Proportions of 10-50% 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% tabletting excipients to 100%

Oral thyroid therapeutics according to the invention which have the following composition in % by weight are particularly preferred: Levothyroxine Sodium 0.1 - 0.5% other active ingredients 0 - 10% antioxidant 0.5 - 5% adsorbent 0.5 - 40% tabletting excipients to 100%

Also 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% tabletting excipients to 100%

Oral thyroid therapeutics according to the invention which have the following composition in % by weight are also preferred: Levothyroxine Sodium 0.1 - 0.5% Liothyronine Sodium 0.01 - 0.5% antioxidant 0.5 - 5% adsorbent 0.5 - 40% tabletting excipients to 100%

Preference is also given to oral thyroid therapeutics according to the invention which have the following composition in % by weight: Levothyroxine Sodium 0.1 - 0.5% iodine salts 0.01 - 5% antioxidant 0.5 - 5% adsorbent 0.5 - 40% tabletting excipients to 100%

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

It is also preferred according to the invention that the oral thyroid therapeutic agent is in the form of a basic preparation with tablets that can be divided once or several times. Particular preference is given here to divisible tablets which have a score line, several score lines arranged parallel to one another, or a cross score line. This makes it possible to achieve individual dosages for patients without having to keep or produce a separate drug for each dosage.

The present invention thus relates to a concept and method for producing a thyroid therapeutic agent in different dosage strengths from a basic or basic granulate, which is produced from the basic preparation in order to achieve linear pharmacokinetics for the thyroid hormone contained, depending on the given dose, after its oral administration receive.

The medicaments of the invention are produced in a known manner with the usual solid or liquid auxiliaries, carriers and/or diluents and the auxiliaries usually used in accordance with the desired type of administration with a suitable dosage. The preferred preparations consist of a dosage form that is suitable for oral administration. Such dosage forms are, for example, solutions, suspensions, tablets, film-coated tablets, capsules, solutions or special slow-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 auxiliaries or agents to achieve a depot effect. The tablets can also consist of several layers.

Correspondingly, microtablets can also be produced, which can then be filled into capsules. But the powder/granules of the basic recipe can also be filled directly into capsules. With the help of conventional capsule filling machines, it is therefore possible to produce preparations in different doses without lengthy changeover times, since the identical basic recipe is always used. It is only necessary to adjust the filling quantity in order to produce differently dosed forms.

Correspondingly, dragees can be produced by coating cores produced analogously to the tablets with agents customarily used in dragee coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. The dragee casing can also consist of several layers, in which case the excipients known to those skilled in the art can be used.

The preparation of the oral pharmaceutical preparations according to the invention is known per se and is described in manuals known to those skilled in the art (e.g. Hager, Hagers Handbuch der Pharmazeutischen Praxis, 5th edition, Springer Verlag, 1999, List et al., Arzneiformenlehre, 2nd edition, Wissenschaftliche Verlagsgesellschaft 1985, Bauer et al., Pharmaceutical Technology, 9th edition, Wissenschaftliche Verlagsgesellschaft mbH, 2012).

The oral thyroid therapeutic agent according to the invention has high stability in all climatic zones. The storage stability compared to conventional preparations is significantly improved. This makes it possible to provide a preparation for all climate zones. In addition, it is possible to provide various dosage forms using a single base preparation. This simplifies production and storage of the preparations and reduces costs.

The following examples explain the invention in more detail without restricting the scope of the invention.

example 1

Table I shows a formulation for a composition according to the invention of an oral thyroid therapeutic agent. The ratio is in wt .-% of
Active ingredient : antioxidant : adsorbent 1 : 7 : 32. Table I component wt% L-Thyroxine Na× _5H2O 0.1 Microcrystalline cellulose 19.2 Pregelatinized Starch 44.8 cornstarch 30.0 L-cysteine × HCl × H ₂ O 0.7 magnesium oxide 3.2 sodium 2.0 100.0

example 2

Table II shows a formulation for a composition according to the invention of an oral thyroid therapeutic agent. The ratio is in wt .-% of
Active ingredient : antioxidant : adsorbent 1 : 5 : 47. Table II component wt% L-Thyroxine Na× _5H2O 0.1 Microcrystalline cellulose 58.5 cornstarch 34.2 L-cysteine × HCl × H ₂ O 0.5 magnesium oxide 4.7 talc 2.0 100.0

Example 3

Table III shows a formulation for an oral thyroid therapeutic composition according to the invention. The ratio is in wt .-% of
Active ingredient : antioxidant : adsorbent 1 : 5 : 32. Table III component wt% L-Thyroxine Na× _5H2O 0.1 Microcrystalline cellulose 19.2 Pregelatinized Starch 45.0 cornstarch 30.0 L-cysteine × HCl × H ₂ O 0.5 magnesium oxide 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 containing 100 μg of levothyroxine-Na active ingredient were produced. In addition, similar tablets were made 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). The preparations were stored for 12 days at a temperature of 70° C. and a relative humidity of 100%. The active ingredient content was determined before storage and after 3, 6, 9 and 12 days of storage. The test results are in the 1 shown. It is found that the formulation according to Example 3 (with antioxidant and adsorbent) showed only a very small reduction in the active ingredient content after 12 days.

Example 5

Production of differently dosed levothyroxine sodium tablets

Using the formulation from Example 1, it is possible to produce differently dosed tablets simply by varying the tablet mass. The percentage composition and thus also the ratio between active ingredient (levothyroxine), antioxidant and adsorbent as well as auxiliary substances remains unchanged.

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

However, when using score lines, it may be necessary to increase the tablet size to achieve better breakability. In this case, the tablet mass for the 100 µg dosage is doubled and is then 208 mg. It should be noted here that the ratio of active substance to antioxidant to adsorbent is not changed. To this end, it is necessary to increase the amounts of the other tabletting excipients accordingly, without changing the ratio of active ingredient, antioxidant and adsorbent according to the invention. The tablet mass to be selected 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 mcg Tablet mass: 156.0 mg Dosage 100 µg Tablet mass: 208.0 mg Dosage 125 mcg Tablet mass: 260.0 mg Dosage 150 mcg 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. With a mass of 104 mg, the tablets have an active ingredient content of 100 µg. 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 pH 7.4.
After 15 minutes, 80% of the active ingredient has already been released, after 60 minutes more than 90%.
This shows that the substances used to stabilize the active ingredient, namely antioxidants and adsorbents, do not negatively affect the release and thus the bioavailability.

Claims (13)

Oral thyroid therapeutic agent, containing 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, the ratio in % by weight of active ingredient: antioxidant: adsorbent being 1: 1: 5 to 1: 50:100, characterized in that the antioxidant is selected from sulphur-containing, organic antioxidants selected from cysteine, cystine, glutathione, dimercaptopropanesulfonic acid and their salts and derivatives and from mixtures of the aforementioned agents. Oral thyroid therapeutic, according to claim 1 , characterized in that the active ingredient in the form of a thyroid hormone is levothyroxine or its pharmaceutically acceptable salts or liothyronine or its pharmaceutically acceptable salts or that mixtures of said active ingredients are contained. Oral thyroid therapeutic, according to claim 1 or 2 , characterized in that a further active substance is contained, the further active substance preferably being at least one iodine salt selected from iodides or iodates of the alkali metals, in particular potassium iodide or potassium iodate, and mixtures of the said iodine salts. Oral thyroid therapeutic agent according to at least one of the preceding claims, characterized in that it also contains pharmaceutically acceptable excipients, carriers and/or diluents. Oral thyroid therapeutic according to at least one of the preceding claims, characterized in that the sulphur-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 therapeutic, according to claim 6 , characterized in that the inorganic basic or oxidic adsorbents are selected from silica gels, zeolites, alkaline earth metal oxides, alkali metal carbonates, alkali metal hydrogen carbonates, alkaline earth metal carbonates, alkaline earth metal hydrogen carbonates and from mixtures of the aforementioned adsorbents. Oral thyroid therapeutic, according to claim 7 , characterized in that the alkaline earth metal oxide is magnesium oxide and/or the alkaline earth metal 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 % by weight of active substance: antioxidant: adsorbent is 1:5:5 to 1:10:40. Oral thyroid therapeutic according to at least one of the preceding claims, characterized in that the active substance content is 0.01 to 0.5% by weight. Oral thyroid therapeutic according to at least one of the preceding claims, characterized in that the active substance content of a single dosage is 25 µg to 150 µg. Oral thyroid therapeutic according to one of the preceding claims, in the form of a tablet that can be divided once or several times. Oral thyroid therapeutic, according to claim 12 , characterized in that the divisible tablet has a break line, several break lines arranged parallel to one another or a cross break line.

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