Levocarnitine-containing tablet

Abstract

To provide a tablet that is of a size suitable for a patient and has high storage stability even with a high content of levocarnitine of a free body.SOLUTION: A film coating tablet has an uncoated tablet containing levocarnitine (free body) and porous calcium silicate in a mass ratio of 1:0.25-2, and a film coating layer that coats the uncoated tablet.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to tablets and the like containing levocarnitine, and in particular to film-coated tablets and the like containing levocarnitine. The contents of all documents described in this specification are incorporated herein by reference. [Background technology]

[0002] Levocarnitine (L-carnitine) is used as a medicine to treat carnitine deficiency, which can be caused by congenital metabolic disorders (carnitine transporter disorders, organic acid metabolism disorders, fatty acid metabolism disorders, etc.), acquired medical conditions (liver cirrhosis, Fanconi syndrome, etc.), or medical procedures (dialysis, drug-induced, etc.).

[0003] The daily dose of levocarnitine (free form) prescribed for the treatment of carnitine deficiency is high, for example, 1.5 to 3 g is usually orally administered in three divided doses in adults. Therefore, there is a need for an oral dosage form that is easy to administer and convenient for providing the daily dose of levocarnitine.

[0004] As for the form (dosage form) of pharmaceutical preparations, tablets are considered to be the most preferable, taking into consideration the ease of administration and ease of handling for patients. However, since levocarnitine (free form) has extremely high hygroscopicity and deliquescent properties, problems in processing, stability, and storage arise in both the raw materials and the final product when used in the form of a solid formulation (especially tablets). In other words, there are problems such as difficulty in process control, manufacturing obstacles such as tableting obstacles, and quality deterioration due to changes in the properties of the final product over time (cracks and wetting of the film coating layer, etc.).

[0005] In order to solve the problems caused by the hygroscopicity and deliquescent nature of levocarnitine, various studies have been conducted, and for example, a solid material obtained by adsorbing carnitine chloride (carnitine chloride) to an adsorbent substance (Patent Document 1), a granulated product containing L-carnitine and a water-soluble polymer such as polyvinylpyrrolidone (Patent Document 2), and carnitine granules consisting of a silica carrier coated with carnitine (Patent Document 3) have been disclosed.

[0006] In addition, a pharmaceutical tablet has been disclosed that contains 40 to 80% by weight of levocarnitine (free form) and 15 to 55% by weight of a water-insoluble additive such as crystalline cellulose or low-substituted hydroxypropylcellulose relative to the total weight of the tablet (Patent Document 4). [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Japanese Patent Application Publication No. 8-012569 [Patent Document 2] Special Publication No. 2002-540153 [Patent Document 3] Special Publication No. 2013-513557 [Patent Document 4] JP 2016-050206 A [Patent Document 5] Japanese Patent Publication No. 54-093698 [Patent Document 6] JP 2013-227205 A Summary of the Invention [Problem to be solved by the invention]

[0008] Pharmaceutical tablets containing levocarnitine (free form) and levocarnitine chloride as active ingredients for the treatment of carnitine deficiency are already on the market, but they are insufficiently resistant to moisture absorption and deliquescence. To ensure the stability and storage stability of the final product, they are packaged in strong SP packaging or double-sided adhesive. However, these packaging formats have problems such as making it difficult to remove the tablets, making it difficult to check the tablets because they are not visible, and the tablets being crushed, so there is a demand for small tablets with high storage stability that can be provided in PTP packages (sandwiched between plastic and aluminum), which are commonly used as tablet packaging, or packaged as individual tablets.

[0009] For this reason, there is a strong demand for tablets that have a high content of free levocarnitine, are of a size suitable for patients, and have high storage stability. [Means for solving the problem]

[0010] As a result of extensive investigations to solve the above problems, the present inventors have found that the effects of hygroscopicity and deliquescence of levocarnitine (free form) can be reduced by forming a tablet containing levocarnitine (free form) and porous calcium silicate. Furthermore, they have found that the effects of hygroscopicity and deliquescence of levocarnitine (free form) can be further reduced by coating the tablet (plain tablet) with a film coating layer containing polyvinyl alcohol and / or a polyvinyl alcohol copolymer.

[0011] The present disclosure includes, for example, the subject matter described in the following sections: Section 1. A plain tablet containing levocarnitine (free form) and porous calcium silicate in a mass ratio of 1:0.25 to 2, and A film coating layer that covers the tablet A film-coated tablet comprising: Section 2. Item 2. The film-coated tablet according to item 1, wherein the porous calcium silicate is gyrolite-type calcium silicate. Section 3. Item 3. The film-coated tablet according to item 1 or 2, wherein the porous calcium silicate has an oil absorption of 300 mL or more per 100 g. Section 4. The porous calcium silicate has the formula: 2CaO·3SiO2·mSiO2·nH2O (where 1 < m < 2 and 2 < n < 3) It is a porous calcium silicate represented by The film-coated tablets according to any one of items 1 to 3. Item 5. The core tablet is a core tablet containing L-carnitine (free form) and porous calcium silicate in a mass ratio of 1:0.25 to 0.5, and is the film-coated tablet according to any one of items 1 to 3. Item 6. The film coating layer contains polyvinyl alcohol and / or a polyvinyl alcohol copolymer, and is the film-coated tablet according to any one of items 1 to 5. Item 7. The polyvinyl alcohol copolymer is a polyvinyl alcohol·acrylic acid·methyl methacrylate copolymer, and is the film-coated tablet according to item 6. Item 8. The film-coated tablet according to any one of items 1 to 7, wherein the film coating layer is provided in an amount of 10 to 40% by mass based on the core tablet. Item 9. The film-coated tablet according to any one of items 1 to 8, wherein L-carnitine (free) is contained in an amount of 50 to 80% by mass of the core tablet. Item 10. A core tablet containing L-carnitine (free form) and porous calcium silicate in a mass ratio of 1:0.25 to 2, and A film coating layer for coating the core tablet is provided in an amount of 10 to 40% by mass based on the core tablet provided that the porous calcium silicate is a gyroite-type calcium silicate having an oil absorption amount of 300 mL or more per 100 g, the film coating layer contains polyvinyl alcohol and / or a polyvinyl alcohol copolymer, L-carnitine (free) is contained in an amount of 50 to 80% by mass of the core tablet, Film-coated tablets.

Advantages of the Invention

[0012] The film-coated tablets included in the present disclosure contain a high dose of levocarnitine (free form), yet have reduced deliquescence and hygroscopicity and exhibit excellent stability even under humid conditions. For this reason, they can be provided in PTP packaging sandwiched between plastic and aluminum. [Brief description of the drawings]

[0013] [Figure 1] FC tablets, which contain levocarnitine and porous calcium silicate (Fluorite PS200), and currently available tablets (Elcartin (registered trademark) FF tablets) were stored unpackaged in a constant temperature and humidity chamber at 25°C and 75% RH (relative humidity), and the moisture absorption (mass increase) was measured over time from the start of storage. The results are shown below. [Diagram 2] FC tablets, which contain levocarnitine and porous calcium silicate (Fluorite PS200), and currently available tablets (Elcartin (registered trademark) FF tablets) were stored unpackaged in a constant temperature and humidity chamber at 25°C and 75% RH (relative humidity), and the moisture absorption (mass increase) was measured over time from the start of storage. The results are shown below. [Diagram 3] The results of storing FC tablets containing levocarnitine and porous calcium silicate (Fluorite PS200) unpackaged in a constant temperature and humidity chamber at 25°C and 75% RH (relative humidity) and measuring the change in moisture absorption (mass increase) over time from the start of storage are shown. [Figure 4] The results of storing FC tablets containing levocarnitine and porous calcium silicate (Fluorite PS200) unpackaged in a constant temperature and humidity chamber at 25°C and 75% RH (relative humidity) and measuring the change in moisture absorption (mass increase) over time from the start of storage are shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Each embodiment included in the present disclosure will be described in more detail. The present disclosure preferably includes tablets (particularly film-coated (FC) tablets) containing levocarnitine (free form) and the manufacturing method of the tablets, but is not limited thereto, and the present disclosure includes all that is disclosed in the present specification and that can be recognized by a person skilled in the art.

[0015] The tablets included in the present disclosure include tablets containing levocarnitine (free form) and porous calcium silicate in a mass ratio of 1:0.2-2, and film-coated tablets in which the tablets (plain tablets) are film-coated. Hereinafter, tablets containing levocarnitine (free form) and porous calcium silicate in a mass ratio of 1:0.2-2 may be referred to as "plain tablets of the present disclosure". In addition, plain tablets containing levocarnitine (free form) and porous calcium silicate in a mass ratio of 1:0.2-2 (i.e., plain tablets of the present disclosure) and film-coated tablets having a film coating layer covering the plain tablets may be referred to as "FC tablets of the present disclosure". In addition, any of these or collectively may be referred to as "tablets of the present disclosure". In addition, the tablets of the present disclosure are preferably pharmaceutical tablets.

[0016] In this disclosure, levocarnitine refers to the free form (inner salt) unless otherwise specified. That is, levocarnitine in this disclosure is a compound represented by the following chemical formula. (The chemical name of the compound is "(R)-3-Hydroxy-4-trimethylammoniobutanoate.")

[0017] [ka] The porous calcium silicate used in the tablet of the present disclosure may be one that complies with the standards for the chemical name "calcium silicate" listed in the pharmaceutical additive standards and food additive standards. More preferably, it is a porous calcium silicate having a large pore size and pore volume, and particularly preferably, it is a calcium silicate having a petal-shaped crystal structure.

[0018] Calcium silicate represented by the formula: 2CaO·3SiO2·mSiO2·nH2O [where 1 < m < 2 and 2 < n < 3] is preferred.

[0019] In addition, as crystal forms of calcium silicate, those such as the gyrolite type, the zonnolite type, the tobermorite type, and the amorphous form are known respectively. Among them, the porous calcium silicate used in the tablets of the present disclosure is preferably of the gyrolite type crystal.

[0020] Calcium silicate with a high oil absorption amount is preferred. Specifically, calcium silicate with an oil absorption amount of 300 mL or more per 100 g is preferred, and calcium silicate with 350 mL or more, 400 mL or more, or 450 mL or more is more preferred. The oil absorption amount here is a value measured as follows.

[0021] Transfer 1.0 g of the calcium silicate to be measured onto a smooth glass plate or plastic plate of 300 mm × 300 mm or more. If it is granular, apply pressure with a spatula to crush the grains. Drop boiled linseed oil from a burette into the sample on the glass plate or plastic plate in 1 mL units, and knead carefully by dispersing it to form small circles so that the mixture becomes uniform. When approaching the end point, add one drop at a time, and take the point when the whole becomes the most compact state as the end point. After 3 minutes from the end, read the dropping amount of the boiled linseed oil in the burette and take it as the oil absorption amount.

[0022] Preferred porous calcium silicate includes gyrolite type calcium silicate having a petal-shaped crystal structure. Such calcium silicate can be produced, for example, with reference to JP-A-54-093698, JP-A-2013-227205, etc. Also, commercially available products can be purchased and used. Specifically, for example, products with the trade names "Florite R", "Florite PS200" (Tomita Pharmaceutical Co., Ltd.) etc. can be purchased and used. Note that "Florite" is a registered trademark.

[0023] The amount of porous calcium silicate contained in the tablet (particularly the plain tablet) of the present disclosure is 0.25 to 2 parts by mass per part by mass of levocarnitine (free form). The upper or lower limit of the range may be, for example, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, or 1.9 parts by mass. For example, the range may be 0.25 to 1.5 parts by mass, 0.25 to 1 part by mass, or 0.25 to 0.5 parts by mass.

[0024] When the ratio of porous calcium silicate to 1 part by mass of levocarnitine (free form) is 0.2 parts by mass or less, deliquescence cannot be sufficiently suppressed, and problems in manufacturability and stability are likely to occur, which is undesirable. Also, when it is more than 2 parts by mass, the tablets become large and difficult to take. Problems may occur.

[0025] The uncoated tablet of the present disclosure may contain ingredients other than levocarnitine (free form) and porous calcium silicate, as long as the effects of the present disclosure are not impaired.

[0026] In preparing the uncoated tablets of the present disclosure, commonly used excipients, binders, disintegrants, lubricants, etc. can be used.

[0027] In addition, buffering agents, preservatives, isotonicity agents, suspending agents, dispersing agents, thickening agents, gelling agents, hardening agents, absorption promoters, adhesives, elasticity agents, plasticizers, fluidizing agents, adsorbents, fragrances, colorants, flavoring agents, antioxidants, light-shielding agents, gloss agents, etc. may be used as necessary.

[0028] Examples of excipients that can be used include lactose, lactose hydrate, crystalline cellulose, corn starch, D-mannitol, erythritol, xylitol, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, and sodium starch glycolate.

[0029] Examples of binders that can be used include hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone (povidone), methyl cellulose, and pregelatinized starch.

[0030] Examples of disintegrants that can be used include hydroxypropyl cellulose (HPC), hypromellose (hydroxypropyl methylcellulose), low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, povidone (polyvinylpyrrolidone), sodium starch glycolate, sodium fumarate, methylcellulose, and pregelatinized starch.

[0031] As the lubricant, for example, carmellose calcium, carmellose sodium, hydrated silicon dioxide, light anhydrous silicic acid, magnesium stearate, calcium stearate, fumaric acid, sodium stearyl fumarate, talc, sucrose fatty acid esters, etc. can be used.

[0032] The content of the disintegrant is not particularly limited, but is preferably about 0.1 to 20 mass% of the total mass of the tablet (or the uncoated tablet before coating in the case of a coated tablet), and more preferably about 2 to 10 mass%.

[0033] The content of the lubricant is not particularly limited, but is preferably about 0.1 to 5 mass% of the total mass of the tablet (or the uncoated tablet before coating in the case of a coated tablet), and more preferably about 0.5 to 3 mass%.

[0034] In the tablet of the present disclosure, the content of levocarnitine (free form) is preferably 50 to 80% by mass, more preferably 55 to 80% by mass or 60 to 80% by mass, and even more preferably 65 to 75% by mass of the total mass of the tablet (in the case of a coated tablet, the uncoated tablet before coating). The content of levocarnitine (free form) is preferably 40 to 70% by mass, more preferably 45 to 65% by mass, and even more preferably 50 to 60% by mass of the total mass of the coated tablet.

[0035] The tablet of the present disclosure is coated and used as a coated tablet (FC tablet). As a result, by combining the above-mentioned plain tablet containing levocarnitine with a film coating layer described later, a tablet is obtained that exhibits excellent long-term storage stability and prevention of deterioration against changes in shape (swelling, cracking, disintegration, etc.) and mass changes due to the hygroscopicity and deliquescence of levocarnitine (free form).

[0036] The film coating layer preferably contains polyvinyl alcohol and / or a polyvinyl alcohol copolymer. The polyvinyl alcohol copolymer is preferably a polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer. In addition, the film coating layer may further contain, for example, talc or titanium oxide.

[0037] Film coating components or compositions are commercially available, and examples of compositions containing polyvinyl alcohol include OPADRY amb, OPADRY amb II, and OPADRY II (Colorcon Japan Co., Ltd.).

[0038] Polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer is commercially available as POVACOAT (registered trademark) (Nisshin Kasei Co., Ltd.), and this can be preferably used.

[0039] Pharmaceutical additives that are typically used in coating (film) treatment of orally administered pharmaceuticals, such as coating agents, plasticizers, dispersants, antifoaming agents, and colorants, can be added to the film coating layer as needed.

[0040] Specific examples of these pharmaceutical additives for coating include cellulose or derivatives thereof, such as crystalline cellulose, methylcellulose, ethylcellulose, carmellose sodium, hydroxypropyl cellulose, and hypromellose (hydroxypropyl methylcellulose); polyethylene glycol (macrogol), titanium oxide, talc, fumaric acid, iron oxide, such as ferric oxide, yellow ferric oxide, and black ferric oxide, β-carotene, Food Blue No. 2, Food Blue No. 2 Aluminum Lake, and riboflavin. These may be used alone or in combination of two or more.

[0041] In the FC tablet of the present disclosure, an undercoating can be applied before applying a film coating containing polyvinyl alcohol and / or a polyvinyl alcohol copolymer. The undercoating can contain pharmaceutical additives used in applying the coating (film) treatment of the above-mentioned normal oral administration pharmaceuticals. Among them, it is preferable to use hypromellose (hydroxypropyl methylcellulose), talc, and fumaric acid. When an undercoating is applied, the FC tablet of the present disclosure has an uncoated tablet, an undercoating layer (first coating layer), and a film coating layer (second coating layer) containing polyvinyl alcohol and / or a polyvinyl alcohol copolymer in this order, and these two coating layers are collectively called the film coating layer. When an undercoating is not applied, the FC tablet of the present disclosure has an uncoated tablet, and a film coating layer containing polyvinyl alcohol and / or a polyvinyl alcohol copolymer in this order, and it is preferable that the film coating layer is only this one layer.

[0042] The content of polyvinyl alcohol and / or polyvinyl alcohol copolymer in the film coating layer is, for example, 1 to 99% by mass, and preferably 10 to 70% by mass. The upper or lower limit of the range may be, for example, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or 65% by mass. For example, the range may be 15 to 50% by mass.

[0043] The amount of the film coating layer is preferably about 10 to 40 parts by mass, more preferably about 15 to 35 parts by mass, and even more preferably about 20 to 30 parts by mass, relative to 100 parts by mass of the uncoated tablet.

[0044] When applying an undercoating, the film coating of the undercoating layer The amount of the film coating layer is not limited as long as it does not impair the effect of the film coating layer containing polyvinyl alcohol and / or a polyvinyl alcohol copolymer. For example, the amount is preferably about 0.5 to 5 parts by mass, and more preferably about 2 parts by mass, per 100 parts by mass of the plain tablet.

[0045] In the tablet of the present disclosure, levocarnitine is preferably contained in an amount of about 50 to 1000 mg, more preferably about 100 to 500 mg. By containing levocarnitine in such a range in the tablet, a tablet is obtained that allows easy intake of a daily dose of levocarnitine, and is also preferable from the pharmacokinetic viewpoint for maintaining the blood concentration of levocarnitine.

[0046] When the tablet of the present disclosure is stored unpackaged at 25°C and 75% RH (relative humidity) for 4 weeks, the mass increase (i.e., the amount of moisture absorption) is preferably 25% by mass or less, more preferably 24, 23, 22, 21, or 20% by mass or less, and even more preferably 19, 18, 17, 16, or 15% by mass or less, of the mass of the film-coated tablet before storage.

[0047] The dosage of the tablet of the present disclosure is appropriately selected depending on the method of use, the age, sex and other conditions of the patient, the degree of the disease, etc. For example, the amount of levocarnitine per day is about 1.5 to 3 g. For adults, this dosage is particularly preferable. For children, the amount of levocarnitine per day is about 25 to 100 mg / kg. This amount may be administered at once, or may be administered in divided doses (e.g., 2 or 3 times) per day.

[0048] The tablets of the present disclosure are manufactured to have the above-mentioned content.

[0049] The present disclosure also includes a method for producing a coated tablet in which a coating is applied to the surface of a tablet containing levocarnitine. The coating can be performed by a known method, for example, by continuously spraying and drying a mixture obtained by mixing an additive and a liquid medium used in the coating layer on a plain tablet produced by tableting using a tablet press. It is preferable to mix and granulate levocarnitine (free form) and porous calcium silicate before tableting, and then use the mixture for tableting after preparing a granulated powder. In addition, when a disintegrant, a lubricant, etc. are also blended, it is preferable to add them to the granulated powder before tableting.

[0050] In addition, in this specification, the term "comprising" includes "consisting essentially of" and "consisting of." In addition, the present disclosure includes all arbitrary combinations of the constituent features described in this specification.

[0051] In addition, the various characteristics (properties, structures, functions, etc.) described in each embodiment of the present disclosure above may be combined in any way to specify the subject matter included in the present disclosure. In other words, the present disclosure includes all subject matter consisting of all combinations of each combinable characteristic described in this specification. EXAMPLES

[0052] Hereinafter, the embodiments of the tablet of the present disclosure will be described in more detail with reference to examples, but the tablet of the present disclosure is not limited to the following examples.

[0053] <Preparation of granulated powders 1 to 5> Granulated powder 1 (calcium silicate, 0.2 times the amount) 600 g of porous calcium silicate (Flolight PS200, Tomita Pharmaceutical Co., Ltd.) was added to an agitation granulator (VG-25, Powrex Co., Ltd.), followed by a solution of 3000 g of levocarnitine (free form) (ILS Co., Ltd.) dissolved in 1200 g of water, and the mixture was agitated at a blade rotation speed of 150 rpm and a chopper rotation speed of 1500 rpm until calcium silicate and levocarnitine (free form) were uniformly dispersed, and agitation granulation was performed to obtain a wet granulated product. The obtained wet granulated product was dried at 80° C. for 12 hours using a vacuum dryer (LCV-232, TABAI ESPEC CORP.). After drying, the mixture was sieved using an 850 μm mesh screen to obtain granulated powder 1.

[0054] Granulated powder 2 (calcium silicate, 0.25 times the amount) Granulated powder 2 was obtained in the same manner as in the preparation of granulated powder 1, except that 750 g of calcium silicate (Fluorite PS200, Tomita Pharmaceutical Co., Ltd.) was used.

[0055] Granulated powder 3 (calcium silicate, 0.3 times the amount) Granulated powder 3 was obtained in the same manner as in the preparation of granulated powder 1, except that 900 g of calcium silicate (Fluorite PS200, Tomita Pharmaceutical Co., Ltd.) was used.

[0056] Granulated powder 4 (calcium silicate, 0.4 times the amount) Granulated powder 4 was obtained in the same manner as in the preparation of granulated powder 1, except that 1200 g of calcium silicate (Fluorite PS200, Tomita Pharmaceutical Co., Ltd.) was used.

[0057] Granulated powder 5 (calcium silicate, 0.3 times the amount) Granulated powder 5 was obtained in the same manner as in the preparation of granulated powder 1, except that the type and amount of calcium silicate used was changed to 900 g of porous calcium silicate (Fluorite R, Tomita Pharmaceutical Co., Ltd.).

[0058] Note that both Fluorolite PS200 and Fluorolite R are gyrolite-type calcium silicates with a petal-shaped crystal structure, represented as 2CaO·3SiO2·mSiO2·nH2O [where 1 < m < 2 and 2 < n < 3], and having an oil absorption of 450 mL or more per 100 g.

[0059] For Granulation Powders 1 to 4, the properties after granulation were confirmed. When the powder-like property was maintained, it was judged as a wet granulated product with good manufacturability. In the case of Granulation Powder 1, when the inside of the container after granulation was checked, slurring of the powder was confirmed, and it was judged that it was difficult to recover the entire amount, so only a part was recovered and the process proceeded to the drying step. Each of the obtained granulation powders was stored in a thermo-hygrostat (LHL-113, Espec Corporation) at 40°C and 75% RH (relative humidity) for 4 weeks, and when the change in properties was confirmed, deliquescence was observed in Granulation Powder 1, and the properties of Granulation Powders 2 to 4 were maintained. From this, it was confirmed that the properties could be maintained if the blending ratio was 1:0.25 or more.

[0060] <Preparation of Compressed Tablets 1 to 14> According to Table 1, one of six disintegrants, namely calcium carboxymethylcellulose (trade name: ECG-505, Nichirin Chemical Industry Co., Ltd.), carboxymethylcellulose (trade name: NS-300, Nichirin Chemical Industry Co., Ltd.), croscarmellose sodium (trade name: Parteck CCS, Merck), sodium starch glycolate (trade name: Primojel, DFE Pharma), crospovidone (trade name: Kollidon CL-F, BASF), and low-substituted hydroxypropylcellulose (trade name: LH-11, Shin-Etsu Chemical Co., Ltd.), was added to Granulation Powders 1 to 5. After mixing in a polyethylene bag, magnesium stearate (vegetable magnesium stearate, Taihei Chemical Industry Co., Ltd.) was added and further mixed to obtain a powder for tableting. Note that the unit of the value of each component described in Table 1 indicates parts by mass.

[0061] The powder for tableting was tableted using a rotary tableting machine (VELA5, Kikusui Seisakusho Co., Ltd.) equipped with a mortar and pestle with a diameter of 10 mm and a corner radius of 10 mm to prepare plain tablets 1 to 14 each containing 250 mg of levocarnitine. The tableting pressure was 6, 8, or 10 kN.

[0062] [Table 1]

[0063] Table 2 shows the tablet physical properties of each uncoated tablet (diameter 10.0 mm) obtained at a tableting pressure of 8 kN.

[0064] The thickness was measured using a thickness balance (MODEL G, PEACOCK Co., Ltd.).

[0065] The hardness was measured in the diameter direction of each uncoated tablet using a tablet hardness tester (MT50, Freund Corporation).

[0066] The tablet strength was calculated by dividing the hardness by the area of ​​the fractured surface (tablet diameter x tablet thickness).

[0067] The disintegration of each uncoated tablet was confirmed in accordance with the "Japanese Pharmacopoeia, 16th Edition, General Test Method, Disintegration Test Method (1) Immediate Release Preparations". Water was used as the test liquid. No auxiliary disk was used. The NT-200 (Toyama Sangyo Co., Ltd.) disintegration tester was used.

[0068] [Table 2]

[0069] The tablets obtained showed uniform disintegration regardless of the amount of fluorite added (see especially plain tablets 1 to 4). Regarding tablet hardness and strength, high hardness and strength were observed when the amount of fluorite added to levocarnitine was 0.25 or more, and tablets that could be used in the subsequent film coating process without problems were obtained. Similar values ​​were obtained when fluorite R was used (plain tablet 5).

[0070] Moreover, even when the type and amount of disintegrant was changed (see especially plain tablets 6 to 14), similar values ​​were obtained.

[0071] Tablet properties when compressed with a compression force of 6 kN and 10 kN were almost equivalent to those when compressed with a compression force of 8 kN.

[0072] For the plain tablets 1 to 5, 7, 12 to 14 (8 kN tableting products), a film coating was applied to each tablet at 2% by mass of the plain tablet mass using an undercoating composition (Table 3) consisting of hypromellose (TC-5R, Shin-Etsu Chemical Co., Ltd.), talc (dry heat talc ML115, Fuji Talc Co., Ltd.), and fumaric acid (special grade reagent, Fuji Film Wako Pure Chemical Co., Ltd.) (first coating). Furthermore, a film coating was applied to each tablet at 23% by mass of the plain tablet mass using a 20% by mass film coating solution (Table 4) of a film coating composition containing polyvinyl alcohol (OPADRY ambII, Colorcon Japan LLC) (second coating). The total amount of film coating was 25% by mass of the plain tablet mass per tablet.

[0073] Film coating was performed using a Driacoater (DRC-200, Driam Co., Ltd.).

[0074] [Table 3]

[0075] [Table 4]

[0076] Ten tablets of each of the film-coated tablets (FC tablets) 1-5, 7, 12-14 obtained by applying the above-mentioned film coating to the plain tablets 1-5, 7, 12-14 were stored unpackaged in a constant temperature and humidity chamber (LHL-113, Espec Corp.) at 25°C and 75% RH (relative humidity). As a control, a commercially available tablet (L-Cartin (registered trademark) FF tablet 250 mg) containing 250 mg of levocarnitine (free form) was used and stored in the same unpackaged state.

[0077] Sampling was performed over time, and the mass increase during humid storage was calculated using the following formula. The results for FC tablets 1 to 4 are shown in Figure 1. Compared to the commercially available tablets, FC tablets 1 to 4 had improved humid stability, and among them, FC tablets 2 to 4 showed improved humid stability for about one month. It was. Mass increase (amount of moisture absorbed) = FC tablet mass after humid storage - initial FC tablet mass The results for FC tablets 3, 7, 12, 13, 5, and 14 are shown in Table 5.

[0078] [Table 5]

[0079] Regardless of the type of fluorite, the type of disintegrant, the amount of blend, etc., improvement in humid stability was observed for about one month.

[0080] From the above results, it was found that the ratio of fluorite to levocarnitine is preferably 1:0.25 or more from the viewpoints of manufacturability and stability.

[0081] <Preparation of plain tablets 15 and FC tablets 15> 75 g of calcium silicate (Florite PS200, Tomita Pharmaceutical Co., Ltd.) was added to an agitation granulator (NSK150, Okada Seiko Co., Ltd.), followed by a solution of 250 g of levocarnitine (free form) (ILS Co., Ltd.) dissolved in 100 g of water, and the mixture was agitated at a rotation speed of 500 rpm until calcium silicate and levocarnitine (free form) were uniformly dispersed, followed by agitation granulation. The resulting wet granules were dried at 60° C. for 24 hours, and then sized by sieving through an 850 μm mesh screen to obtain a granulated powder.

[0082] To the obtained granulated powder, carmellose calcium (product name: ECG-505, Nichirin Chemical Industry Co., Ltd.) was added and mixed in a polyethylene bag. After that, magnesium stearate (vegetable magnesium stearate, Taihei Chemical Industry Co., Ltd.) was added and further mixed to obtain a powder for tableting.

[0083] The powder for tableting was compressed at a tableting pressure of 6 kN using a rotary tablet press (VELA5, Kikusui Seisakusho Co., Ltd.) equipped with a pestle and mortar with a diameter of 10 mm and a corner radius of 10 mm to obtain uncoated tablets 15 each containing 250 mg of levocarnitine.

[0084] The formulation of uncoated tablet 15 is shown in Table 6. The values ​​of each component in Table 6 indicate parts by weight.

[0085] [Table 6]

[0086] The tablet hardness of uncoated tablet 15 was 98N (n=10), and the disintegration time was 11.0 (n=6) minutes. .

[0087] The uncoated tablet 15 was film-coated with an undercoating composition (Table 7) containing hypromellose (TC-5R, Shin-Etsu Chemical Co., Ltd.) and talc (dry heat talc ML115, Fuji Talc Co., Ltd.) so that the film coating was 2% of the uncoated tablet mass per tablet (first coating). This undercoated tablet was further film-coated with a 15% by mass film coating solution (Table 8) of a film coating composition (OPADRY amb II, Colorcon Japan LLC) containing polyvinyl alcohol so that the total amount of film coating was 15%, 20%, and 25% by mass of the uncoated tablet mass per tablet (second coating). The FC tablet with a total film coating amount of 15% by mass of the uncoated tablet mass per tablet is designated FC tablet 15-1, 20% by mass of the FC tablet is designated FC tablet 15-2, and 25% by mass of the FC tablet is designated FC tablet 15-3.

[0088] Film coating was performed using a Driacoater (DRC-200, Driam Co., Ltd.).

[0089] [Table 7]

[0090] [Table 8]

[0091] FC tablets 15-1 to 15-3 were stored unpackaged in a constant temperature and humidity chamber (LHL-113, Espec Corp.) at 25°C and 75% RH (relative humidity). As a control, a commercially available tablet (L-Cartin (registered trademark) FF tablet 250 mg) containing 250 mg of levocarnitine (free form) was used and stored in the same unpackaged state.

[0092] Sampling was performed over time, and the increase in mass during humid storage was calculated. The results are shown in Figure 2.

[0093] Compared to commercially available tablets, FC Tablets 15-1 to 15-3 have improved humid stability. It was confirmed that:

[0094] <Preparation of plain tablets 16 and FC tablets 16-1 to 16-2> The powder for tableting according to the formula of uncoated tablet 11 in Table 1 was compressed at a tableting pressure of 8 kN using a rotary tablet press (VIRGO, Kikusui Seisakusho Co., Ltd.) equipped with a pestle and mortar with a diameter of 9.5 mm and a corner radius of 10 mm, to obtain uncoated tablets 16 each containing 250 mg of levocarnitine. The tablet thickness of uncoated tablets 16 was 5.23 mm (n=10), the tablet hardness was 265 N (n=10), and the tablet strength was 5.33 N / mm 2 (n=10), and the disintegration time was 10.8 min (n=6).

[0095] Plain tablet 16 (diameter 9.5 mm, tableting pressure 8 kN) was film-coated with a film-coating composition (Table 9, solids concentration 15% by mass) prepared by dissolving and dispersing PVA copolymer (polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, product name: POVACOAT type F, Daido Chemical Industry Co., Ltd.) and talc (dry heat talc ML115, Fuji Talc Industry Co., Ltd.) in a 10% by mass ethanol solution to obtain FC tablet 16-1.

[0096] In addition, uncoated tablet 16 (diameter 9.5 mm, tableting pressure 8 kN) was coated with an undercoating composition (first coating) consisting of hypromellose and talc in Table 7, and a second coating consisting of a film coating composition (Table 9, solid content concentration 15% by mass) consisting of PVA copolymer (polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, trade name: POVACOAT type F, Daido Chemical Industry Co., Ltd.) and talc dissolved and dispersed in a 10% by mass ethanol solution, to obtain FC tablet 16-2 (Table 10: each value is in parts by mass). The amount of film in each tablet was formulated so that the amount of FC in FC tablet 16-1 was 25% by mass relative to the uncoated tablet mass, and the amount of film in the second coating layer was the same as the amount of film per unit area in FC tablet 16-1.

[0097] Film coating is performed using a Powrex coater (PRC-GTXmini, Powrex Corporation) This was carried out using a .

[0098] [Table 9]

[0099] [Table 10]

[0100] FC tablets 16-1 and 16-2 were stored unpackaged in a constant temperature and humidity chamber (LHL-113, Espec Corp.) at 25°C and 75% RH (relative humidity), and samples were taken over time and stored in a humidified condition. The mass increase during incubation was calculated, and the results are shown in FIG.

[0101] <Consideration of the combination of fluorite and film coating> Carmellose calcium (product name: ECG-505, Nichirin Chemical Industry Co., Ltd.) was added to the granulated powder 3 and mixed in a polyethylene bag, after which magnesium stearate (vegetable magnesium stearate, Taihei Chemical Industry Co., Ltd.) was added and further mixed to obtain a powder for tableting. The powder for tableting was compressed at a tableting pressure of 8 kN using a rotary tableting machine (VELA5, Kikusui Seisakusho Co., Ltd.) equipped with a mortar and pestle with a diameter of 10 mm and a corner radius to obtain uncoated tablets 17 containing 250 mg of levocarnitine per tablet.

[0102] The formulation of uncoated tablet 17 is shown in Table 11 (each value is in parts by weight).

[0103] [Table 11]

[0104] The plain tablet 17 was coated with the film coating solution (15% by mass OPADRY amb II) in Table 8 so that the mass ratio of the film coating to the plain tablet was 20% by mass or 25% by mass (FC tablet 17-1). The coating was performed using a Driacoater (DRC-200, Driam Co., Ltd.).

[0105] The plain tablet 17 was coated with a hypromellose (hydroxypropyl methylcellulose)-based film coating to confirm its effect. A film coating solution was prepared by dissolving and dispersing OPADRY (trade name: OPADRY, Colorcon Japan LLC), a premixed product for film coating based on hypromellose (hydroxypropyl methylcellulose), in purified water to a concentration of 5% by mass, and the plain tablet was coated with a film coating of 20% by mass or 25% by mass (FC tablet 17-2). The coating was performed using a Driacoater (DRC-200, Driam Co., Ltd.).

[0106] The uncoated tablet used in the commercially available Elcartin FF tablet 250 mg (containing 250 mg of levocarnitine (free form), low-substituted hydroxypropylcellulose, crystalline cellulose, hydroxypropylcellulose, light anhydrous silicic acid, and magnesium stearate as additives) was coated using the film coating solution (15% by mass OPADRY amb II) in Table 8. The amount of film coating per unit area of ​​the uncoated tablet in the coated tablet was the same as the amount of film coating per unit area of ​​the uncoated tablet 17 in FC tablet 17-1 (FC tablet 17-3). The coating was performed using Driacoater (DRC-200, Driam Co., Ltd.).

[0107] FC tablets 17-1, 17-2, 17-3 and the currently available tablets (Elcartin FF tablets) were stored unpackaged in a constant temperature and humidity chamber (LHL-113, Espec Corp.) at 25°C and 75% RH (relative humidity). Sampling was done over time and the increase in mass during humid storage was calculated. The results for the 25% by mass FC tablets are shown in Figure 4.

[0108] As a result of checking the mass increase and tablet properties during humid storage, it was found that porous calcium silicate (flow It was confirmed that a significant improvement in stability could be achieved by combining a film coating containing polyvinyl alcohol with a PEG-20 ...

Claims

1. A plain tablet containing levocarnitine (free form) and porous calcium silicate in a mass ratio of 1:0.25 to 2; and A film coating layer that covers the tablet A film-coated tablet comprising:

2. 2. The film-coated tablet according to claim 1, wherein the porous calcium silicate is gyrolite-type calcium silicate.

3. 3. The film-coated tablet according to claim 1 or 2, wherein the porous calcium silicate has an oil absorption of 300 mL or more per 100 g.

4. The porous calcium silicate has the formula: 2CaO・3SiO ２ ・mSiO ２ ・nH ２ O (Wherein, 1<m<2 and 2<n<3) It is a porous calcium silicate represented by the formula: The film-coated tablet according to any one of claims 1 to 3.

5. The film-coated tablet according to any one of claims 1 to 3, wherein the uncoated tablet contains levocarnitine (free form) and porous calcium silicate in a mass ratio of 1:0.25 to 0.

5.

6. The film-coated tablet according to any one of claims 1 to 5, wherein the film coating layer contains polyvinyl alcohol and / or a polyvinyl alcohol copolymer.

7. 7. The film-coated tablet according to claim 6, wherein the polyvinyl alcohol copolymer is a polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

8. The film-coated tablet according to any one of claims 1 to 7, wherein the film coating layer is provided in an amount of 10 to 40% by mass relative to the uncoated tablet.

9. The film-coated tablet according to any one of claims 1 to 8, wherein levocarnitine (free) is contained in an amount of 50 to 80% by mass of the uncoated tablet.

10. A plain tablet containing levocarnitine (free form) and porous calcium silicate in a mass ratio of 1:0.25 to 2; and The film coating layer covering the tablet is 10 to 40% by mass based on the tablet. Preparation, The porous calcium silicate is a gyrolite-type calcium silicate having an oil absorption of 300 mL or more per 100 g, The film coating layer contains polyvinyl alcohol and / or a polyvinyl alcohol copolymer, The tablet contains 50 to 80% by mass of levocarnitine (free). Film-coated tablets.

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