JP2021155359A - Tablet containing levocarnitine as active ingredient - Google Patents

Abstract

To provide a levocarnitine-containing tablet suitable for size reduction of the tablet.SOLUTION: A tablet contains levocarnitine, a free body, and a hydrophilic lubricant as active ingredients.SELECTED DRAWING: Figure 1

Description

The present invention relates to a pharmaceutical tablet containing levocarnitine as an active ingredient.

Levocarnitine is used as a medicine for the treatment of carnitine deficiency.
Free-form levocarnitine, which is a pharmaceutical product, is known to have high hygroscopicity and deliquescent property, and is one of the causes of various problems in formulation.
In addition, the daily dose of this drug is large, and it is preferable to reduce the size of tablets in order to improve the ingestibility of the drug.

For example, Patent Document 1 proposes the use of a water-insoluble additive for the purpose of improving the difficulty of tableting due to the high hygroscopicity and deliquescent property of levocarnitine (free form).
In each of the preferable components in the tablets disclosed in the same publication, magnesium stearate, which is a hydrophobic lubricant having low hydrophilicity, is used as the lubricant.

Japanese Unexamined Patent Publication No. 2016-50206

An object of the present invention is to provide a free-form levocarnitine-containing tablet that is effective for reducing the size of a tablet.

The tablet according to the present invention is characterized by containing a free form of levocarnitine and a hydrophilic lubricant as active ingredients.
Here, the "hydrophilic" lubricant means a lubricant having a hydrophilic group.
For example, the hydrophilic lubricant is preferably stearyl fumarate or a sucrose fatty acid ester.

In the present invention, it is preferable that at least a sugar alcohol is further contained as an excipient.
Examples of the sugar alcohol used in the present invention include D-mannitol, maltitol, reduced isomaltulose, lactitol, erythritol, and xylitol.

In the present invention, the tablet contains 40 to 70% by mass of free levocarnitine, 10 to 40% by mass of excipient, 5 to 15% by mass of disintegrant, and 0.5 to 5% by mass of hydrophilic lubricant. Is preferable.
Further, the binder may be contained in an amount of 0.5 to 3.0% by mass.

Examples of the excipient used in the present invention include sugar alcohol, crystalline cellulose, light anhydrous silicic acid, lactose hydrate, potato starch, corn starch, and hydrous silicon dioxide.
Examples of the disintegrant used in the present invention include low-degree-of-substitution hydroxypropyl cellulose, croscarmellose sodium, carmellose, carmellose calcium, and crospovidone.
Examples of the binder used in the present invention include hydroxypropyl cellulose, hypromellose, methyl cellulose, polyvinyl alcohol, ethyl cellulose, and hypromellose phthalate ester.
Examples of the lubricant used in the present invention include hydrophilic sodium lubricant, stearyl fumarate, and sucrose fatty acid ester.

The tablet according to the present invention can be used as an uncoated tablet without film coating, or can also be used as a coated tablet with film coating.
Examples of the coating agent used in the present invention include hypromellose, macrogol, titanium oxide, talc, ethyl cellulose, and triacetin.

In the formulation of free-form levocarnitine-containing tablets having high hygroscopicity and deliquescent property as an active ingredient, a hydrophobic lubricant has been conventionally used, whereas in the present invention, the lubricant is hydrophilic. By using the tablet, the content of additives such as excipients and disintegrants can be reduced, and the size of tablets can be reduced.

The active ingredient of the tablet according to the present invention is levocarnitine, which is a free form (intramolecular salt), and the chemical name is (R) -3-Hydroxy-4-timelylammoniobutanoate.
The present invention relates to tablets containing free levocarnitine as an active ingredient and a hydrophilic lubricant.

As the lubricant, as described above, stearyl fumarate or sucrose fatty acid ester, which are hydrophilic lubricants, are preferable from the viewpoint of good miniaturization of tablets, and stearyl fumarate is particularly preferable.
As the lubricant, the hydrophilic lubricant may be used alone, or two or more of the hydrophilic lubricant and the hydrophobic lubricant may be mixed and used.
The content of the hydrophilic lubricant in tablets (hereinafter, simply referred to as uncoated tablets) is not particularly limited, but is preferably 0.5 to 5% by mass with respect to the tablets. 0.5 to 2% by mass is more preferable.

In addition to the active ingredient, free levocarnitine, and the above-mentioned predetermined lubricant, tablets include, for example, excipients, fluidizers, disintegrants, surfactants, binders, stabilizers, and colorants. Such as, additives commonly used in this field can be included.
In the present invention, the tablet preferably contains 10 to 40% by mass of an excipient, 5 to 15% by mass of a disintegrant, and 0.5 to 5% by mass of a hydrophilic lubricant, and further contains 0 binder. .5 to 3.0% by mass may be contained.

The excipient is not particularly limited, and examples thereof include sugar alcohol, crystalline cellulose, light anhydrous silicic acid, lactose hydrate, potato starch, corn starch, and hydrous silicon dioxide, and among them, sugar alcohol. Is preferable, and the excipient may be used alone or in combination of two or more.
Examples of the sugar alcohol include D-mannitol, maltitol, reduced isomaltulose, lactitol, erythritol, and xylitol, and D-mannitol is particularly preferable.

The tablet according to the present invention will be described below based on a specific formulation example.

First, Table 1 below shows a formulation example in which tablets are comparatively evaluated.

<Tablet manufacturing method>
Levocarnitine (free form), crystalline cellulose (Theoras PH-101: Asahi Kasei), low-substituted hydroxypropyl cellulose (L-HPC LH-21: Shin-Etsu Chemical), light anhydrous silicic acid (Adsolider 101: Fuji Silysia Chemical) Place in a stirring granulator (VG-05: Paulec) and granulate while adding a mixed solution of water and ethanol in which hydroxypropyl cellulose (HPC-L: Nihon Soda) is dissolved.
The granulated product is crushed with a granulator (Komil: Paulek) and dried using a fluidized bed dryer (MP-01: Paulek).
Sieve the dried product.
Add D-mannitol (Granitol S: Freund Sangyo) or crystalline cellulose (Theoras PH-101: Asahi Kasei) and low-substituted hydroxypropyl cellulose (L-HPC LH-21: Shin-Etsu Chemical) to the sized product and mix. do.
Add sodium stearyl fumarate (PRUV: JRS PHARMA), magnesium stearate (magnesium stearate-S: NOF), or both to the mixture and mix.
By tableting the mixture with a tableting machine (VIRGO 0518SS: Kikusui Seisakusho) with a diameter of 8.0 mm (Comparative Example 3) or a diameter of 7.5 mm (Examples 1 to 5, Comparative Examples 1 and 2). Manufacture tablets.

Next, the physical characteristic values of the tablets, which are the formulation examples in Table 1 above, are shown in Table 2 below.

In Table 2, the diameter and hardness were measured using a tablet measuring machine (Kikusui Seisakusho: TM5-1).
The disintegration time was measured according to the 17th revised Japanese Pharmacopoeia disintegration test method (test solution: water), and the disintegration time of 6 tablets was measured, and the minimum and maximum values were described.

In Examples 1 to 4, hydrophilic sodium stearyl fumarate was used alone as a lubricant, and in Example 5, hydrophilic sodium fumarate and hydrophobic magnesium stearate were used in combination. There is.
From the results, in Examples 1 to 5, by using hydrophilic stearyl fumarate as a lubricant, a predetermined hardness was obtained while maintaining disintegration, and a tablet having a diameter of 8.0 mm was obtained with a diameter of 7.5 mm. We were able to reduce the size of the tablets.
Specifically, Comparative Example 3 is a formulation example based on the formulation example of (Uncoated Tablets 8) of Patent Document 1.
On the other hand, in Examples 1 to 5 and Comparative Examples 1 and 2 were miniaturized by using D-mannitol, which is a sugar alcohol, as an excipient, but hydrophobic magnesium stearate was used as a lubricant. Comparative Example 1 in which 2.3 mg was added had insufficient disintegration property, and Comparative Example 2 in which the addition amount was reduced to 1.3 mg caused sticking and could not be locked normally.
From the viewpoint of disintegration and hardness, it is more preferable to use hydrophilic stearyl fumarate alone (Examples 1 to 4) as a lubricant.
From the results, the content of D-mannitol in the tablet is preferably 10 to 30% by mass with respect to the tablet.
Summarizing the above, by using the hydrophilic sodium stearyl fumarate as the lubricant, it was possible to obtain a predetermined hardness and reduce the size while maintaining the disintegration property.

<Dissolution test>
In order to confirm the dissolution property, the dissolution test was performed on the tablets (n = 3 each) produced in Example 2 and Comparative Examples 1 and 2.
The dissolution test was performed by the paddle method in the dissolution tester (NTR-6400AT: Toyama Sangyo) according to the dissolution test method of the Japanese Pharmacopoeia, test solution: purified water, test solution volume: 900 mL, temperature: 37 ± 0.5 ° C. The paddle rotation was carried out under the condition of 50 rpm.
The results are shown in FIG. 1 as average values.
The amount of levocarnitine was measured by HPLC for each tablet at a predetermined time.
HPLC analysis conditions include a detector: ultraviolet absorptiometer (measurement wavelength: 225 nm), column: inner diameter 4.6 mm, length 15 cm, particle diameter 3 μm phenyl column, mobile phase: 15 mM sodium 1-octanesulfonate. The phosphate buffer (pH 2.5) / acetonitrile mixture (97: 3) was used, and the flow rate was 0.8 mL / min.
From the results of FIG. 1, the dissolution rate of Example 2 using hydrophilic sodium fumarate was faster than that of Comparative Example 1 in which the amount of hydrophobic magnesium stearate added was increased to an amount that did not cause tableting damage. The result was that the disintegration property of the tablet and the dissolution property were correlated.

<Coated lock>
A formulation example (Example 6) of a coated tablet obtained by applying a film coating to the tablet produced in Example 2 is shown in Table 3 below.

The tablets manufactured by the above manufacturing method are placed in a coating machine (HC-FZ-LABO 20: Freund Sangyo), hypromellose (TC-5R: Shin-Etsu Chemical Co., Ltd.), Macrogol 6000 (Macrogal 6000P: NOF), and talc ( A coated tablet is manufactured by film-coating with a mixed solution of water and ethanol in which Crown Talk: Matsumura Sangyo) and Titanium Oxide (Tipaque A-100: Ishihara Sangyo) are dissolved and dispersed.
By coating the tablets, the stickiness of the tablets due to moisture absorption can be suppressed.

The dissolution test results are shown.

Claims (5)

A tablet containing free levocarnitine as an active ingredient and a hydrophilic lubricant. The tablet according to claim 1, further containing at least a sugar alcohol as an excipient. Claim that the tablet contains 40 to 70% by mass of free levocarnitine, 10 to 40% by mass of excipient, 5 to 15% by mass of disintegrant, and 0.5 to 5% by mass of hydrophilic lubricant. The tablet according to 1 or 2. The tablet according to any one of claims 1 to 3, wherein the hydrophilic lubricant is stearyl fumarate or a sucrose fatty acid ester. A coated tablet obtained by film-coating the tablet according to any one of claims 1 to 4.

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