WO2022075436A1

WO2022075436A1 - A method of producing thyroid hormone-containing formulation

Info

Publication number: WO2022075436A1
Application number: PCT/JP2021/037281
Authority: WO
Inventors: Takahisa Saito; Kazuhiro Sasaki; Haruna MASUDA
Original assignee: Aska Pharmaceutical Co., Ltd.
Priority date: 2020-10-09
Filing date: 2021-10-08
Publication date: 2022-04-14
Also published as: TW202227047A

Abstract

The present invention aims at improving the stability of a thyroid hormone-containing solid formulation. More specifically, the present invention aims at developing a technique capable of further improving the stability of a thyroid hormone-containing solid formulation. The inventors of the present invention extensively conducted further studies to develop a technique for improving the stability of the thyroid hormone-containing solid formulation and found that the stability of the thyroid hormone-containing solid formulation was significantly enhanced when a step of granulating a mixture of thyroid hormone and additives by a wet granule compression method was included in the formulation procedure. The present invention has been accomplished based on this finding.

Description

A METHOD OF PRODUCING THYROID HORMONE-CONTAINING FORMULATION

The present invention relates to a method for producing a formulation comprising thyroid hormone such as Sodium Levothyroxine. More specifically, the present invention relates to a method for producing a thyroid hormone-containing formulation with improved stability.

A thyroid hormone-containing formulation such as a Sodium Levothyroxine formulation is commercially available in the form of a solid formulation as a therapeutic agent for conditions such as hypothyroidism, myxedema, cretinism, and goiter. Since the thyroid hormone-containing formulation is generally sensitive to external stimuli such as temperature, moisture, light exposure, and oxidation, continued research and improvement are under way to stabilize the formulation.

Previous thyroid hormone-containing formulations had each contained considerable amounts of crystalline cellulose. Hence, R&D efforts were made with a view to providing a stabilized thyroid hormone-containing solid formulation which is substantially free of crystalline cellulose and this has led to the following findings: when inorganic compounds (as selected from the group consisting of sodium hydrogen phosphate, calcium carbonate, calcium silicate, magnesium oxide, magnesium hydroxide and synthetic aluminum silicate) are incorporated as stabilizing agents in the formulation, less iodine is dissociated from the thyroid hormone, whereupon the stability of the thyroid hormone-containing solid formulation is significantly enhanced; since this stability enhancing effect is generated irrespective of the kind and amount of the additive such as excipient that is used, crystalline cellulose which is the conventional additive for thyroid hormone containing-solid formulations need not be intentionally employed (Patent Document 1).

However, the thyroid hormone containing-solid formulation disclosed in Patent Document 1 which is free of crystalline cellulose but contains an inorganic compound as a stabilizing agent has a problem in that the addition of an inorganic compound alone is still insufficient to provide desired stability as a pharmaceutical composition and it has been considered necessary to provide a technique capable of further improving the stability of the formulation.

Japanese Patent No. 4291962

The present invention aims at improving the stability of a thyroid hormone-containing solid formulation. More specifically, the present invention aims at developing a technique capable of further improving the stability of a thyroid hormone-containing solid formulation.

The inventors of the present invention extensively conducted further studies to develop a technique for improving the stability of the thyroid hormone-containing solid formulation and found that, regardless of presence or absence of the inorganic compounds used as stabilizing agents in Patent Document 1, the stability of the thyroid hormone-containing solid formulation was significantly enhanced when a step of granulating a mixture of thyroid hormone and additives by a wet granule compression method was included in the formulation procedure. The present invention has been accomplished based on this finding.

More specifically, the present application provides the following embodiments to solve the problems described above:
[1] A method for producing a thyroid hormone-containing solid formulation with improved stability in the formulation, which comprises a step of granulating a mixture of thyroid hormone and additives by a wet granule compression method.
[2] The method for producing a thyroid hormone-containing solid formulation as described in [1], in which the step of granulating the mixture by the wet granule compression method is conducted by adding water to the mixture of thyroid hormone and the additives and stirring the mixture.
[3] The method for producing a thyroid hormone-containing solid formulation as described in [1] or [2], wherein the thyroid hormone is Sodium Levothyroxine.
[4] The method for producing a thyroid hormone-containing solid formulation as described in any one of [1]-[3], wherein the solid formulation is prepared in the form of tablets, fine granules, granules, or capsules.
[5] The method for producing a thyroid hormone-containing solid formulation as described in any one of [1]-[4], which comprises an excipient, a disintegrator, a binder and a lubricant as additives.
[6] The method for producing a thyroid hormone-containing solid formulation as described in [5], which may further comprise a stabilizing agent and/or a coloring agent as additives.
[7] A thyroid hormone-containing solid formulation with improved stability in the formulation, which is prepared by a method comprising a step of granulating a mixture of thyroid hormone and additives by a wet granule compression method.
[8] The thyroid hormone-containing solid formulation as described in [7], in which the step of granulating the mixture by the wet granule compression method is conducted by adding water to the mixture of thyroid hormone and the additives and stirring the mixture.
[9] The thyroid hormone-containing solid formulation as described in [7] or [8], wherein the thyroid hormone is Sodium Levothyroxine.
[10] The thyroid hormone-containing solid formulation as described in any one of [7]-[9], wherein the solid formulation is prepared in the form of tablets, fine granules, granules, or capsules.
[11] The thyroid hormone-containing solid formulation as described in any one of [7]-[10], which comprises an excipient, a disintegrator, a binder and a lubricant as additives.
[12] The thyroid hormone-containing solid formulation as described in [11], which may further comprise a stabilizing agent and/or a coloring agent as additives.

When a step of granulating a mixture of thyroid hormone and additives by a wet granule compression method in which water is added to the mixture of thyroid hormone and additives followed by stirring the mixture is conducted in the preparation method of the present invention, the percent residue of thyroid hormone in the formulation under storage condition and, hence, the stability of the formulation is improved.

Fig. 1 shows the percent residue of Levothyroxine in each of the formulations of Production Examples 1-5 and Comparative Examples 1-3 after storage for 3 days (72 hours), 7 days (168 hours) or 14 days (336 hours), with the content of Levothyroxine at the start of the storage being taken as 100.0.

Generally, a pharmaceutical formulation is produced by the following steps:
(i) a step of mixing a medicinal ingredient with additives such as an excipient, a disintegrator, a binder, a stabilizing agent, a coloring agent, etc. and stirring the mixture,
(ii) a step of granulating the mixture,
(iii) a step of drying and subsequent grain size adjustment,
(iv) a step of mixing with a lubricant,
(v) a step of preparing a desired dosage form.

In the technical art of the present invention, "granulate" or "granulation" refers to a step in which a bulk powder consisting of a single or multiple components is treated with a binder and the like so as to prepare grains larger than the bulk powder. Techniques of "granulation" in the step (ii) above may be classified as:
- Granulation by a wet granule compression method in which granules are formed with a solvent such as water;
- Granulation by a dry granule compression method in which granules are formed without solvent.

In the above-mentioned Patent Document 1, no solvent such as water was added in the step of granulation and this means that granulation was conducted by a dry granule compression method. On the other hand, the present invention is characterized in that in the process of producing a thyroid hormone-containing solid formulation, granulation in a step corresponding to the step (ii) above is conducted by a wet granule compression method. Therefore, in an embodiment, the present invention provides a method for producing a thyroid hormone containing-solid formulation with improved stability in the formulation, which comprises a step of granulating a mixture of thyroid hormone and additives by a wet granule compression method.

In the present invention, the step of granulation by a wet granule compression method is conducted by adding water to the mixture of thyroid hormone and additives and then stirring the mixture. In this step, water may be added to the mixture in an amount ranging between 1 - 30 weight %, preferably 10 - 30 weight %, more preferably 15 - 25 weight %, of the total weight of the mixture of thyroid hormone and additives. In the step, the duration of the stirring operation after addition of water may range between 30 - 180 seconds, preferably 60 - 150 seconds, more preferably 80 - 120 seconds.

It has become clear that, when a step of granulating a mixture of thyroid hormone and additives by a wet granule compression method in which water is added to the mixture of thyroid hormone and additives followed by stirring the mixture is conducted in the preparation method of the present invention, the percent residue of thyroid hormone in the formulation under storage condition and, hence, the stability of the formulation is improved.

In the present invention, specific examples of thyroid hormone which can be used as a medicinal ingredient include, but are not limited to, Levothyroxine and its sodium salt, liothyronine and its sodium salt, dried thyroid gland, and so on. Among these, Sodium Levothyroxine is preferably used.

The content of thyroid hormone in the solid formulation may appropriately be adjusted in accordance with the kind of thyroid hormone, the dosage form of the solid formulation and so on. For example, in the case of a tablet comprising Sodium Levothyroxine, the content of Sodium Levothyroxine may be determined to range between 25 - 300 micro g per tablet.

In the present invention, the term "solid formulation" refers to such a formulation that the mixture of a medicinal ingredient and additives in it is a solid material. The solid formulation may generally encompass tablets, fine granules, granules, pills, capsules, suppositories, and so on. It is particularly preferred that the solid formulation used in the present invention assumes the form of tablets, fine granules, granules, or capsules. Tablets are prepared by a process comprising the steps of granulating the mixture of a medicinal ingredient and additives by a wet granule compression method, drying and subsequent grain size adjustment, mixing with a lubricant, and pelletizing to prepare the desired dosage form. Fine granules and granules are prepared by the steps of granulating the mixture of a medicinal ingredient and additives by a wet granule compression method, drying and subsequent grain size adjustment, and screening to obtain a specified grain size. Capsules are prepared by the steps of granulating the mixture of a medicinal ingredient and additives by a wet granule compression method, drying and subsequent grain size adjustment, and filling into capsules.

Additives which can be used with the medicinal ingredient for producing these solid formulations may include, but are not limited to, an excipient, a disintegrator, a binder, a lubricant, a stabilizing agent, a coloring agent, a coating agent, a flavor and so on. In the formulation procedure, the additives can appropriately be selected and used. Among these additive components, an excipient, a disintegrator, a binder, and a lubricant can be used as main additives, which can be incorporated in the solid formulation of the present invention in the amounts known per se in the pharmaceutical art.

Specific examples of the excipient may include, but are not limited to, lactose, glucose, D-mannitol, anhydrous dibasic calcium phosphate, starch, sucrose, and so on. For example, in the case where the dosage form of formulation is a tablet, the excipient may be incorporated in an amount ranging between 10.0 - 99.0 weight %, preferably 50.0 - 90.0 weight %, of the total weight of the thyroid hormone-containing solid formulation.

Specific examples of the disintegrator may include, but are not limited to, carboxymethyl cellulose, carboxymethyl cellulose calcium, Croscarmellose sodium, Crospovidone, starch, partly pregelatinized starch, low-substituted hydroxypropyl cellulose, and so on. For example, in the case where the dosage form of formulation is a tablet, the disintegrator may be incorporated in an amount ranging between 0 - 40.0 weight %, preferably 5.0 - 30.0 weight %, of the total weight of the thyroid hormone-containing solid formulation.

Specific examples of the binder may include, but are not limited to, hydroxypropyl cellulose, ethyl cellulose, gum arabic, starch, partly pregelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol, and so on. For example, in the case where the dosage form of formulation is a tablet, the binder may be incorporated in an amount ranging between 0 - 10.0 weight %, preferably 2.0 - 5.0 weight %, of the total weight of the thyroid hormone-containing solid formulation.

Specific examples of the lubricant may include, but are not limited to, magnesium stearate, calcium stearate, talc, hydrated silicon dioxide, hydrogenated oil, and so on. For example, in the case where the dosage form of formulation is a tablet, the lubricant may be incorporated in an amount ranging between 0 - 3.0 weight %, preferably 0.5 - 2.0 weight %, of the total weight of the thyroid hormone-containing solid formulation.

Further, if necessary, in addition to the excipient, disintegrator, binder, and lubricant, a stabilizing agent, a coloring agent, a coating agent and/or a flavor may appropriately be incorporated when the solid formulation is prepared.

The stabilizing agent used may be exemplified by pharmaceutically acceptable inorganic compounds which are non-toxic and solid at room temperature; specific examples include, but are not limited to, oxides, hydroxides, halides, or inorganic acid salts of metals such as potassium, sodium, calcium, magnesium, aluminum, and so on. More specific examples of the stabilizing agent may include, but are not limited to, sodium hydrogen carbonate, sodium carbonate, sodium hydrogen phosphate, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium silicate, magnesium oxide, magnesium hydroxide, synthetic aluminum silicate, potassium iodide, and so on. These stabilizing agents may be used either alone or in appropriate combinations of two or more species in the solid formulation of the present invention. For example, in the case where the dosage form of formulation is a tablet, the stabilizing agent may be used in a proportion ranging between 0.1 - 5.0 weight %, preferably 0.2 - 3.0 weight %, of the total weight of the thyroid hormone-containing solid formulation.

The coloring agent may be exemplified by red ferric oxide, yellow ferric oxide, titanium oxide, tar dye, and so on.

The coating agent may be exemplified by white soft sugar, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, polyvinylpyrrolidone, and so on.

The flavor may be exemplified by citric acid, aspartame, ascorbic acid, menthol, and so on.

As described above, it has become clear that when a step of granulating the mixture of thyroid hormone and additives by a wet granule compression method in which water is added to the mixture of thyroid hormone and additives followed by stirring the mixture is conducted in the preparation method of the present invention, the percent residue of thyroid hormone in the formulation under storage condition and, hence, the stability of the formulation is improved. As a result, in an embodiment of the present invention, a thyroid hormone-containing solid formulation with improved stability in the formulation can be provided by conducting a step of granulating a mixture of thyroid hormone and additives by a wet granule compression method.

On the following pages, the present invention will be described in detail by means of Examples, which are simply descriptions of embodiments of the present invention and should not be construed as limiting.

In the Examples, the respective formulations were prepared in accordance with the recipes summarized in the table below (Table 1). The Examples describe specific formulations for granule. However, various other formulation types such as tablet, capsule, or fine granule may also be prepared by respective known formulation methods.

The respective formulations were produced by the following preparation methods.

Production Example 1 (Prod. Ex. 1):
Sodium Levothyroxine (0.025 weight %), D-mannitol (82.475 weight %), corn starch (10 weight %), magnesium hydroxide (0.5 weight %), partly pregelatinized starch (5 weight %), and red ferric oxide (0.02 weight %) were homogeneously mixed using a stirring mixer for 20 minutes. Purified water (20 weight %) was added to the mixture, which was then granulated for 120 seconds (2 minutes). The thus obtained granules were dried using a fluidized-bed dryer with air supplied at a temperature setting of 50 °C, and then the granules were passed through JP No. 16 sieve (opening of sieve = 1000 micro m) for grain size adjustment. To the size-adjusted granules, talc (1.0 weight %) and magnesium stearate (1.0 weight %) were added and the mixture was blended using a container rotary mixer for 2 minutes to produce the formulation of Production Example 1 (Prod. Ex. 1).

Production Example 2 (Prod. Ex. 2):
Sodium Levothyroxine (0.025 weight %), D-mannitol (82.475 weight %), corn starch (10 weight %), magnesium hydroxide (0.5 weight %), and partly pregelatinized starch (5 weight %) were homogeneously mixed using a stirring mixer for 20 minutes. Purified water (20 weight %) was added to the mixture, which was then granulated for 120 seconds (2 minutes). The thus obtained granules were dried using a fluidized-bed dryer with air supplied at a temperature setting of 50 °C, and then the granules were passed through JP No. 16 sieve (opening of sieve = 1000 micro m) for grain size adjustment. To the size-adjusted granules, talc (1.0 weight %) and magnesium stearate (1.0 weight %) were added and the mixture was blended using a container rotary mixer for 2 minutes to produce the formulation of Production Example 2 (Prod. Ex. 2).

Production Example 3 (Prod. Ex. 3):
Sodium Levothyroxine (0.05 weight %), D-mannitol (82.45 weight %), corn starch (10 weight %), magnesium hydroxide (0.5 weight %), and partly pregelatinized starch (5 weight %) were homogeneously mixed using a stirring mixer for 20 minutes. Purified water (20 weight %) was added to the mixture, which was then granulated for 120 seconds (2 minutes). The thus obtained granules were dried using a fluidized-bed dryer with air supplied at a temperature setting of 50 °C, and then the granules were passed through JP No. 16 sieve (opening of sieve = 1000 micro m) for grain size adjustment. To the s size-adjusted granules, talc (1.0 weight %) and magnesium stearate (1.0 weight %) were added and the mixture was blended using a container rotary mixer for 2 minutes to produce the formulation of Production Example 3 (Prod. Ex. 3).

Production Example 4 (Prod. Ex. 4):
Sodium Levothyroxine (0.025 weight %), D-mannitol (82.975 weight %), corn starch (10 weight %), partly pregelatinized starch (5 weight %), and red ferric oxide (0.02 weight %) were homogeneously mixed using a stirring mixer for 20 minutes. Purified water (20 weight %) was added to the mixture, which was then granulated for 120 seconds (2 minutes). The thus obtained granules were dried using a fluidized-bed dryer with air supplied at a temperature setting of 50 °C, and then the granules were passed through JP No. 16 sieve (opening of sieve = 1000 micro m) for grain size adjustment. Then To the size-adjusted granules, talc (1.0 weight %) and magnesium stearate (1.0 weight %) were added and the mixture was blended mixed using a container rotary mixer for 2 minutes to produce the formulation of Production Example 4 (Prod. Ex. 4).

Production Example 5 (Prod. Ex. 5):
Sodium Levothyroxine (0.025 weight %), D-mannitol (82.975 weight %), corn starch (10 weight %), and partly pregelatinized starch (5 weight %) were homogeneously mixed using a stirring mixer for 20 minutes. Purified water (20 weight %) was added to the mixture, which was then granulated for 120 seconds (2 minutes). The thus obtained granules were dried using a fluidized-bed dryer with air supplied at a temperature setting of 50 °C, and then the granules were passed through JP No. 16 sieve (opening of sieve = 1000 micro m) for grain size adjustment. To the size-adjusted granules, talc (1.0 weight %) and magnesium stearate (1.0 weight %) were added and the mixture was blended using a container rotary mixer for 2 minutes to produce the formulation of Production Example 5 (Prod. Ex. 5).

Comparative Example 1 (Comp. Ex. 1):
Sodium Levothyroxine (0.025 weight %), D-mannitol (82.475 weight %), corn starch (10 weight %), magnesium hydroxide (0.5 weight %), partly pregelatinized starch (5 weight %), and red ferric oxide (0.02 weight %) were homogeneously mixed using a stirring mixer for 20 minutes. To the mixed powder, talc (1.0 weight %) and magnesium stearate (1.0 weight %) were added and the mixture was blended using a container rotary mixer for 2 minutes to produce the formulation of Comparative Example 1 (Comp. Ex. 1).

Comparative Example 2 (Comp. Ex. 2):
Sodium Levothyroxine (0.025 weight %), D-mannitol (82.475 weight %), corn starch (10 weight %), magnesium hydroxide (0.5 weight %), and partly pregelatinized starch (5 weight %) were homogeneously mixed using a stirring mixer for 20 minutes. To the mixed powder, talc (1.0 weight %) and magnesium stearate (1.0 weight %) were added and the mixture was blended using a container rotary mixer for 2 minutes to produce the formulation of Comparative Example 2 (Comp. Ex. 2).

Comparative Example 3 (Comp. Ex. 3):
Sodium Levothyroxine (0.025 weight %), D-mannitol (82.975 weight %), corn starch (10 weight %), partly pregelatinized starch (5 weight %), and red ferric oxide (0.02 weight %) were homogeneously mixed using a stirring mixer for 20 minutes. To the mixed powder, talc (1.0 weight %) and magnesium stearate (1.0 weight %) were added and the mixture was blended using a container rotary mixer for 2 minutes to produce the formulation of Comparative Example 3 (Comp. Ex. 3).

Storage stability test:
The foregoing formulations of Production Examples 1-5 and Comparative Examples 1-3 were each placed in a brown bottle and, without sealing the bottle, stored at high temperature and high humidity (i.e., 60 °C, 75% humidity); thereafter, the formulations were tested for their stability under the storage condition.

The storage stability test was conducted by the following test method:
A stored sample was dissolved to prepare a sample solution, which was subjected to liquid chromatography using the following column and mobile phase. Then, the content of Levothyroxine was measured using an ultraviolet spectrophotometer (measurement wavelength: 224 nm).

<Column> A stainless steel tube (inner diameter = 6 mm, length = about 15 cm) filled with cyanopropyl silylated silica gel for liquid chromatography (particle diameter = about 5 micro m) .

<Mobile Phase> Water/Acetonitrile/phosphoric acid mixed solution (65: 35: 0.1).

With the content of Levothyroxine just after liquid chromatography at the start of the test being taken as 100.0 %, the content of Levothyroxine in each formulation after storage for 3 days (72 hours), 7 days (168 hours), or 14 days (336 hours) was measured and divided by the baseline to calculate the relative proportion (percent residue). The percent residue (%) of Sodium Levothyroxine was used as an index of stability of the formulation in the present specification (Table 2).

The content of Sodium Levothyroxine for each storage time as measured in each case was expressed as percent residue and is shown in Table 2. The respective trends of the percent residue are shown in Figure 1.

Comparison of Production Examples 1-3 and that of Production Examples 4 and 5 showed that presence or absence of red ferric oxide in a formulation’s recipe has no effect on the stability of Levothyroxine in the formulation.

Comparison of Production Examples 1 and 4 and that of Production Examples 2, 3 and 5 showed that presence of magnesium hydroxide in a formulation’s recipe contributes, although slightly, to improve the stability of Levothyroxine in the formulation. However, the degree of improvement in the stability of the Levothyroxine was small and the present inventors concluded that magnesium hydroxide has no effect on the stability of Levothyroxine in the formulation.

On the other hand, comparison between Production Example 1 and Comparative Example 1, comparison between Production Examples 2 and 3 and Comparative Example 2, and comparison between Production Example 4 and Comparative Example 3 showed that granulation by a wet granule compression method contributes to improve the stability of Levothyroxine in a formulation after granulation.

This improvement of stability can be calculated as percent elevation of stability relative to Comparative Example 1, yielding the data as shown in Table 3 below. As a result, it was shown that the method of the present invention in which granulation is conducted by a wet granule compression method enabled the stability of Levothyroxine to be significantly elevated over Comparative Example 1 (i.e., conventional method).

Claims

A method for producing a thyroid hormone-containing solid formulation with improved stability in the formulation, which comprises a step of granulating a mixture of thyroid hormone and additives by a wet granule compression method.
The method for producing a thyroid hormone-containing solid formulation as claimed in Claim 1, in which the step of granulating the mixture by the wet granule compression method is conducted by adding water to the mixture of thyroid hormone and the additives and stirring the mixture.
The method for producing a thyroid hormone-containing solid formulation as claimed in Claim 1 or 2, wherein the thyroid hormone is Sodium Levothyroxine.
The method for producing a thyroid hormone-containing solid formulation as claimed in any one of Claims 1-3, wherein the solid formulation is prepared in the form of tablets, fine granules, granules, or capsules.
The method for producing a thyroid hormone-containing solid formulation as claimed in any one of Claims 1-4, which comprises an excipient, a disintegrator, a binder and a lubricant as additives.
The method for producing a thyroid hormone-containing solid formulation as claimed in Claim 5, which may further comprise a stabilizing agent and/or a coloring agent as additives.
A thyroid hormone-containing solid formulation with improved stability in the formulation, which is prepared by a method comprising a step of granulating a mixture of thyroid hormone and additives by a wet granule compression method.
The thyroid hormone-containing solid formulation as claimed in Claim 7, in which the step of granulating the mixture by the wet granule compression method is conducted by adding water to the mixture of thyroid hormone and the additives and stirring the mixture.
The thyroid hormone-containing solid formulation as claimed in Claim 7 or 8, wherein the thyroid hormone is Sodium Levothyroxine.
The thyroid hormone-containing solid formulation as claimed in any one of Claims 7-9, wherein the solid formulation is prepared in the form of tablets, fine granules, granules, or capsules.
The thyroid hormone-containing solid formulation as claimed in any one of Claims 7-10, which comprises an excipient, a disintegrator, a binder and a lubricant as additives.
The thyroid hormone-containing solid formulation as claimed in Claim 11, which may further comprise a stabilizing agent and/or a coloring agent as additives.