Abstract
The present invention provides magnesium oxide suitable for use as a medicine or food additive, specifically, provides magnesium oxide particles that can reduce tableting problems and abnormal quality characteristics of tablets during tableting, and provides magnesium oxide particles that can reduce tableting problems and abnormal quality characteristics of tablets and have low heavy metal content and high magnesium oxide purity. The present invention provides magnesium oxide particles for use as a medicine or food additive, wherein the BET specific surface area is 7 to 50 m2/g and the CAA80/CAA40 is 2 to 7.
Description
Magnesium oxide particles for medical use or food additives
Technical field
The present invention relates to magnesium oxide particles for medical use or food additives.
Background technology
Magnesium oxide tablets are used in many aspects such as pharmaceutical laxatives and mineral supplements (for example, patent documents 1 to 3).
Generally speaking, tablets are manufactured by compressing raw materials into tablet shapes. And the process of performing this compression molding is called a tableting process. In the tableting process, the compression operation is performed continuously and at a high speed. Under such conditions, stress and density are dispersed inside the tablet, so that the internal structure is never uniform, and this non-uniformity is considered to be the main cause of tableting problems and abnormal quality characteristics.
As the tableting problems, there are top cracking, waist cracking, sticking, and adhesion. Top cracking is a phenomenon in which the tablet peels off in a cap-like shape during or after being discharged from the die ring after the tablet is formed, and waist cracking is a phenomenon in which the top crack becomes more serious and peels off in layers along the side of the tablet rather than the upper surface. Punch sticking is a phenomenon in which powder adheres to the punch (compression rod) during the compression stroke and damages the tablet surface in the form of a depression. Flake cracking is also a phenomenon in which the tablet surface is slightly damaged for the same reason. These tableting problems are mainly caused by the properties of the raw materials.
In addition, as the above-mentioned quality characteristic abnormality, there can be cited the state that the tablets are cracked, defective or powdered even under normal use conditions. Such quality characteristic abnormality is mainly caused by insufficient strength (hardness) of the tablets.
In the manufacture of magnesium oxide tablets, especially when high-purity magnesium oxide is used as a raw material, there is also a problem that the above-mentioned tableting problems and quality characteristic abnormalities are easy to occur.
However, in the manufacturing method of magnesium oxide, there is a method of calcining magnesium carbonate, and a method of adding calcium hydroxide to seawater or magnesium chloride aqueous solution (brine or salt water) to generate magnesium hydroxide and filtering, drying and then calcining (Patent Document 4).
For the magnesium oxide produced by calcining magnesium hydroxide, its properties and uses vary depending on the calcination temperature. For example, the product of magnesium hydroxide fired at a high temperature of more than 1500°C is almost inactive and has high-temperature refractory properties. It is used as a refractory material for raw materials of alkaline refractory bricks and monolithic refractory materials. In addition, magnesium oxide obtained by firing magnesium hydroxide at 450-1300°C has a relatively high activity and is used as a magnesia cement material or a source of minerals for additives to fertilizers, foods, etc., raw materials for pharmaceuticals such as antacids and laxatives, etc. This magnesium oxide is used as an additive to fertilizers, foods, etc., a raw material for pharmaceuticals, or as a raw material for cosmetics in order to be directly or indirectly ingested by the human body, so it is hoped that the amount of heavy metals mixed in or contained is small and the purity is high.
Therefore, it is hoped that a magnesium oxide that can be used as a pharmaceutical or food additive, has high purity, and can reduce problems during tableting can be developed.
Invention content
In view of the above situation, the main subject of the present invention is to provide a magnesium oxide that can be used as a medicine or food additive. Specifically, the subject is to provide a magnesium oxide particle that can reduce tableting problems and abnormal quality characteristics of tablets during tableting, and to provide a magnesium oxide particle that can reduce tableting problems and abnormal quality characteristics of tablets and has a low amount of heavy metal mixed and a high purity of magnesium oxide.
In order to solve the above problems, the present inventors conducted intensive research and obtained the following new insights. They also repeatedly conducted research and completed the present invention: by using magnesium oxide particles with a BET specific surface area of about 7 to about 50 m2/g and an activity (see the following description) within a specified range, unexpectedly, the tablet strength during tableting can be improved and the tableting problems in the manufacture of magnesium oxide tablets can be reduced.
That is, the present invention relates to the following.
(1) A magnesium oxide particle for medicine or food additive, wherein the BET specific surface area is 7 to 50 m2/g and CAA80/CAA40 is 2 to 7.
(2) The magnesium oxide particles according to (1), wherein the BET specific surface area is 10 to 45 m2/g and the CAA80/CAA40 is 2.2 to 6.
(3) The magnesium oxide particles according to (1) or (2), wherein the bulk density is 700 to 1000 g/L.
(4) The magnesium oxide particles according to any one of (1) to (3), wherein the purity (assay) of magnesium oxide is 96% or more.
(5) The magnesium oxide particles according to any one of (1) to (4), wherein the particles having a particle size of less than 150 μm account for less than 10% by weight of the total.
(6) The magnesium oxide particles according to any one of (1) to (5), wherein the content of Pb is less than 20 ppm and the content of As is less than 4 ppm based on the weight of the magnesium oxide particles.
(7) A method for producing magnesium oxide particles as described in any one of the above (1) to (6), comprising: a step of mixing medium-activity magnesium oxide and low-activity magnesium oxide in a weight ratio of 10:90 to 80:20; a step of pressurizing the mixture; and a step of pulverizing the mixture.
(8) A method for producing magnesium oxide tablets, characterized in that the magnesium oxide particles as described in any one of the above (1) to (6) are tableted.
(9) A magnesium oxide tablet containing the magnesium oxide particles as described in any one of the above (1) to (6).
According to the magnesium oxide particles of the present invention, tableting problems in the production of magnesium oxide tablets can be reduced, and abnormal quality characteristics of magnesium oxide tablets caused by insufficient tablet strength can be reduced. Furthermore, the magnesium oxide particles of the present invention have a low content of heavy metals and a high purity of magnesium oxide. Therefore, according to the present invention, safe magnesium oxide particles suitable for use as medicine or food additives can be provided.
Specific embodiments
One embodiment of the present invention relates to magnesium oxide particles for pharmaceutical or food additive use. By using the magnesium oxide particles of the present invention, it is possible to preferably improve the tableting problem during tablet manufacturing and/or the tablet strength during tableting.
First, the physical properties of the magnesium oxide particles of the present invention are described.
In addition, in this specification, magnesium oxide is sometimes referred to as “MgO”.
The BET specific surface area of the magnesium oxide particles of the present invention is generally about 7 to about 50 m2/g, and from the viewpoint of improving the tableting problem during tablet manufacturing or improving the tablet strength, it is preferably about 10 to about 45 m2/g, and more preferably about 12 to about 40 m2/g.
In addition, the CAA80/CAA40 of the magnesium oxide particles of the present invention is generally about 2 to about 7, and from the viewpoint of improving the tableting problem during tablet manufacturing and/or improving the tablet strength, it is preferably about 2.2 to about 6, and more preferably about 2.4 to about 5.
In the present invention, “CAA” is an index indicating the activity of magnesium oxide, and is expressed by the time required for citric acid to react with a specified amount of magnesium oxide. In addition, CAA80 represents the time required for 80 mol% of the total amount of magnesium oxide added to react after a predetermined amount of magnesium oxide is added to citric acid, and similarly, CAA40 represents the time required for 40 mol% of the total amount of magnesium oxide added to react after a predetermined amount of magnesium oxide is added to citric acid. For specific measurement methods, reference can be made to the description of the embodiments described below.
In addition, “CAA80/CAA40” represents the ratio of CAA80 to CAA40.
In addition, regarding CAA, Japanese Patent Publication No. 7-187662 describes the measurement of the activity of magnesium oxide by the same method.
In one embodiment of the present invention, the BET specific surface area of the magnesium oxide particles is about 7 to about 50 m2/g, and CAA80/CAA40 is about 2 to about 7. From the viewpoint of improving tableting problems in tablet manufacturing and/or improving tablet strength, preferably, the BET specific surface area is about 10 to about 45 m2/g, and CAA80/CAA40 is about 2.2 to about 6, and more preferably, the BET specific surface area is about 12 to about 40 m2/g, and CAA80/CAA40 is about 2.4 to about 5.
In addition, in another embodiment of the present invention, the bulk density of the magnesium oxide particles is not particularly limited as long as the tableting problem or tablet strength is improved, and is preferably about 700 to about 1000 g/L, and more preferably about 750 to about 990 g/L.
In addition, in the present invention, the “bulk density” is the bulk density specified in the Japanese Pharmacopoeia.
In a preferred embodiment of the present invention, the BET specific surface area of the magnesium oxide particles is about 7 to about 50 m2/g, CAA80/CAA40 is about 2 to about 7, and the bulk density is about 700 to about 1000 g/L.
Furthermore, in one embodiment of the present invention, the particle size of the magnesium oxide particles is not particularly limited as long as the tableting problem or tablet strength is improved, and the particles with a particle size of less than 150 μm are generally less than about 10% by weight of the whole, preferably less than about 9% by weight, and more preferably less than about 8% by weight.
In addition, the average particle size of the magnesium oxide particles is not particularly limited, for example, it is generally about 150 to about 425 μm, and from the perspective of improving the tableting problem or tablet strength, it is preferably about 180 to about 400 μm, and more preferably about 200 to about 380 μm. In addition, as for the method for measuring the particle size of the magnesium oxide particles, any method can be used as long as it is a method commonly used in the art. Regardless of the value obtained by any measuring method, as long as it falls within the above range, it is within the technical scope of the present invention.
In another embodiment of the present invention, from the perspective of use for medicine or food additives, the purity (detection) of the magnesium oxide particles is preferably about 96% or more, more preferably about 96.5% or more, and particularly preferably 97% or more.
In addition, in the present invention, the purity (detection) of the magnesium oxide particles is a value determined in accordance with the United States Pharmacopeia (USP). Specifically, it is obtained by measuring 0.5 g of magnesium oxide that is calcined at 800°C to a constant weight, adding 30 mL of 1N sulfuric acid to dissolve it, and titrating the solution with 1N sodium hydroxide.
In addition, in a preferred embodiment of the present invention, regarding the magnesium oxide particles, the content of lead (Pb) is about 20 ppm or less and the content of arsenic (As) is about 4 ppm or less in the total weight of the magnesium oxide particles, and more preferably, the content of Pb is about 10 ppm or less and the content of As is about 3 ppm or less. As long as it is such magnesium oxide particles, it can be safely used as medicine or food additives.
Next, the method for producing the magnesium oxide particles of the present invention is described.
The magnesium oxide used in the production of the magnesium oxide particles of the present invention can be produced according to a known method, a method known per se, or a method based on these methods.
In one embodiment of the present invention, the magnesium oxide is produced by calcining magnesium hydroxide. In addition, the method for producing magnesium hydroxide used in the present invention has been sufficiently determined in the past, and thus the present invention can also follow this production method. In addition, commercially available products can also be used for magnesium hydroxide.
In one embodiment of the present invention, when the magnesium hydroxide is calcined to produce magnesium oxide, it is preferred to produce magnesium oxide with different activities by changing the calcination temperature of magnesium hydroxide.
Here, in the present invention, magnesium oxide obtained by calcining magnesium hydroxide at a calcination temperature of about 1000°C to about 2000°C is referred to as “low-activity magnesium oxide”, and magnesium oxide obtained by calcining at a calcination temperature of about 450°C to about 900°C is referred to as “medium-activity magnesium oxide”. In addition, the calcination time is not particularly limited, for example, it is usually about 30 minutes to about 5 hours, preferably about 1 hour to about 3 hours.
The BET specific surface area of the low-activity magnesium oxide is preferably about 0.05 to about 15 m2/g, and more preferably about 0.1 to about 10 m2/g. In addition, the CAA80 of the low-activity magnesium oxide is preferably about 550 to about 850 seconds, more preferably about 600 to about 800 seconds, and the CAA40 is preferably about 250 to about 550 seconds, more preferably about 300 to about 500 seconds.
The BET specific surface area of the medium-activity magnesium oxide is preferably about 20 to about 80 m2/g, more preferably about 25 to about 75 m2/g. In addition, the CAA80 of the medium-activity magnesium oxide is preferably about 100 to about 300 seconds, more preferably about 100 to about 250 seconds, and the CAA40 is preferably about 50 to about 100 seconds, more preferably about 60 to about 95 seconds.
In the present invention, the method for measuring the BET specific surface area is not particularly limited as long as it is a method commonly used in the art. Regardless of the value obtained by which measurement method, as long as it falls within the above range, it is within the technical scope of the present invention. Regarding the method for measuring the BET specific surface area, specifically, for example, a BET specific surface area measuring device can be used to measure the measurement sample (magnesium oxide particles) that has been subjected to a heat treatment in a nitrogen atmosphere as a pretreatment by a nitrogen adsorption method. The pretreatment can be performed at about 130°C for about 30 minutes in a nitrogen atmosphere, for example. The device used for the pretreatment and the BET specific surface area measuring device are not particularly limited, and any device commonly used in the art can be used.
In a preferred embodiment of the present invention, preferably, the magnesium oxide particles are prepared by mixing the low-activity magnesium oxide and the medium-activity magnesium oxide and crushing them after applying pressure. In this embodiment, the mixing ratio of low-activity magnesium oxide and medium-activity magnesium oxide is not particularly limited. From the perspective of making the physical properties of the obtained magnesium oxide particles become the desired values, it is usually preferably in the range of medium-activity magnesium oxide: low-activity magnesium oxide = 10:90 to 80:20 in terms of weight %. In addition, the above-mentioned mixing ratio can be appropriately selected so that the obtained magnesium oxide particles have the desired physical properties. If the proportion of low-activity magnesium oxide is increased, the bulk density and purity will increase, but the BET specific surface area and tablet strength will decrease.
In the manufacture of the magnesium oxide particles, the conditions for pressurizing the mixture of low-activity magnesium oxide and medium-activity magnesium oxide are not particularly limited, and are generally about 5 to about 35 MPa. From the perspective of obtaining magnesium oxide particles with desired physical properties, it is preferably about 8 to about 30 MPa, and more preferably about 10 to about 25 MPa. In addition, the device used for pressurization is not particularly limited, and for example, a roller press can be used.
In addition, the crushing method in the crushing process after pressurization is not particularly limited, and for example, a granulator can be used for crushing. As the granulator, it is not particularly limited, and for example, a roller granulator can be cited. The crushing method can be specifically a method of using a roller granulator with three-stage rollers installed vertically, and passing the pressurized magnesium oxide through the gap between the rotating rollers to crush it.
The scope of the rights of the present invention also includes magnesium oxide tablets containing the magnesium oxide particles. The manufacturing method of tablets has been well established in the past, so in the present invention, the manufacturing of tablets can also be based on these methods. Specifically, for example, the magnesium oxide tablet of the present invention can be manufactured by combining the magnesium oxide particles, a binder, and a disintegrant. By using the magnesium oxide particles of the present invention, the occurrence of tableting problems such as top cracking, waist cracking, sticking, and adhesion during tableting is reduced.
As the binder, it is not particularly limited, and for example, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, crystalline cellulose, or starch (such as corn starch) can be cited. In addition, as the disintegrant, it is not particularly limited, and for example, calcium carboxymethyl cellulose, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, or sodium carboxy starch can be cited. The amount of the binder is not particularly limited, and for example, it can be about 1 to about 10% by weight in the tablet, preferably about 1 to about 8% by weight. In addition, the amount of the disintegrant is not particularly limited, and for example, it can be about 1 to about 10% by weight in the tablet, and preferably about 1 to about 5% by weight.
In addition, the tablet may further contain excipients, lubricants, and the like. The excipient is not particularly limited, and examples thereof include lactose, white sugar, mannitol, corn starch or crystalline cellulose. In addition, the lubricant is not particularly limited, and examples thereof include sucrose fatty acid esters, polyethylene glycol, talc, stearic acid or stearates (Na, Mg or Ca salts), etc.
Further, the tablet may contain one or more additives such as plasticizers, coating agents, anticoagulants, solubilizers, sweeteners, acidulants, flavoring agents, pH regulators, dissolution aids, colorants or flavors as desired. Examples of the plasticizer include triethyl citrate, glycerol fatty acid esters, polyethylene glycol, etc. Examples of the coating agent include ethyl cellulose, hydroxypropyl methylcellulose, etc. Examples of the anticoagulant include talc, calcium stearate, etc. Examples of the solubilizer include sucrose fatty acid esters, sorbitan monostearate, sodium lauryl sulfate, etc. As the sweetener, for example, aspartame, saccharin, dipotassium glycyrrhizinate, stevia, etc. can be cited. As the acidulant (organic acid), for example, citric acid, malic acid, ascorbic acid, fumaric acid, etc. can be cited. As the flavoring agent, for example, l-menthol, sodium chloride, acesulfame potassium, sucralose, etc. can be cited. As the pH adjuster, for example, citrate, phosphate, carbonate, acetate, etc. can be cited. As the dissolution aid, for example, cyclodextrin, arginine, lysine, triaminomethane, etc. can be cited. As the colorant, for example, yellow ferric oxide, ferric oxide, sodium copper chlorophyllin, etc. can be cited. As the flavoring agent, for example, orange oil, lemon oil, mint oil, eucalyptus oil, etc. can be cited.
From the viewpoint of improving quality characteristics, the strength of the tablet of the present invention is preferably about 60N to about 200N.
In addition, in a preferred embodiment of the present invention, the tablet is preferably an orally disintegrating tablet. In the present embodiment, the disintegration time of the tablet in the oral cavity is not particularly limited, and is, for example, generally about 1 to about 60 seconds, preferably about 5 to 45 seconds, and more preferably about 5 to 20 seconds.
Examples
The present invention is further specifically described below by way of experimental examples and examples, but the present invention is not limited to these examples and can be modified in various ways by a person having ordinary knowledge in the art within the technical concept of the present invention.
<CAA measurement method>
(1) Adjust 100 mL of 0.4 N citric acid to 30°C.
(2) Add 1 drop of phenolphthalein solution to the citric acid in (1).
(3) After adding magnesium oxide particles to the solution in (2), stir the solution by rotating a magnetic stirrer at 550 rpm.
(4) After starting stirring, measure the time required for the color of the measurement solution to change from colorless to purple-red, and take the time (seconds) as the CAA value.
※When measuring CAA40, 0.05 mol of the above magnesium oxide particles are added for measurement. When 0.02 mol of magnesium oxide particles (40% of the total) react, the color of the measurement solution changes from colorless to purple-red. In addition, when measuring CAA80, the addition amount of the above-mentioned magnesium oxide particles was set to 0.025 mol for measurement.
<Method for measuring purity>
The purity of magnesium oxide particles was measured in accordance with the United States Pharmacopeia (USP).
<Method for measuring bulk density>
The measurement was performed in accordance with the first method of the bulk density measurement method of the Japanese Pharmacopeia.
<Method for measuring Pb and As content>
The measurement was performed by ICP-MS. Specifically, the sample (magnesium oxide particles) was dissolved in 7N nitric acid, and the sample solution was diluted with pure water, and then measured using a SPQ-9000 coaxial nebulizer (manufactured by Seiko Instruments Inc.). A calibration curve was prepared using standard samples of Pb and As, and the contents of Pb and As in the magnesium oxide particles were calculated by the calibration curve method.
<Tableting method and tablet strength measurement method>
(1) Using a tablet press (HATA: HT-AP18SS-II Model No. 750), 300 mg of magnesium oxide particles to which 4 to 10% by weight of a binder are added are subjected to a pressure of 5 MPa to form a tablet having a thickness of 4 mm. Starch is used as the binder.
(2) The tablet strength of the formed tablet is measured using a tablet breaking strength tester (Toyama Industry: TH303MP).
<Reference Example 1> Preparation of medium-active magnesium oxide
Using an electric furnace, magnesium hydroxide (manufactured by Shinjima Chemical Industry Co., Ltd., grade name: #200) is calcined at 900°C for 2 hours to produce medium-active magnesium oxide. The BET specific surface area of the medium-active magnesium oxide thus obtained is 51 m2/g.
<Reference Example 2> Manufacture of low-activity magnesium oxide
Using an electric furnace, magnesium hydroxide (produced by Shinjima Chemical Industry Co., Ltd., grade name: #200) was calcined at 1100°C for 2 hours to produce low-activity magnesium oxide. The BET specific surface area of the low-activity magnesium oxide thus obtained was 3m2/g.
<Example 1>
Using a horizontal roller press made by FREUND TURBO, a mixture of medium-activity magnesium oxide (hereinafter referred to as medium-activity MgO) with a BET specific surface area of 51m2/g produced in Reference Example 1 and low-activity magnesium oxide (hereinafter referred to as low-activity MgO) with a BET specific surface area of 3m2/g produced in Reference Example 2 was mixed in a ratio of medium-activity MgO: low-activity MgO = 80:20 (weight %) and a roller pressure of 10MPa was applied. Thereafter, the mixture was crushed using a granulator (produced by Japan Granulator Co., Ltd., model: GRN1031).
After crushing, the particles were sieved using a vibrating screen (20 mesh and 60 mesh) to remove particles larger than 20 mesh and smaller than 60 mesh, thereby preparing magnesium oxide particles.
<Example 2>
Except that the mixing ratio of medium-activity MgO to low-activity MgO was 60:40 (weight %), magnesium oxide particles were prepared in the same manner as in Example 1.
<Example 3>
Except that the mixing ratio of medium-activity MgO to low-activity MgO was 40:60 (weight %), magnesium oxide particles were prepared in the same manner as in Example 1.
<Example 4>
Except that the mixing ratio of medium-activity MgO to low-activity MgO was 20:80 (weight %), magnesium oxide particles were prepared in the same manner as in Example 1.
<Example 5>
Except that the mixing ratio of medium-activity MgO to low-activity MgO was 10:90 (weight %), magnesium oxide particles were prepared in the same manner as in Example 1.
<Comparative Example 1>
Except that only medium-activity MgO was used, magnesium oxide particles were prepared in the same manner as in Example 1.
<Comparative Example 2>
Except that only low-activity MgO was used, magnesium oxide particles were prepared in the same manner as in Example 1.
<Comparative Example 3>
Except that magnesium oxide having a BET specific surface area of 22 m2/g was used, magnesium oxide particles were prepared in the same manner as in Example 1.
The physical properties of the magnesium oxide particles, tablet strength, and the presence or absence of tableting problems are shown in Table 1.
The magnesium oxide particles of Examples 1 to 4, which are embodiments of the present invention, do not have problems such as sticking and capping during tableting, and the strength of the obtained tablets is sufficient.
Industrial Applicability
The magnesium oxide particles of the present invention can reduce tableting problems in the manufacture of magnesium oxide tablets, and can reduce abnormal quality characteristics of magnesium oxide tablets caused by insufficient tablet strength, thereby significantly improving the manufacturing efficiency of magnesium oxide tablets. Furthermore, the magnesium oxide particles of the present invention have a low content of heavy metals and a high purity of magnesium oxide, so according to the present invention, a safe magnesium oxide particle suitable for use as a medicine or food additive can be provided.