KR20170112509A - Solid formulation for oral administration containing melatonin and a process for the preparation thereof - Google Patents

Abstract

The present invention provides an oral solid preparation comprising melatonin or a pharmaceutically acceptable salt thereof and a cellulose derivative as a sustained release agent, and a preparation method thereof.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a melatonin-containing oral solid preparation and a preparation method thereof,

The present invention relates to an oral solid preparation containing melatonin as an active ingredient, and more particularly to a sustained-release oral solid preparation containing melatonin with improved stability of the active ingredient.

Melatonin is a hormone secreted from the pineal gland of the brain, known as a hormone that plays a major role in the induction and regulation of sleep. Melatonin has the chemical structure of 5-methoxy-N-acetyl-tryptamine. Melatonin was first isolated from bovine pineal gland and is found in all plants and plants, including bacteria and algae. In animals, it is biosynthesized in the pineal gland of the brain and released into the blood, and acts as a hormone involved in the regulation of circadian rhythm, seasonal rhythm and photoperiodism.

Melatonin is effective in the treatment of sleep disorders due to abnormal production of melatonin due to the use of aging-related diseases or certain medicaments (for example, beta adrenoceptor blockers), and specifically to reduce the amount of time it takes to fall asleep And improve sleep quality and daytime activity. However, melatonin is effective for the treatment of sleep disorders, but the melatonin has a short half-life of 35 to 50 minutes, which is insufficient for a single administration. Therefore, melatonin may have to be prepared as sustained-release preparations that continuously release the active ingredient during the 8 hours, there is a current standing kadin ^® (Circadin ^®) as the name of sustained release tablet for oral sex (tablet) is commercially available. Standing kadin ^® is a sustained-release tablet of a matrix containing the Eudragit RSPO (Ammonio Methacrylate Copolymer, Type B) for the acrylic resin is used as sustained release agents. However, in order for the sustained-release preparation of melatonin to exhibit a stable drug efficacy, it is necessary to develop a preparation having improved shelf stability of the active ingredient as well as sustained release of the active ingredient.

One aspect of the present invention is to provide a melatonin-containing oral solid preparation having sustained release and storage stability of the active ingredient.

Another aspect of the present invention is to provide a method for producing a solid preparation for oral administration containing melatonin, in which sustained release of the active ingredient and storage stability are secured.

One aspect of the present invention is

Melatonin or a pharmaceutically acceptable salt thereof, and a cellulose derivative as a sustained release agent.

In another aspect of the present invention,

Preparing a mixture of raw materials comprising melatonin or a pharmaceutically acceptable salt thereof, a cellulose derivative as a sustained release agent, and a diluent; And

Mixing said mixture with a pharmaceutical additive and tableting to produce tablets.

There is provided a method of producing an oral solid preparation according to an aspect of the present invention.

The oral solid preparation according to one aspect of the present invention is capable of achieving the sustained release of melatonin and is more active than the conventional commercially available melatonin formulation without the need for additional stabilization due to the use of the sustained release agent used for obtaining the sustained release The storage stability of the component is remarkably excellent. Therefore, according to one aspect of the present invention, there can be provided a sustained release solid preparation containing melatonin which can stably exhibit the therapeutic effect of melatonin on sleeping disorders, and which is excellent in stability and safety.

1 is a graph showing the results of dissolution tests according to the United States Pharmacopoeia second method paddle method for tablets of Examples 1 to 3 and Comparative Example 1. Fig.
FIG. 2 is a graph showing the results of dissolution tests according to the United States Pharmacopoeia second method paddle method for tablets of Examples 4 to 6 and Comparative Example 1. FIG.
3 is a graph showing the results of dissolution tests according to the United States Pharmacopoeia second method paddle method for the tablets of Examples 7 to 9 and Comparative Example 1. Fig.
FIG. 4 shows the results of the tablets of Examples 2 and 7 to 9 and the tablets of Comparative Examples 1 to 4 in an HDPE bottle and stored for 1 week, 2 weeks, 3 weeks, or 4 weeks under harsh conditions (60 ° C) The content of the melatonin softening material A is analyzed.
5 is a graph showing the results of dissolution test according to the United States Pharmacopoeia second method paddle method before and after storage of the tablets of Example 2 and Comparative Example 1 in a HDPE bottle for 4 weeks under harsh conditions (60 ° C).

All technical terms used in the present invention are meant to be understood by those skilled in the art to which the present invention pertains in general, unless otherwise defined. In addition, preferred methods or samples are described in this specification, but similar or equivalent ones are also included in the scope of the present invention. The contents of all publications referred to in this specification are incorporated herein by reference in their entirety.

Melatonin is known to have a very short half-life of 35 to 50 minutes, and therefore it is necessary to exhibit sustained release for about 7 to 8 hours, which is known as proper sleeping time, in order to produce it as a medicament for treating sleep disorders. , It is necessary to develop a formulation which ensures the storage stability of the active ingredient. As a result of the study, it was found that the use of a cellulose derivative as a sustained release agent to prepare a sustained-release solid preparation containing melatonin not only exhibited sufficient sustained release of melatonin but also significantly improved the storage stability of melatonin as compared with a commercially available control preparation .

One aspect of the present invention is

Melatonin or a pharmaceutically acceptable salt thereof, and a cellulose derivative as a sustained release agent.

As used herein, " melatonin or a pharmaceutically acceptable salt thereof " is interpreted to include melatonin, a melatonin analog, a pharmaceutically acceptable salt or ester thereof, or a prodrug thereof, which are known in the art. In one embodiment, the melatonin or a pharmaceutically acceptable salt thereof is a melatonin free base.

In the present specification, the term "solid preparation" means a preparation which is formed by molding or spraying the drug into a certain shape. The oral solid preparations may be any oral solid preparations which may exhibit sustained release of the active ingredient (s) in the art, for example, pellets, capsules, tablets (including single layer tablets, Or the like, but the present invention is not limited thereto. The oral solid preparation may be, for example, a sustained-release tablet or a multi-layer tablet containing a sustained-release tablet.

The cellulose derivative may be any cellulose derivative known in the art as a release agent. The cellulose derivative is selected from the group consisting of, for example, ethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, cellulose acetate, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, and any combination thereof . In one embodiment, the cellulose derivative is ethylcellulose, methylcellulose, hydroxypropylmethylcellulose, or hydroxypropylcellulose.

The cellulose derivative may be contained in the oral solid preparation in an amount of about 5 to 40% by weight, and the proper amount may vary depending on the specific type. In one embodiment, the oral solid preparation is a solid formulation comprising ethyl cellulose as the cellulose derivative in an amount of about 5 to 40% by weight based on the total weight of the solid preparation.

The cellulose derivative enables the sustained release of the active ingredient melatonin or a pharmaceutically acceptable salt thereof in the solid preparation. As a result of the experiment, it was confirmed that the sustained-release tablet according to one embodiment of the present invention prepared using various cellulose derivatives as a sustained release agent showed sustained release equal to or more than that of the sustained release tablet of the commercial formulation (Test Example 1, Fig. 1 -3). In addition, the sustained-release tablet according to one embodiment of the present invention is more effective than the sustained-release tablet prepared by using various sustained release agents other than the cellulose derivative including Eudragit RSPO contained in the sustained release sustained-release formulation, As a result of the test, the degree of increase of the melatonin softening agent A was remarkably low and the stability of melatonin was remarkably excellent (see Test Example 2, Figs. 4 and 5). An increase in the amount of the substance may indicate unintended side effects and may lead to a decrease in the efficacy of the drug, so that the decrease in the degree of increase in the amount of the substance is very important from the viewpoint of efficacy and safety of the drug. Therefore, a sustained-release oral solid preparation containing melatonin containing a cellulose derivative as a sustained release agent exhibits an adequate melatonin-sustaining property as compared with the case of containing other sustained release agents, but exhibits remarkable storage stability of the active ingredient without separate active ingredient stabilization means It is possible to provide a solid preparation for oral administration containing melatonin with improved safety and efficacy as a result.

The oral solid preparations may additionally contain any pharmaceutical additives known to be usable for the preparation of solid preparations in addition to the sustained release agents. The pharmaceutical additive may be selected from the group consisting of diluents, binders, lubricants, and any combination thereof.

The diluent may be selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sucrose, lactose, sorbitol, xylitol, glucose, calcium hydrogen phosphate, and any combination thereof, but is not limited thereto. In one embodiment, the diluent is a combination of lactose and calcium hydrogen phosphate. The diluent may be contained in an amount of about 20-85% by weight based on the total weight of the solid preparation.

The binder may be selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylalcohol, polyvinylpyrrolidone (PVP), carboxymethylcellulose sodium, and any combination thereof, but is limited thereto It is not. The binder may be present in an amount of about 1-5% by weight based on the total weight of the solid formulation.

The lubricant may be selected from the group consisting of calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulphate, sodium stearyl fumarate, zinc stearate, stearic acid, cured vegetable oil, polyethylene glycol, But are not limited to, sodium, silicon dioxide, talc, and any combination thereof. In one embodiment, the lubricant is a combination of magnesium stearate, talc, and silicon dioxide. The glidant may be contained in an amount of about 0.5 to 6% by weight based on the total weight of the solid preparation.

In one embodiment, the oral solid preparation is a multi-layer tablet containing a sustained release tablet or a sustained release tablet.

The sustained-release tablet may be prepared according to any production method that can be used in the production of tablets, and includes, for example, a direct powder compression method or a granular compression method. The granular compression method includes a dry granular compression method or a wet granular compression method. The direct powder compacting method, the dry granulating compacting method, and the wet granulating compacting method may be carried out according to a method known in the art.

In one embodiment, the oral solid preparation is an oral solid preparation in which the melatonin softening agent A is present in an amount of 0.25% by weight or less in a severe stability test under the condition of about 60 캜 in an HDPE bottle.

Such oral solid preparations can be used for the treatment or prevention of any indications for which melatonin or a pharmaceutically acceptable salt thereof is effective and are particularly useful for indications that require sustained drug efficacy over a period of about 7 to 8 hours in one administration Lt; / RTI > In one embodiment, the indication is a sleep disorder. Such sleep disorders include sleep disorders due to abnormal production of melatonin. Such sleep disorders include insomnia, particularly those above 55 years of age, in which the quality of sleep is lowered.

In one embodiment, the solid formulation may exhibit sustained release of melatonin for at least about 7 to 8 hours, so that the efficacy of the melatonin may be sustained for a period of time following oral administration prior to sleep.

The oral solid preparations may contain about 1-8 mg of melatonin free base per unit dosage form, for example about 2 mg per unit dosage form.

In another aspect of the present invention,

Preparing a mixture of raw materials comprising melatonin or a pharmaceutically acceptable salt thereof, a cellulose derivative as a release agent, and a diluent; And

There is provided a method for producing an oral solid preparation according to an aspect of the present invention, comprising the step of mixing the mixture with a pharmaceutical additive and tabletting to prepare tablets.

The details of the method for producing the oral solid preparation according to this aspect may be applied to the description of the solid preparation according to one aspect of the present invention as it is.

The preparation of the mixture of the raw materials may be carried out according to any mixing method known in the art. In one embodiment, the mixture may be prepared by sieving together the melatonin or a pharmaceutically acceptable salt thereof, a cellulose derivative as a release agent, and a mixture of raw materials comprising a diluent. It is possible to control the particle size of the raw materials used in the preparation of the tablets through the step of sieving, and the tablets prepared by the subsequent tableting are more excellent in terms of the uniformity of content since the mixing is made more uniform (see Test Example 3 ). Therefore, by the manufacturing method including the step of sieving, it may be possible to produce a solid preparation containing melatonin which is more advantageous in terms of quality control.

For example, the sieving process may be performed by sieving a sieve having a sieve size of about 100 to 450 μm (for example, about 140 to about 40 pharmacopeia) Can be performed.

The size of the particles of the melatonin raw material may be a fine powder having a size of about X ₉₀ (average particle size of the lower 90% of particles) of 50 μm or less, preferably 30 μm or less, more preferably 10 μm or less have. It may be advantageous in terms of the dissolution rate of the oral solid preparation in the above range of the particle size.

The step of preparing the tablet may be carried out by mixing the mixture of the raw materials with a pharmaceutical additive, followed by direct powder compression, or by dry granulation or wet granulation followed by granulation. The direct powder compression method, the manufacture of dry granules or wet granules, and the granulation method may be carried out according to any method known in the art.

[Example]

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example  1 to 6: melatonin and Ethyl cellulose  Manufacture of Containing Tablets

Melatonin, an active ingredient, was sieved in a 60-well (sieve size 250 쨉 m) together with lactose hydrate according to the composition shown in the following Table 1, and then mixed with calcium hydrogenphosphate, silicon dioxide, and ethylcellulose for about 30 minutes. Talc and magnesium stearate were added to the resulting mixture, mixed for about 5 minutes, and the resulting mixture was tableted using a tablet machine.

[Table 1]

Example  7 to 9: Preparation of Tablets Containing Melatonin and Cellulose Derivatives

Were prepared in the same manner as in Examples 1 to 6 according to the compositions shown in Table 2 below.

[Table 2]

Example  10: Shed  Change the size of melatonin and Ethyl cellulose  Manufacture of Containing Tablets

Melatonin, which is an active ingredient, was sieved in a 40-well tongue (425 μm sieve) together with lactose, and then mixed with calcium hydrogenphosphate, silicon dioxide, and ethyl cellulose for about 30 minutes in the same ratio as that of Example 2 above. Talc and magnesium stearate were added to the resulting mixture, mixed for about 5 minutes, and the resulting mixture was compressed using a tablet machine

Example  11: melatonin and Ethyl cellulose  Preparation of tablets containing wet granules containing

Melatonin as an active ingredient was mixed with lactose, calcium monohydrogenphosphate, silicon dioxide and ethylcellulose, and the resulting mixture was combined with about 30 mg of water per one unit. The mixture was dried, ) To prepare wet granules. Talc and magnesium stearate were added to the obtained granules, mixed for about 5 minutes, and the resulting mixture was tableted using a tablet machine.

Example  12: Melatonin and Ethylcellulose  Preparation of Tablets Containing Dry Granules Containing

Melatonin, which is an active ingredient, was sieved with 40 lactose in the same proportion as the composition of Example 2, mixed with calcium monohydrogen phosphate, silicon dioxide, and ethyl cellulose, and then mixed using a roller compactor at an oil pressure of 5.0 MPa , And a roller speed of 2 rpm to form granules on the flakes. The resulting flakes were pulverized and sized with a No. 40 sieve (sieve size 425 탆), and then talc and magnesium stearate were added thereto, followed by mixing for about 5 minutes, and the resulting mixture was compressed by a tablet machine.

Comparative Example  One : Control formulation

A commercially available product, Circadin ( ^R) , containing 2 mg of melatonin as an active ingredient, was used.

Comparative Example  2 to 4: Preparation of tablets containing melatonin and other sustained release agents

Were prepared in the same manner as in Examples 1 to 6 according to the compositions shown in Table 3 below.

[Table 3]

Example  13: Melatonin and Ethyl cellulose  Manufacture of Containing Tablets

In the same manner as in Example 2, the active ingredient, melatonin, was mixed with lactose, calcium monohydrogen phosphate, silicon dioxide, and ethyl cellulose for about 30 minutes. Talc and magnesium stearate were added to the resulting mixture, mixed for about 5 minutes, and the resulting mixture was tableted using a tablet machine.

Example  14: melatonin and Ethyl cellulose  Preparation of tablets containing dry granules containing

Melatonin, lactose, calcium monohydrogen phosphate, silicon dioxide and ethylcellulose were mixed in the same proportions as in Example 2, and then the mixture was pulverized using a roller compactor at an oil pressure of 5.0 MPa and a roller speed of 2 rpm Lt; / RTI > to form granules on the flakes. The obtained flakes were pulverized and sieved through a No. 40 sieve, and then talc and magnesium stearate were added thereto, mixed for about 5 minutes, and the resulting mixture was compressed by a tablet machine.

Test Example  1: dissolution test

The tablets prepared in Examples 1 to 9 and Comparative Example 1 were subjected to a dissolution test at 50 rpm, water and 900 mL using the USP 2nd Method Paddle Method (USP apparatus 2) Are shown in Figs.

<Analysis Conditions of Melatonin>

Column: 4.6 mm X 150 mm, 5.0 占 퐉 (Inertsil ODS-2)

Mobile phase: 0.375 g of potassium dihydrogenphosphate was dissolved in 750 ml of purified water, adjusted to pH 3.5 with phosphoric acid, and then mixed with 250 ml of acetonitrile

Detector: Ultraviolet absorption spectrophotometer (measurement wavelength: 222 nm)

Temperature: 25 ℃

Flow rate: 1.0 ml / min

Injection volume: 10 μl

1 and 2, the change in the dissolution rate depending on the amount of ethyl cellulose used for the preparation of the tablets can be confirmed. According to the results, it was confirmed that the release of the drug was controlled according to the amount of ethylcellulose to control the dissolution rate. In particular, the dissolution profile of Example 2 was similar to that of Comparative Example 1, which is a commercially available product.

According to Fig. 3, the dissolution profile of the sustained-release drug was also exhibited in the case of Example 7-9 in which the melatonin sustained release using a cellulose derivative other than ethylcellulose.

Test Example  2: Severe stability test

The tablets of Examples 2 and 7 to 9 and the tablets of Comparative Examples 1 to 4 were stored in a HDPE bottle for 1 week, 2 weeks, 3 weeks, or 4 weeks under harsh conditions (60 ° C). Upon elapse of the harsh condition storage period, the melatonin softening material A in the tablets was analyzed. The analysis of the melatonin softening material A was carried out according to the following conditions, and the results are shown in FIG.

In addition, the dissolution test was carried out for Example 2 and Comparative Example 1 in the same manner as in Test Example 1 before and after 4 weeks of the harsh condition, and the results are shown in FIG.

&Lt; Conditions for analyzing the content of the melatonin &

Column: 4.6 mm X 150 mm, 5.0 占 퐉 (Inertsil ODS-2)

Mobile phase A: acetonitrile

Mobile phase B: 0.375 g of potassium dihydrogenphosphate was dissolved in 750 ml of purified water and adjusted to pH 3.5 with phosphoric acid

&Lt; Mobile phase concentration gradient condition >

Detector: Ultraviolet absorption spectrophotometer (measurement wavelength: 240 nm)

Flow rate: 1.0 ml / min

Injection volume: 10 μl

Column temperature: 25 ° C

Figure 4 shows the changes of melatonin related compound A (RRT 0.4) over time in tablets of Examples 2 and 7 to 9 and tablets of Comparative Examples 1 to 4 when stored at harsh conditions (60 ° C) Graph.

FIG. 5 is a graph showing the results of performing a dissolution test on the tablets of Example 2 and Comparative Example 1 by the same method as in Test Example 1 before and after four weeks of harsh conditions. FIG.

According to the results of FIG. 4, the increase in the amount of the flexible material was significantly lower in Examples 2 and 7 to 9 as compared with Comparative Examples 1 to 4. Furthermore, as can be seen from FIG. 5, Example 2 showed little change in dissolution pattern even after 4 weeks of storage under harsh conditions, whereas Comparative Example 1 showed a significant drop, indicating that Example 2 is more effective than Comparative Example 1 The stability was remarkably excellent.

Test Example  3: Content uniformity test

10 tablets of Examples 2 and 10 to 14 were subjected to a content uniformity test and the results are shown in Table 4 below.

[Table 4]

The criterion for determination of uniformity in the preparations of Korean Pharmacopoeia according to the content uniformity test is 15. The tablets of Examples 2 and 10 were prepared by directly sieving the active ingredient together with a diluent using a 60-well (sieve size 250 탆) and a 40-well (sieve size 425 탆) It is a tablets produced by direct powder mixing method without simple mixing. It was confirmed that the tablets of Example 13 were inadequate for the content uniformity test because the tablets exceeded 15, and the tablets of Examples 2 and 10 prepared after the tablet had a tabularity of less than 15, thus being suitable for the content uniformity test. Examples 11 and 12 were wet granules and dry granules, respectively, which were then tableted and were all suitable for content uniformity testing. However, Example 14 was tableted using dry granules, but when dry granules were prepared, the dry granules were prepared without being mixed with the active ingredient diluent. As a result, the dry granules were inferior to the content uniformity test exceeding 15 tablets. Therefore, it has been found that, in the preparation of melatonin tablets, it is preferable in terms of quality control, including content uniformity, to carry out a process of sieving a mixture containing an active ingredient and a diluent together.

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the above-described embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (15)

Melatonin or a pharmaceutically acceptable salt thereof, and a cellulose derivative as a sustained release agent. The oral solid preparation according to claim 1, wherein the oral solid preparation is a sustained-release tablet or a multilayer tablet containing a sustained-release layer. The oral solid preparation according to claim 1, wherein the cellulose derivative is selected from the group consisting of ethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, and any combination thereof. The solid preparation according to claim 1, wherein the cellulose derivative is contained in an amount of 5 to 40% by weight based on the total amount of the solid preparation. The solid preparation according to claim 1, wherein ethyl cellulose as the cellulose derivative is contained in an amount of 5 to 40% by weight based on the total amount of the solid preparation. The oral solid preparation of claim 1, further comprising a pharmaceutical additive selected from the group consisting of diluents, binders, lubricants, and any combination thereof. The method according to claim 6,
Wherein the diluent is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sucrose, lactose, sorbitol, xylitol, glucose, calcium hydrogen phosphate,
Wherein the binder is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylalcohol, polyvinylpyrrolidone (PVP), carboxymethylcellulose sodium, and any combination thereof,
The lubricant may be selected from the group consisting of calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulphate, sodium stearyl fumarate, zinc stearate, stearic acid, cured vegetable oil, polyethylene glycol, Sodium, silicon dioxide, talc, and any combination thereof. The solid formulation according to claim 7, wherein the diluent comprises 20 to 80% by weight, the binder is 1 to 5% by weight, or the lubricant is contained in an amount of 0.5 to 5% by weight based on the total amount of the solid preparation. The oral solid preparation according to claim 8, which is a multilayer tablet containing a sustained-release tablet or a sustained-release tablet prepared by a direct powder compression method or a granular compression method. The oral solid preparation according to claim 1, wherein the melatonin softening agent A is present in an amount of 0.25% by weight or less in a severe stability test under the condition of 60 占 폚 in a HDPE bottle. 2. The oral solid preparation according to claim 1, wherein the solid preparation is for treating sleep disorders. Preparing a mixture of raw materials comprising melatonin or a pharmaceutically acceptable salt thereof, a cellulose derivative as a sustained release agent, and a diluent; And
13. A method for preparing a solid preparation for oral use according to any one of claims 1 to 11, comprising the step of mixing the mixture with a pharmaceutical additive and tabletting to prepare tablets. 13. The method according to claim 12, wherein the mixture is obtained by sieving a raw material. 14. The method according to claim 13, wherein the step of sieving is sieved through a sieve having a sieve size of 100 to 450 mu m. 13. The method according to claim 12, wherein the step of preparing the tablet is carried out by a direct powder compression method or by dry granulation or wet granulation after granulation.

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