JP7366612B2 - Tablets containing levocarnitine - Google Patents

Description

The present invention relates to a tablet containing levocarnitine as an active ingredient and a method for producing the same.

Levocarnitine ((R)-3-Hydroxy-4-trimethylammoniobutanoate) is used to treat carnitine deficiency. Levocarnitine is known to be extremely hygroscopic and deliquescent. For example, if a tablet containing levocarnitine is left exposed to the outside air, it will quickly absorb moisture and deliquesce.

Although the hygroscopic and deliquescent problems can be solved to some extent by using levocarnitine chloride (levocarnitine chloride), it is known that levocarnitine chloride has concerns about side effects.

Therefore, in order to solve the problem of hygroscopicity and deliquescence even with pharmaceutical tablets of free form levocarnitine, JP 2016-50206A (Patent Document 1) proposes that levocarnitine (free form) be added at 40 to 80% by weight. It has been proposed that the containing pharmaceutical tablets contain 15-55% by weight of water-insoluble excipients.

JP2016-50206A

However, even when water-insoluble additives are added, tablet hardness decreases due to moisture absorption, adhesion to equipment during the manufacturing process, etc., and the problems of hygroscopicity and deliquescence have not been sufficiently solved.

Therefore, an object of the present invention is to provide a tablet containing levocarnitine with reduced hygroscopicity and deliquescentity.

The tablet according to the present invention includes a plain tablet portion containing levocarnitine and polyvinylpyrrolidone, and a film coating layer containing polyvinyl alcohol that covers the plain tablet portion.

In the tablet according to the present invention, the uncoated tablet portion preferably contains a granulated product of levocarnitine and polyvinylpyrrolidone.

Preferably, tablets according to the invention contain less than 15% by weight of water-insoluble additives.

In the tablet according to the present invention, the surface of the plain tablet portion is preferably formed by one or more smooth planes and/or curved surfaces.

In the tablet according to the present invention, the surface of the uncoated tablet portion preferably does not have any recesses.

In the tablet according to the present invention, it is preferable that no markings are formed on the surface of the uncoated tablet portion.

The method for manufacturing any of the above tablets according to the present invention includes (a) manufacturing a plain tablet portion containing levocarnitine and polyvinylpyrrolidone, and (b) coating the plain tablet portion with a film coating layer containing polyvinyl alcohol. and a step of covering the.

In the method for manufacturing tablets according to the present invention, step (a) and step (b) are preferably performed in an environment with a humidity of 30% or less.

In the method for manufacturing a tablet according to the present invention, the film coating liquid for forming the film coating layer may contain ethanol, but is more preferably water only.

A method for suppressing moisture absorption and/or deliquescence of a tablet containing levocarnitine according to the present invention includes the step of coating a plain tablet portion containing levocarnitine and polyvinylpyrrolidone with a film coating layer containing polyvinyl alcohol.

In the method for suppressing moisture absorption and/or deliquescence of a levocarnitine-containing tablet according to the present invention, the manufacturing process of the uncoated tablet portion is preferably performed in an environment with a humidity of 30% or less.

In the method for suppressing moisture absorption and/or deliquescence of tablets containing levocarnitine according to the present invention, the film coating liquid for forming the film coating layer may contain ethanol, but is more preferably water only. .

In the present invention, levocarnitine means a free form (inner salt) unless otherwise specified.

The tablet of the present invention includes a plain tablet portion containing levocarnitine and polyvinylpyrrolidone, and a film coating layer containing polyvinyl alcohol that covers the plain tablet portion. The uncoated tablet portion preferably contains a granulated product of levocarnitine and polyvinylpyrrolidone.

The content of levocarnitine in the uncoated tablet portion is preferably 20 to 80% by weight, more preferably 30 to 70% by weight, and even more preferably 40 to 60% by weight.

The content of polyvinylpyrrolidone in the uncoated tablet portion is preferably 2 to 10% by weight, more preferably 2 to 7% by weight, and even more preferably 2 to 4% by weight.

Preferably, the uncoated tablet portion further contains a water-insoluble additive. The content of the water-insoluble additive is preferably less than 15% by weight of the uncoated tablet portion.

In the present invention, a "water-insoluble" additive means an additive that is hardly soluble in water as defined in the Japanese Pharmacopoeia General Rules. According to the general rules of the Japanese Pharmacopoeia, solubility is defined as the solubility of a solid additive that dissolves within 30 minutes when the additive is made into a powder, placed in water, and shaken vigorously for 30 seconds every 5 minutes at 20±5°C. An additive that is "almost insoluble" in water refers to an additive in which the amount of water required to dissolve 1 g or 1 mL of the additive is 10,000 mL or more. Specifically, for example, cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropyl cellulose, and carboxymethyl cellulose, chemically modified starches and celluloses such as carboxymethyl starch and sodium carboxymethyl starch, and crosslinked polyvinylpyrrolidones such as crospovidone. , ethyl cellulose, methacrylic acid copolymers, carboxymethyl ethyl cellulose, aminoalkyl methacrylate copolymers, magnesium stearate, calcium stearate, and talc may be mentioned as water-insoluble additives in the present invention.

In the tablet according to the present invention, the weight of the film coating layer is preferably 2 to 15%, more preferably 5 to 10%, of the weight of the plain tablet.

The tablet according to the invention may further contain additives such as excipients, disintegrants, binders, lubricants and the like.

Examples of excipients include sugars or sugar alcohols such as white sugar, lactose, D-mannitol, sorbitol, xylitol, and maltitol, cellulose derivatives such as crystalline cellulose, and starch derivatives such as corn starch, potato starch, and dextrin. Excipients may be used, preferably D-mannitol is used.

Examples of disintegrants include cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropyl cellulose, and carboxymethyl cellulose, chemically modified starches and celluloses such as carboxymethyl starch and sodium carboxymethyl starch, and crosslinked polyvinylpyrrolidones such as crospovidone. , etc. may be used.

As the binder, known binders such as carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and polyvinylpyrrolidone can be used, and polyvinylpyrrolidone is preferably used.

As the lubricant, known lubricants such as stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, talc, colloidal silica, and waxes may be used.

In the tablet according to the present invention, letters, symbols, numbers, figures, etc. can be engraved on the uncoated tablet portion. The characters to be engraved are, for example, formed by grooves with a line width of 0.15 to 0.80 mm and a depth of 0.10 to 0.30 mm, more preferably a line width of 0.25 to 0.50 mm and a depth of 0.10 to 0.30 mm. It is formed by a groove of 0.13-0.22 mm. However, in the tablet according to the present invention, it is preferable that no markings are formed on the surface of the uncoated tablet portion. The surface of the uncoated tablet portion is preferably formed by one or more smooth planes and/or curved surfaces, and preferably does not have recesses such as those formed by stamping, for example. More specifically, it is more preferable that a groove having a width of 0.15 mm or more and a depth of 0.10 mm or more is not formed on the surface of the uncoated tablet portion. By doing so, it is possible to delay the deliquescence of the tablet obtained by film-coating the uncoated tablet portion, and it is also possible to suppress the increase in tablet weight due to moisture absorption. When no markings are formed on the surface of the plain tablet, it is preferable to laser print letters, symbols, numbers, figures, etc. on the surface of the film-coated tablet to facilitate identification of the tablet.

The method for manufacturing a tablet according to the present invention includes (a) a step of manufacturing a plain tablet portion containing levocarnitine and polyvinylpyrrolidone, and (b) a step of covering the plain tablet portion with a film coating layer containing polyvinyl alcohol. including.

Preferably, the step of manufacturing the uncoated tablet portion includes a step of granulating it using levocarnitine, polyvinylpyrrolidone, and other additives. The granulation method is not limited, and known methods can be used. The granulated product is sized, dried, and made into granules for tabletting using a conventional method. The granules for tableting are mixed with other additives to form a mixed powder for tabletting, which is then compressed to obtain uncoated tablets.

The obtained uncoated tablet is coated with a film coating layer containing polyvinyl alcohol as the uncoated tablet portion. A known method is used as the film coating method. The film coating liquid for forming the film coating layer may contain ethanol, but preferably contains only water. By doing so, it is possible to delay the deliquescence of the tablet obtained by film-coating the uncoated tablet portion, and it is also possible to suppress the increase in tablet weight due to moisture absorption.

In the method for manufacturing tablets according to the present invention, step (a) is preferably performed in an environment with a humidity of 30% or less.

Further, the method for suppressing moisture absorption and/or deliquescence of a tablet containing levocarnitine according to the present invention includes the step of coating a plain tablet portion containing levocarnitine and polyvinylpyrrolidone with a film coating layer containing polyvinyl alcohol. .

In the method for suppressing moisture absorption and/or deliquescence of a levocarnitine-containing tablet according to the present invention, the manufacturing process of the uncoated tablet portion is preferably performed in an environment with a humidity of 30% or less.

In the method for suppressing moisture absorption and/or deliquescence of tablets containing levocarnitine according to the present invention, the film coating liquid for forming the film coating layer may contain ethanol, but is more preferably water only. .

Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto.

[Example]
In order to confirm the effect of reducing hygroscopicity and deliquescence of the levocarnitine tablet according to the present invention, a plain tablet portion of a film-coated tablet was manufactured as follows. The amount of each raw material per tablet is as shown in Table 1.

[Manufacturing process of uncoated tablet part of Example 1]
The uncoated tablet portion was manufactured in an environment with a humidity of 30% or less. Levocarnitine, D-mannitol, polyvinylpyrrolidone, and light anhydrous silicic acid were put into a stirring granulator in the amounts shown in Table 1, and ethanol was added and granulated with stirring, followed by wet sizing and drying to obtain drug granules. Ta. Next, the obtained drug granules were mixed with D-mannitol, light anhydrous silicic acid, croscarmellose sodium, and magnesium stearate in the amounts shown in Table 1 to obtain a mixed powder for tabletting. The obtained mixed powder for tableting was compressed using a rotary tableting machine at a tableting pressure of 11 kN to obtain uncoated tablets. The plain tablet was engraved with a symbol consisting of two letters of the alphabet and three letters of the number. The engraved characters had a line width of 0.27 to 0.62 mm and a depth of 0.14 to 0.21 mm.

The uncoated tablet portions of Comparative Examples 1 and 2 were manufactured in the same process as the uncoated tablet portion of Example 1, except that hydroxypropylcellulose (Comparative Example 1) and hypromellose (Comparative Example 2) were used instead of polyvinylpyrrolidone. It was done.

[Confirmation of deliquescence during tableting]
The mixed powder for tabletting obtained in the manufacturing process of the uncoated tablet portion of Example 1 and Comparative Examples 1 and 2 was adjusted to 30% RH in the outside air using a dehumidifier, and 50 g of each powder was compressed using a rotary tablet machine. When the sample was continuously rotated on a turntable at 30 rpm, the time required for fixation (deliquescence) to occur was measured. The results are shown in Table 2.

As shown in Table 2, the mixed powder for tabletting used in the uncoated tablet portion of Example 1 took a longer time to adhere to the tableting machine than Comparative Examples 1 and 2. In this way, by using polyvinylpyrrolidone as a binder, it was possible to reduce adhesion to manufacturing equipment during tablet compression and improve productivity.

[Checking the hygroscopicity and deliquescence of the uncoated tablet]
Five tablets each of the uncoated tablets of Example 1 and Comparative Example 1 were placed in a Petri dish and left in an environment of 25° C. and 60% RH, and the surface condition was checked. In addition, the rate of increase in weight was measured. The results are shown in Table 3.

As shown in Table 3, it was found that in the uncoated tablet portion of Example 1, weight increase was suppressed and moisture absorption was suppressed compared to the uncoated tablet portion of Comparative Example 1. In addition, in the uncoated tablet part of Example 1, the symbol engraved on the uncoated tablet surface could be identified even after being left for 30 minutes, but in the uncoated tablet part of Comparative Example 1, which was left for 20 or 30 minutes. I could not identify the symbol engraved on it. As described above, it was found that by using polyvinylpyrrolidone as a binder, the hygroscopicity and deliquescence of the uncoated tablet portion can be reduced.

[Film coating process of tablets of Example 1]
Polyvinyl alcohol (Gohsenol EG-05) and polyethylene glycol (Macrogol 6000) were added to purified water and dissolved, talc (Talcan Hayashi) was further dispersed, and ethanol was added to prepare a film coating liquid. The uncoated tablet portion of Example 1 was coated with a film coating solution to obtain a film coated tablet. The amount of each raw material per tablet was as shown in Table 4.

The uncoated tablet of Comparative Example 1 was also coated in the same manner as in Example 1 to obtain a film-coated tablet of Comparative Example 1.

[Confirmation of hygroscopicity and deliquescent properties of film-coated tablets]
Five film-coated tablets of Example 1 and Comparative Example 1 were each placed in a Petri dish and left in an environment of 25° C. and 60% RH, and the surface condition was checked. In addition, the rate of increase in weight was measured. The results are shown in Table 5.

In Example 1 and Comparative Example 1, the base material of the film coating was the same, but as shown in Table 5, the film coated tablet of Example 1 was able to suppress weight increase and reduce moisture absorption. Further, there were no water droplets on the surface of the film-coated tablet of Example 1 even when left for 10 hours, but in the film-coated tablet of Comparative Example 1, water droplets were observed when left for 4 hours, confirming deliquescence. Thus, it was found that by using polyvinylpyrrolidone as a binder for the uncoated tablet portion, moisture absorption and deliquescence of film-coated tablets containing levocarnitine can be suppressed.

[Study of film coating base material]
Film-coated tablets of Example 2 and Comparative Example 2 were prepared using the same manufacturing method as the film-coated tablet of Example 1 using the formulations shown in Table 6. However, in the film coating process, when adding talc, titanium oxide was also added.

[Confirmation of hygroscopicity and deliquescent properties of film-coated tablets]
Five film-coated tablets of Example 2 and Comparative Example 2 were each placed in a Petri dish and left in an environment of 25° C. and 75% RH, and the surface condition was checked. In addition, the rate of increase in weight was measured. The results are shown in Table 7.

Although the uncoated tablet portions of Example 2 and Comparative Example 2 were the same, as shown in Table 7, the film-coated tablet of Example 2 was able to suppress weight increase and reduce moisture absorption. In addition, there were no water droplets on the surface of the film-coated tablet of Example 2 until it was left for 2 hours, but in the film-coated tablet of Comparative Example 2, water droplets were already observed after it was left for 1 hour, and deliquescence was confirmed. In this way, it was found that moisture absorption and deliquescence of film-coated tablets containing levocarnitine can be suppressed by using polyvinylpyrrolidone as a binder for the plain tablet portion and coating the plain tablet with a film coating layer containing polyvinyl alcohol. .

[Examination of whether there is a stamp 1]
Levocarnitine, D-mannitol, polyvinylpyrrolidone, and light anhydrous silicic acid were charged into a stirring granulator in the amounts shown in Table 8, wet granulated, and dried to obtain drug granules. Next, the obtained drug granules were mixed with D-mannitol, light anhydrous silicic acid, croscarmellose sodium, and magnesium stearate in the amounts shown in Table 8 to obtain a mixed powder for tabletting. The obtained mixed powder for tableting was tableted using a rotary tableting machine at a tableting pressure of 11 kN to obtain uncoated tablets. The uncoated tablets of Examples 3 and 5 were engraved with symbols consisting of two alphabetic characters and three numerical characters. No characters or symbols were engraved on the plain tablet of Example 4. The surface of the uncoated tablet of Example 4 was composed of an upper surface and a lower surface formed by smooth curved surfaces, and no recesses were formed on the upper surface and the lower surface.

The film coating liquid of Examples 3 and 4 was prepared by dissolving polyvinyl alcohol (Gohsenol EG-05) and polyethylene glycol (Macrogol 6000) in purified water, and further adding talc (Talcan Hayashi) and titanium oxide (A-HR). It was prepared by dispersing and adding ethanol. The film coating liquid of Example 5 was prepared by adding and dissolving polyvinyl alcohol (Gohsenol EG-05) and polyethylene glycol (Macrogol 6000) in purified water, and further dispersing talc (Talcan Hayashi) and titanium oxide (A-HR). It was prepared by The uncoated tablet portions of Examples 3 to 5 were coated with a film coating solution to obtain film-coated tablets. The amount of each raw material per tablet was as shown in Table 8.

[Confirmation of hygroscopicity and deliquescent properties of film-coated tablets]
Five film-coated tablets of Examples 3 to 5 were each placed in a Petri dish and left in an environment of 25° C. and 60% RH, and the surface condition was checked. In addition, the rate of increase in weight and the amount of increase in tablet thickness were measured. The results are shown in Tables 9 to 12.

Water droplets were observed on the surface of the film-coated tablet of Example 3 after standing for 9 hours, confirming deliquescence. Water droplets were observed on the surface of the film-coated tablet of Example 4 after standing for 168 hours, confirming deliquescence. Water droplets were observed on the surface of the film-coated tablet of Example 5 after standing for 24 hours, confirming deliquescence.

As shown in Tables 9 and 11, the film-coated tablet of Example 4 using plain tablets without markings suppressed weight increase and deliquescence for the longest period of time compared to Examples 3 and 5. was completed. Furthermore, when uncoated tablets with stamps were used, weight increase and deliquescence could be suppressed for a longer period of time in Example 5, which used water as the film coating liquid, than in Example 3, which used ethanol.

[Examination of whether there is a stamp 2]
Example 6 was a film-coated tablet obtained by producing plain tablets in the same manner as in Example 2, but without stamping any characters or symbols on the plain tablets, and applying film coating in the same manner as in Example 2. The surface of the uncoated tablet of Example 6 was composed of an upper surface and a lower surface formed by smooth curved surfaces, and no recesses were formed on the upper surface and the lower surface.

[Confirmation of hygroscopicity and deliquescent properties of film-coated tablets]
Five film-coated tablets of Example 2 and Example 6 were each placed in a petri dish and left in an environment of 25° C. and 60% RH, and the surface condition was checked. In addition, the rate of increase in weight and the amount of increase in tablet thickness were measured. The results are shown in Tables 13 to 16.

Water droplets were observed on the surface of the film-coated tablet of Example 2 after being left for 31 hours, confirming deliquescence. Water droplets were observed on the surface of the film-coated tablet of Example 6 after standing for 50 hours, confirming deliquescence.

As shown in Tables 13 and 15, the film-coated tablet of Example 6, which used plain tablets without markings, was able to suppress weight increase and deliquescence for a longer period of time compared to Example 2. Ta.

The embodiments and examples disclosed above should be considered to be illustrative in all respects and not restrictive. The scope of the present invention is indicated by the claims rather than the above description, and includes meanings equivalent to the claims and all modifications within the scope.

Claims (12)

A plain tablet portion containing levocarnitine and polyvinylpyrrolidone;
A tablet comprising a film coating layer containing polyvinyl alcohol that covers the uncoated tablet portion. The tablet according to claim 1, wherein the uncoated tablet portion contains a granulated product of levocarnitine and polyvinylpyrrolidone. 3. A tablet according to claim 1 or claim 2, containing less than 15% by weight of water-insoluble additives. The tablet according to any one of claims 1 to 3, wherein the surface of the uncoated tablet portion is formed by one or more smooth planes and/or curved surfaces. The tablet according to any one of claims 1 to 4, wherein the surface of the uncoated tablet portion does not have a recess. The tablet according to any one of claims 1 to 5, wherein no marking is formed on the surface of the uncoated tablet portion. (a) a step of manufacturing a plain tablet portion containing levocarnitine and polyvinylpyrrolidone;
(b) The method for manufacturing a tablet according to any one of claims 1 to 6, comprising the step of coating the uncoated tablet portion with a film coating layer containing polyvinyl alcohol. The manufacturing method according to claim 7, wherein the step (a) is performed in an environment with a humidity of 30% or less. The manufacturing method according to claim 7 or 8, wherein the film coating liquid for forming the film coating layer contains water and/or ethanol. A method for suppressing moisture absorption and/or deliquescence of a tablet containing levocarnitine, comprising the step of coating a plain tablet portion containing levocarnitine and polyvinylpyrrolidone with a film coating layer containing polyvinyl alcohol. 11. The suppression method according to claim 10, wherein the step of manufacturing the uncoated tablet portion is performed in an environment with a humidity of 30% or less. The suppression method according to claim 10 or 11, wherein the film coating liquid for forming the film coating layer contains water and/or ethanol.