JP2024035117A - solid composition - Google Patents

Abstract

[Problem] To provide a solid preparation in which the total amount of acetaminophen and glycine is 55% or more, the solid preparation is improved in resistance to cracking and chipping, and has sufficient hardness. [Solution] The present invention is a solid preparation containing (A) acetaminophen, (B) glycine, and (C) a silicate having a primary particle size of 1 μm or less, and the total content of the (A) component and the (B) component is 55% by mass or more. As the (C) silicate having a primary particle size of 1 μm or less, magnesium aluminometasilicate, hydrous silicon dioxide, or light anhydrous silicic acid is preferred. [Selected Figures] None

Description

The present invention relates to a solid formulation containing acetaminophen and glycine.

Acetaminophen (paracetamol) is a para-aminophenol-based antipyretic analgesic that is commonly used to relieve headaches, muscle pain, menstrual pain, toothache, etc., as well as to relieve fever and analgesia in acute upper respiratory tract inflammation (non-patented). Reference 1).
Glycine (also known as aminoacetic acid) is a type of amino acid, and among the α-amino acids in which the amino group is directly connected to the carbon to which the carboxyl group is bonded (α-carbon), it is the only one with D- and L-stereoisomerism. It is an amino acid classified as a non-polar side chain amino acid. In addition, glycine is classified as a non-essential amino acid that can be made in the human body, and is involved in various bodily functions, especially porphyrin, which is related to the function of transporting oxygen in the blood, creatine, which is necessary for muscle exercise, and antioxidant. It is also known as a substance that makes up glutathione and purines in nucleic acids. Furthermore, glycine is an amphoteric compound and has a buffering effect on gastric juice (Non-Patent Document 2).

Several preparations containing acetaminophen and glycine are known. For example, in Patent Document 1, glycine is used as a stabilizer for acetaminophen in an aqueous composition. Patent Document 2 discloses a tablet containing acetaminophen and glycine that is effective in preventing eye strain. Furthermore, Patent Document 3 discloses a pharmaceutical composition containing acetaminophen and glycine that has an improved antipyretic effect.

WO2012/077696 Japanese Patent Application Publication No. 2014-156458 Japanese Patent Application Publication No. 2004-123712

18th Revised Japanese Pharmacopoeia Manual C-146 to C-150 18th Revised Japanese Pharmacopoeia Manual C-1617 to C-1620

According to the approval standards for the manufacture and sale of over-the-counter medicines for cold medicines and antipyretic analgesics, acetaminophen and glycine can both be combined in high doses, with a maximum daily dose of 900 mg. Therefore, when producing tablets containing these in high doses, there is a concern that the dosage will increase (increase in tablet size, increase in the number of tablets to be taken, etc.). Furthermore, in the case of powders and granules, the weight of each package increases, leading to concerns about increased dosage.
When the present inventors manufactured a solid preparation in which the total amount of acetaminophen and glycine was 55% by mass or more, it was found that the manufactured solid preparation cracked or chipped. Since cracks or chips in solid preparations affect the quality, it is desirable that the occurrence rate be 0%. It was also found that tablets did not have sufficient tablet hardness. In the case of powders and granules, the increase in fine powder due to chipping of particles may affect the ease of administration, such as making it difficult to swallow.

An object of the present invention is to provide a solid preparation in which the total amount of acetaminophen and glycine is 55% by mass or more, and which does not crack or chip. Another object of the present invention is to provide a solid preparation in which the total amount of acetaminophen and glycine is 55% by mass or more in the solid preparation and has sufficient hardness.

The present inventors conducted various studies to solve the above problems, and surprisingly found that cracking or chipping of solid preparations was improved by incorporating silicate with a primary particle size of 1 μm or less. I discovered that. It was also found that the hardness of the tablets was improved.

That is, the present invention
(1) Contains (A) acetaminophen, (B) glycine, (C) silicate with a primary particle diameter of 1 μm or less, and the total content of the component (A) and the component (B) is 55% A solid preparation that is not less than % by mass,
(2) (C) The silicate having a primary particle diameter of 1 μm or less is at least one selected from the group consisting of magnesium aluminate metasilicate, hydrated silicon dioxide, and light anhydrous silicic acid, according to (1). solid preparations,
(3) The solid preparation according to (1) or (2), wherein (A) acetaminophen is 0.2 to 15 parts by mass per 1 part by mass of (B) glycine;
(4) The solid preparation according to any one of (1) to (3), wherein the solid preparation is a tablet;
(5) the solid preparation according to any one of (1) to (4), wherein the tablet has a diameter of 11 mm or less;
(6) A method for improving cracking and chipping of a tablet in which the total content of (A) acetaminophen and (B) glycine is 55% by mass or more, wherein the tablet has (C) a primary particle diameter of 1 μm. A method for improving cracking and chipping of the tablet, comprising the following silicate;
It is.

According to the present invention, it has become possible to provide a solid preparation in which cracking or chipping of the solid preparation is improved even if the total amount of acetaminophen and glycine is 55% by mass or more in the solid preparation. Furthermore, it has become possible to provide tablets with sufficient hardness.

Acetaminophen (A) used in the present invention is acetaminophen based on the Japanese Pharmacopoeia, and can be produced by a known method or a commercially available product can be used.

The solid preparation of the present invention is not particularly limited, but for example, the content of acetaminophen contained in the tablet is preferably 10 to 90% by mass, more preferably 10 to 80% by mass, particularly preferably 10 to 70% by mass, Most preferably it is 25 to 50% by weight.

The daily amount of acetaminophen in the present invention is not particularly limited, but is preferably 150 to 1500 mg, more preferably 150 to 1200 mg, even more preferably 150 to 900 mg per day.

Glycine (B) used in the present invention is a glycine based on the Japanese Pharmacopoeia, and can be produced by a known method or a commercially available one can be used.

Although the solid preparation of the present invention is not particularly limited, for example, the content of glycine contained in the tablet is preferably 3 to 90% by weight, more preferably 3 to 80% by weight, particularly preferably 3 to 60% by weight, and most preferably is 25 to 50% by mass.

The daily amount of glycine in the present invention is not particularly limited, but is preferably 60 to 900 mg, more preferably 180 to 900 mg per day.

Further, the solid preparation of the present invention is not particularly limited, but for example, the content of (A) acetaminophen in the tablet is preferably 55 to 90% by mass, more preferably 65 to 90% by mass. Further, it is preferably 0.1 to 20 parts by weight, more preferably 0.2 to 15 parts by weight, per 1 part by weight of glycine (B). In the present invention, if (C) silicate with a primary particle size of 1 μm or less is not included, cracking or chipping of the solid preparation will occur if the total content of acetaminophen and glycine is 55% by mass or more of the entire solid preparation. do.

The primary particle size in the present invention refers to the particle size of particles that constitute the powder and cannot be divided into smaller particles.

In the present invention, the silicate having a primary particle diameter of 1 μm or less is not particularly limited as long as it is pharmaceutically acceptable, but the primary particle diameter is preferably 0.001 μm to 1 μm, more preferably 0.001 μm to It is 0.5 μm, more preferably 0.001 μm to 0.1 μm. Note that the primary particle diameter can be calculated from the volume and surface area, and can also be measured by shape observation using an electron microscope or the like in addition to a particle size distribution measuring device such as a laser diffraction method or a dynamic light scattering method. Furthermore, the silicate according to the present invention may be either an inorganic acid or an organic acid, and these may be derived from natural products or may be synthetic products. Further, these can be used alone or in combination of two or more. Among these, magnesium aluminate metasilicate, light anhydrous silicic acid, and hydrated silicon dioxide are preferable as silicates having a primary particle size of 1 μm or less, and magnesium aluminate metasilicate and light anhydrous silicic acid are preferable from the viewpoint of the effect of the present invention. More preferred is magnesium aluminate metasilicate. These silicates having a primary particle diameter of 1 μm or less may be commercially available products, or may be produced by known methods.

Although the solid preparation of the present invention is not particularly limited, for example, the content of (C) silicate with a primary particle size of 1 μm or less contained in the tablet is preferably 0.1 to 45% by mass, more preferably The content is 0.1 to 20% by weight, more preferably 0.1 to 5% by weight.

(C) When magnesium aluminate metasilicate is used as the silicate with a primary particle size of 1 μm or less, the solid preparation in the present invention is not particularly limited, but for example, the content of magnesium aluminate metasilicate in the tablet is It is preferably 0.1 to 45% by weight, more preferably 0.1 to 20% by weight, even more preferably 0.5 to 5% by weight, particularly preferably 0.5 to 3% by weight.

In the present invention, the blending ratio of the total amount of (C) magnesium aluminate metasilicate, (A) acetaminophen, and (B) glycine is determined from the viewpoint of the effect of the present invention. With respect to 1 part by mass of the total amount of glycine, magnesium aluminate metasilicate is preferably 0.001 to 1 part by mass, more preferably 0.01 to 1 part by mass, and even more preferably 0.01 to 0.07 part by mass. Particularly preferred is 0.01 to 0.05 parts by mass.

(C) When light silicic anhydride is used as the silicate with a primary particle size of 1 μm or less, the solid preparation in the present invention is not particularly limited, but the content of light silicic anhydride contained in the tablet, for example, is preferably is 0.1 to 20% by weight, more preferably 0.1 to 15% by weight, even more preferably 0.1 to 10% by weight, particularly preferably 0.7 to 5% by weight, most preferably 1 to 5% by weight. It is.

(C) When using hydrated silicon dioxide as the silicate with a primary particle size of 1 μm or less, the solid preparation in the present invention is not particularly limited, but for example, the content of hydrated silicon dioxide contained in the tablet is preferably 0. .1 to 20% by weight, more preferably 0.1 to 15% by weight, even more preferably 0.1 to 10% by weight, particularly preferably 0.1 to 5% by weight.

In the present invention, the blending ratio of the total amount of (C) light anhydrous silicic acid or hydrated silicon dioxide, (A) acetaminophen, and (B) glycine is determined from the viewpoint of the effect of the present invention. B) With respect to 1 part by mass of the total amount of glycine, (C) light anhydrous silicic acid or hydrated silicon dioxide is preferably 0.01 to 10 parts by mass, more preferably 0.01 to 1 part by mass, and 0.01 to 1 part by mass. 0.05 parts by mass is more preferred.

The solid preparation of the present invention is not particularly limited as long as it is in a dosage form specified in the general rules for preparations of the Japanese Pharmacopoeia, but preferably tablets, powders, fine granules, granules, pills, capsules, Particularly preferred are tablets, powders, fine granules, and granules, and most preferred are tablets.
Furthermore, the tablets of the present invention are not particularly limited as long as they are tablets that are normally prescribed in the General Rules for Preparations of the Japanese Pharmacopoeia. Tablets stipulated in the Japanese Pharmacopoeia's general rules for formulations include orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible and dissolving tablets, film-coated tablets, sugar-coated tablets, laminated tablets, etc. Furthermore, the tablet can be provided with a score line, a mark for improving identification, or a stamp. Furthermore, the tablets of this preparation may be round tablets, irregularly shaped tablets, or minitablets.
The powders and granules of the present invention are not particularly limited as long as they are normally prescribed in the general rules for formulations of the Japanese Pharmacopoeia. Those stipulated in the Japanese Pharmacopoeia's general rules for formulations include powders, granules, and effervescent granules. It also includes the contents of granules before tableting, mixed powder before tableting, and capsules.

According to the present invention, it has become possible to incorporate acetaminophen and glycine in a high concentration of 55% by mass or more in a solid preparation, thereby making it possible to reduce the size of tablets. It has also become possible to reduce the number of tablets taken at a time. The tablet diameter of the tablet of the present invention is preferably 1 to 11 mm, more preferably 8 mm to 10 mm. Further, the number of tablets to be taken at one time can be 1 to 3 tablets. In addition, powders and granules allow for smaller doses per dose.

The hardness of the tablet of the present invention can be measured using a tablet hardness meter. The hardness of the tablet of the present invention is preferably 30 to 200N, more preferably 30 to 180N, and particularly preferably 30 to 150N.
The solid preparation of the present invention may contain other commonly used active ingredients, excipients, disintegrants, binders, flow agents, lubricants, and acidic agents within a qualitative and quantitative range that does not impair the effects of the present invention. Agents, sweeteners, flavoring agents, cooling agents, coloring agents, foaming agents, surfactants, plasticizers, fragrances, coating agents, and the like can be added.

Other active ingredients that can be incorporated into the solid preparation of the present invention include, for example, antipyretic and analgesic ingredients, antihistamine ingredients, antitussive ingredients, bronchodilator ingredients, expectorant ingredients, hypnotic and sedative ingredients, vitamins, amino acids, anti-inflammatory ingredients, gastrointestinal Examples include mucosal protective ingredients, herbal medicines, Chinese herbal formulas, caffeine, antacids, etc., and one or more selected from the group consisting of these may be contained.

Examples of excipients that can be incorporated into the solid preparation of the present invention include lactose, starches, crystalline cellulose, sucrose, sugar alcohols, calcium hydrogen phosphates, etc., with crystalline cellulose being preferred.
The solid preparation of the present invention is not particularly limited, but for example, the crystalline cellulose used in the tablet is preferably one that complies with the Japanese Pharmacopoeia or food additives, and more preferably the crystalline cellulose that complies with the Japanese Pharmacopoeia. Crystalline cellulose can be produced by a known method, or commercially available products can be used. Although the solid preparation of the present invention is not particularly limited, for example, the particle form of crystalline cellulose used in tablets is not particularly limited, but is preferably fine powder or fibrous, and more preferably fibrous.

Although the solid preparation of the present invention is not particularly limited, for example, the content of crystalline cellulose in the tablet is preferably 1 to 70% by weight, more preferably 5 to 60% by weight, and 7 to 45% by weight based on the total weight of the tablet. % is more preferable.

Examples of disintegrants that can be incorporated into the solid preparation of the present invention include low-substituted hydroxypropyl cellulose, sodium starch glycolate, crospovidone, carmellose, croscarmellose sodium, carmellose calcium, pregelatinized starch, etc. Examples of lubricants include hydroxypropylcellulose, hypromellose, gelatin, pregelatinized starch, polyvinylpyrrolidone, pullulan, etc., and lubricants include sucrose fatty acid ester, hydrogenated oil, stearic acid, magnesium stearate, calcium stearate, etc. .

The tablet of the present invention can be manufactured by a conventional tablet manufacturing method. In other words, this preparation can be prepared by mixing the active pharmaceutical ingredient and the above-mentioned additives in a suitable mixer such as a mixer to produce a mixed powder for tablets, and then directly compressing the mixed powder into tablets; It can be manufactured by a method of manufacturing granules through a granulation process and compressing the granules into tablets. The granules can be produced by a dry granulation method (slug method, roller compactor method) or a wet granulation method, preferably a wet granulation method. The granulation device or method may be a roller compactor, stirring granulation method, fluidized bed granulation method, extrusion granulation method, rolling granulation method, spray granulation, etc., and preferably stirring granulation. This is a fluidized bed granulation method. As a machine for compressing and tableting the mixed powder for tablets or the granules of the mixed powder, a single-shot tableting machine, a rotary tableting machine, etc. can be used.
The powders and granules of the present invention can be produced by conventional methods for producing powders and granules. That is, the present preparation can be manufactured into granules by a method of preparing a mixed powder by mixing the pharmaceutically active ingredient and the above-mentioned additives in a suitable mixer such as a mixer, or by a granulation process. . The granules can be produced by a dry granulation method (slug method, roller compactor method) or a wet granulation method, preferably a wet granulation method. The granulation device or method may be a roller compactor, stirring granulation method, fluidized bed granulation method, extrusion granulation method, rolling granulation method, spray granulation, etc., and preferably stirring granulation. This is a fluidized bed granulation method.
The evaluation method for cracking and chipping of the present invention is not particularly limited, but in the case of tablets, friability test method and visual inspection may be used, and in the case of powders and granules, calculation of the increase rate of fine powder by particle size distribution measurement may be mentioned. It will be done.

EXAMPLES The present invention will be explained in more detail with reference to Examples and Comparative Examples below, but the present invention is not limited to these Examples.

(Preparation of tablets)
(Examples 1 to 8, Comparative Examples 1 to 5)
After weighing each raw material component according to the composition shown in Table 1, it was mixed uniformly. Each tablet weighed approximately 300 mg and was compressed using a single tablet press (HANDTAB) at a compression pressure of approximately 10 kN to obtain tablets with a diameter of 8.5 mm. Incidentally, finely pulverized glycine was used. In addition, the primary particle diameters of the silicate used this time were magnesium aluminate metasilicate 0.02 to 0.1 μm, light anhydrous silicic acid 0.007 to 0.04 μm, calcium silicate approximately 30 μm, and talc 5 to 8 μm. It is.

(Evaluation of tablet cracking and chipping)
The obtained tablets were tested based on the tablet friability test method of the Japanese Pharmacopoeia, and the tablets were observed after the test to evaluate cracking and chipping. The percentage of tablets with cracks or chips to all the tablets tested was calculated, and the incidence of cracks or chips in the tablets was calculated. The results are shown in Table 1.

As shown in Table 1, in Comparative Example 1 in which the total content of acetaminophen and glycine was 50%, no cracking or chipping of the tablet was observed. In Comparative Examples 2 and 3, in which the total content of acetaminophen and glycine was 55% or more, cracking and chipping of the tablets occurred. For tablets with acetaminophen and glycine contents of 55% or more, even if the silicates of Comparative Examples 4 and 5 were added, cracking and chipping of the tablets could not be suppressed, resulting in a high occurrence of cracking and chipping. The rate was shown. On the other hand, in Examples 1 to 8 in which silicate with a primary particle size of 1 μm or less was blended, the incidence of cracking and chipping of tablets was 0%.

(Measurement of tablet hardness)
The tablet hardness of the tablets of Comparative Examples 3 to 5 and Examples 1 to 8 was measured using a tablet hardness meter (Pharmatron Dr. Schleuniger 8M type), and the average hardness (N) was determined. The results are shown in Table 2.

As shown in Table 2, compared to the tablets of Comparative Examples 4 and 5, it became clear that the tablets containing silicate with a primary particle diameter of 1 μm or less had higher hardness.

(Formulation example)
Formulation Examples 1 to 7 of the present invention are prepared using the materials shown in Table 3 below. Formulation Examples 1 to 5 are in the form of chewable tablets, Formulation Example 6 is in the form of tablets, and Formulation Example 7 is in the form of granules. Further, Formulation Examples 1 to 7 are produced by a wet granulation method using a solvent.

According to the present invention, even if the total content of acetaminophen and glycine is 55% by mass or more, it can be manufactured using general manufacturing equipment, and furthermore, no cracking or chipping occurs during transportation. Moreover, an excellent solid preparation having high hardness can be provided.

Claims (6)

Contains (A) acetaminophen, (B) glycine, and (C) silicate with a primary particle diameter of 1 μm or less, and the total content of the (A) component and the (B) component is 55% by mass or more. Solid formulation. The solid preparation according to claim 1, wherein (C) the silicate having a primary particle diameter of 1 μm or less is at least one selected from the group consisting of magnesium aluminate metasilicate, hydrated silicon dioxide, and light anhydrous silicic acid. The solid preparation according to claim 1 or 2, wherein (A) acetaminophen is contained in an amount of 0.2 to 15 parts by mass per 1 part by mass of glycine (B). The solid preparation according to claim 1 or 2, wherein the solid preparation is a tablet. The solid preparation according to claim 4, wherein the tablet has a diameter of 11 mm or less. A method for improving cracking and chipping of a tablet in which the total content of (A) acetaminophen and (B) glycine is 55% by mass or more, the tablet comprising (C) silicone with a primary particle size of 1 μm or less. A method for improving cracking and chipping of tablets, which comprises containing an acid salt.