Tablet and method for producing the same

Abstract

To provide a novel tablet that offers sufficient hardness while containing lactoferrin, lactoperoxidase, and whey protein, and a method for producing the same.SOLUTION: The present invention provides a tablet containing, in total, 75% (w / w) or more of lactoferrin, lactoperoxidase, whey protein, hydroxypropyl methylcellulose, and hydroxypropyl cellulose, the tablet having a hardness of 10 kgf or more in an uncoated state. The present invention also provides a method for producing a tablet, the method comprising the steps of: mixing lactoferrin, lactoperoxidase, and whey protein; granulating the resulting mixture to prepare granules; mixing hydroxypropyl methylcellulose and hydroxypropyl cellulose with the granules such that the combined amount of lactoferrin, lactoperoxidase, whey protein, hydroxypropyl methylcellulose, and hydroxypropyl cellulose reaches 75% (w / w) or more; and tableting the resulting mixture.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a tablet and a method for producing the same. [Background technology]

[0002] Lactoferrin is a harmless and natural iron-binding protein found in tears, saliva, peripheral blood, milk, etc., and is known to have antibacterial properties against harmful microorganisms such as Escherichia coli, Candida, and Clostridium. Generally, tablets are used in many medicines, health foods, etc., because they are easy to take as a single unit of measurement, are easy to administer, and are relatively easy to manufacture. Although tablets containing lactoferrin are also commercially available, they have a very low hardness and are a major problem in terms of tablet strength (for example, International Publication No. 98 / 030235 (Patent Document 1), page 4, lines 15-17, states that "considering commercially available lactoferrin-containing tablets, their hardness is an average of about 3.1 kg in the horizontal direction and about 1.6 kg in the vertical direction, which is very low and is a major problem in terms of tablet strength."

[0003] It is known that when tablets are manufactured by granulating a mixture of tablet raw materials and compressing the granules, the hardness increases compared to when the powder raw materials are directly compressed. However, on page 4, lines 21-24 of Patent Document 1, it is stated that "The inventors also granulated a mixture of all the raw materials for the tablets or a mixture of a portion of the tablet raw materials to form granules, and attempted to compress the tablets by conventional methods. In this case, the hardness increased compared to when the powder raw materials were directly compressed, and an improvement in tablet strength was observed, but it was still insufficient to produce stable tablets that could withstand distribution as a product."

[0004] Furthermore, WO 2016 / 163463 (Patent Document 2) and Japanese Patent No. 65890979 (Patent Document 3) state that tablets containing high concentrations of lactoferrin need to be compressed at high pressure to reduce tablet friability because the binding strength of lactoferrin powder is low. However, tablets molded at high pressure tend to have lower disintegration properties than tablets compressed at low pressure, taking advantage of the binding strength of the powder, and tablets containing high concentrations of powder with low binding strength such as lactoferrin inevitably have the problem of poor disintegration properties (paragraph

[0003] of Patent Document 2, paragraph

[0003] of Patent Document 3).

[0005] This kind of lactoferrin is combined with lactoperoxidase and whey protein to provide dietary supplements in tablet form, but still, even when powder raw materials are directly compressed into tablets, and even when a mixture of tablet raw materials is granulated and then compressed into tablets, it is not possible to obtain tablets with sufficient hardness to be practical.In addition, enteric coated tablets and capsule tablets have also been attempted, but there are cases where they do not dissolve in the body and are excreted together with feces. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] WO 98 / 030235 [Patent Document 2] International Publication No. 2016 / 163463 [Patent Document 3] Patent No. 65890979 Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention has been made to solve the above problems, and an object of the present invention is to provide a novel tablet that contains lactoferrin, lactoperoxidase and whey protein and has sufficient hardness, and a method for producing the same. [Means for solving the problem]

[0008] The tablet of the present invention is characterized by containing lactoferrin, lactoperoxidase, whey protein and hydroxypropylmethylcellulose in a total amount of 65% (w / w) or more and having a hardness of 10 kgf or more in the uncoated tablet form.

[0009] The tablet of the present invention further contains a binder, and the total content of lactoferrin, lactoperoxidase, whey protein, hydroxypropylmethylcellulose and binder is preferably 75% (w / w) or more.

[0010] The binder in the tablets of the present invention is preferably hydroxypropyl cellulose.

[0011] The tablet of the present invention preferably has both gastric and enteric properties.

[0012] The present invention also provides a method for producing tablets, comprising the steps of mixing lactoferrin, lactoperoxidase, and whey protein to obtain a first mixture, granulating the first mixture to obtain a granulated product, mixing the granulated product with hydroxypropyl methylcellulose so that the total amount of lactoferrin, lactoperoxidase, whey protein, and hydroxypropyl methylcellulose is 65% (w / w) or more to obtain a second mixture, and compressing the second mixture into tablets.

[0013] In the method for producing tablets of the present invention, in the step of obtaining a second mixture, it is preferable to mix hydroxypropyl methylcellulose and a binder with the granulated material so that the total amount of lactoferrin, lactoperoxidase, whey protein, hydroxypropyl methylcellulose and the binder is 75% (w / w) or more.

[0014] In the tablet manufacturing method of the present invention, the binder is preferably hydroxypropyl cellulose. Effect of the Invention

[0015] According to the present invention, there are provided a novel tablet which contains lactoferrin, lactoperoxidase and whey protein and yet has sufficient hardness, and a method for producing the same. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] [1] Tablets The tablet of the present invention is characterized by containing lactoferrin, lactoperoxidase, whey protein and hydroxypropyl methylcellulose in a total amount of 65% (w / w) or more. By containing lactoferrin, lactoperoxidase, whey protein and hydroxypropyl methylcellulose in a total amount of 65% (w / w) or more, the number of tablets taken at one time can be reduced, and the burden on consumers can be reduced. On the other hand, when the total amount of lactoferrin, lactoperoxidase, whey protein and hydroxypropyl methylcellulose is less than 65% (w / w), the tablet can be manufactured by a known method, and the problem of the difficulty of tableting caused by the high content of lactoferrin, lactoperoxidase, whey protein and hydroxypropyl methylcellulose does not occur in the first place. The total amount of lactoferrin, lactoperoxidase, whey protein and hydroxypropyl methylcellulose in the tablet of the present invention is preferably 70% (w / w) or more, more preferably 75% (w / w) or more. In addition, the total of lactoferrin, lactoperoxidase, whey protein and hydroxypropyl methylcellulose in the tablet of the present invention is not particularly limited in its upper limit, but since a manufacturing aid is required for the purpose of ensuring the minimum fluidity and preventing static electricity in manufacturing the tablet, it is preferably 85% (w / w) or less, more preferably 80% (w / w) or less.In addition, the total of lactoferrin, lactoperoxidase, whey protein and hydroxypropyl methylcellulose is 65% (w / w) or more from the tablet, for example, lactoferrin can be quantitatively analyzed by known quantitative analysis using high performance liquid chromatography (https: / / www.pref.chiba.lg.jp / sanken / kenkyuu / library / r03 / documents / citri19-p03-4pp.pdf), and hydroxypropyl methylcellulose can be quantitatively analyzed by utilizing the hypromellose quantitative analysis method listed in the Japanese Pharmacopoeia.Although lactoperoxidase and whey protein cannot be directly quantitatively analyzed, the total amount of protein can be calculated by the protein analysis method using the Kjeldahl method or the combustion method, and the combined amount of lactoperoxidase and whey protein can be confirmed by subtracting the result of the lactoferrin analysis mentioned above.

[0017] The tablet of the present invention is also characterized in that the hardness of the uncoated tablet is 10 kgf or more. The term "uncoated tablet" refers to a tablet that has been compressed by a tablet press and has not been coated on the surface. Here, the hardness is the hardness in the lateral direction (the direction in which the tablet can be compressed relative to the diameter) measured, for example, in accordance with the provisions of the Japanese Pharmacopoeia. Specifically, the hardness can be suitably measured using a Kiya hardness tester KHT-20N (manufactured by Fujiwara Seisakusho Co., Ltd.). The tablet of the present invention preferably has a hardness of 12 kgf or more in the uncoated tablet state in order to prevent surface abrasion caused by impact during transportation within a factory, feeding into a filling and packaging machine or a metal detector, and distribution. In addition, the higher the hardness of the tablet, the better. For reasons such as proper disintegration of the tablet after taking it and prevention of metal wear of the tablet press and tableting punch and die, the hardness of the uncoated tablet of the present invention is preferably 20 gf or less, more preferably 15 kgf or less.

[0018] The tablet of the present invention preferably further comprises a binder, and in this case, the total amount of lactoferrin, lactoperoxidase, whey protein, hydroxypropylmethylcellulose and binder is preferably 75% (w / w) or more.By making the total amount of lactoferrin, lactoperoxidase, whey protein, hydroxypropylmethylcellulose and binder 75% (w / w) or more, the main component can be tableted at a high concentration, which is advantageous for consumers to minimize the number of pills they take.As binder, for example, hydroxypropylcellulose, pullulan, guar gum, xanthan gum, locust bean gum, gellan gum, gum arabic, etc. can be mentioned, and hydroxypropylcellulose is preferred because it can maintain high stability of physical properties over time. Hydroxypropyl cellulose has various average molecular weights, such as 40000, 100000, 140000, 620000, and 910000, and from the viewpoint of high binding performance in simple mixing, a grade with a molecular weight of 100000 is preferred, and a more preferred grade is a molecular weight of 40000. Furthermore, hydroxypropyl cellulose is classified into particle sizes of 40 to 155 μm, 50 to 80 μm, and 20 μm or less, and 20 μm or less is preferred because it efficiently penetrates into the gaps between particles to exert binding performance.

[0019] The tablet of the present invention preferably has a sustained release of 1 hour or more. Here, "sustained release" means that the disintegration time measured using PTZ AUTO 2EZ (manufactured by Pharma Test Co., Ltd.) is 1 hour or more according to the provisions of the disintegration test method described in the Japanese Pharmacopoeia. According to the present invention, even if lactoferrin, lactoperoxidase and whey protein are used in combination, the tablet has a hardness of 10 kgf or more as a plain tablet, which is not found in conventional lactoferrin-containing tablets, so that a tablet having such sustained release properties while containing lactoferrin can be realized. The tablet of the present invention further preferably has a sustained release of 2 hours or more. In addition, the upper limit of the sustained release of the tablet of the present invention is preferably 18 hours or less, more preferably 12 hours or less, because the release of the component is delayed to prevent it from being excreted in feces.

[0020] The tablet of the present invention is preferably gastric and enteric soluble. Conventional lactoferrin-containing tablets did not have sufficient hardness, so they mainly dissolved only in the stomach. On the other hand, enteric coated tablets and capsule tablets have been tried, but there have been cases where they did not dissolve in the body and were excreted as is with the feces. The present invention realizes a lactoferrin-containing tablet that dissolves in both the stomach and intestines (has gastric and enteric properties) because the uncoated tablet has a hardness of 10 kfg or more, which is unprecedentedly practical, and preferably has a sustained release property of 1 hour or more.

[0021] The lactoferrin contained in the tablet of the present invention can be suitably used as a commercially available product.The content of lactoferrin in the tablet of the present invention is not particularly limited, as long as the total content of lactoferrin, lactoperoxidase, whey protein and hydroxypropylmethylcellulose is 65% (w / w) or more as mentioned above.

[0022] The lactoperoxidase contained in the tablet of the present invention can also be suitably used as a commercially available product.The content of lactoperoxidase in the tablet of the present invention is not particularly limited, as long as the total of lactoferrin, lactoperoxidase, whey protein and hydroxypropylmethylcellulose is 65% (w / w) or more as mentioned above.

[0023] The whey protein contained in the tablet of the present invention can also be suitably used as commercially available products.The whey protein content in the tablet of the present invention is not particularly limited, as long as the total content of lactoferrin, lactoperoxidase, whey protein and hydroxypropylmethylcellulose is 65% (w / w) or more as mentioned above.

[0024] The hydroxypropyl methylcellulose contained in the tablet of the present invention can also be suitably used as a commercially available product. The content of hydroxypropyl methylcellulose in the tablet of the present invention is not particularly limited as long as the total of lactoferrin, lactoperoxidase, whey protein and hydroxypropyl methylcellulose is 65% (w / w) or more as described above, but is preferably within the range of 1-20% (w / w), more preferably within the range of 5-15% (w / w). When the content of hydroxypropyl methylcellulose in the tablet of the present invention is less than 1% (w / w), the tablet tends not to have sufficient effect of extending the disintegration time of the tablet, i.e., sustained release, while when the content of hydroxypropyl methylcellulose in the tablet of the present invention is more than 20% (w / w), the powder compression moldability during tableting is poor, and the tablet hardness tends to decrease.

[0025] The tablet of the present invention may contain additives such as excipients, flow improvers, and lubricants that are generally used in the formulation of tablets for normal oral administration, within the range that does not inhibit the effects of the present invention. Examples of excipients include maltitol, lactose, xylitol, erythritol, sorbitol, maltose, lactitol, crystalline cellulose, powdered cellulose, and dextrin. Examples of flow improvers include tricalcium phosphate, fine silicon dioxide, milk calcium, seaweed calcium, scallop powder, oyster shell powder, and bone powder. Examples of lubricants include calcium stearate, magnesium stearate, sucrose fatty acid esters, powdered oils and fats, and glycerin fatty acid esters.

[0026] [2] Tablet manufacturing method The present invention also provides a method for producing tablets, which comprises the steps of: mixing lactoferrin, lactoperoxidase, and whey protein to obtain a first mixture; granulating the first mixture to obtain a granulated product; mixing hydroxypropyl methylcellulose with the granulated product so that the total amount of lactoferrin, lactoperoxidase, whey protein, and hydroxypropyl methylcellulose is 65% (w / w) or more to obtain a second mixture; and compressing the second mixture. By using the method for producing tablets of the present invention, it becomes possible to produce tablets having sufficient hardness, which have been difficult to obtain by directly compressing lactoferrin, lactoperoxidase, whey protein, and hydroxypropyl methylcellulose that are mixed in a total amount of 65% (w / w) or more and have poor fluidity and compressibility.

[0027] In the tablet manufacturing method of the present invention, first, lactoferrin, lactoperoxidase and whey protein are mixed to obtain a first mixture.Here, other than lactoferrin, lactoperoxidase and whey protein, appropriate additives may be mixed within the range that does not inhibit the effect of the present invention.

[0028] Next, the first mixture is granulated. The granulation conditions are not particularly limited, but for example, a fluidized bed granulation dryer FLOW COATER FLO-5A (manufactured by Freund Corporation) is used, with an intake air temperature of 90°C, an exhaust air temperature of 39.7 to 62.3°C, and an air volume of 0.8 m 3 The powder is granulated by spraying water at a spray air pressure of 0.2 MPa at a condition of 1000 / min. In the tablet manufacturing method of the present invention, lactoferrin, lactoperoxidase and whey protein are mixed and granulated in the state before mixing with hydroxypropylmethylcellulose. The particle size of the obtained granulated product is not particularly limited, but in order to ensure the flowability suitable for feeding to a tablet press and to increase the hardness of the tablet, the ratio of particles passing through a 100 sieve is preferably within the range of 40% to 70% and the ratio of particles passing through a 140 sieve is preferably within the range of 10% to 50%.

[0029] Next, hydroxypropyl methylcellulose is mixed with granules so that the total amount of lactoferrin, lactoperoxidase, whey protein and hydroxypropyl methylcellulose is more than 65% (w / w) to obtain second mixture.Here, if the total amount of lactoferrin, lactoperoxidase, whey protein and hydroxypropyl methylcellulose is more than 65% (w / w), suitable additives can be mixed in this step as long as they do not inhibit the effect of the present invention.

[0030] In the tablet manufacturing method of the present invention, in the step of obtaining this second mixture, it is preferred to mix hydroxypropyl methylcellulose and binder with granule so that the total amount of lactoferrin, lactoperoxidase, whey protein, hydroxypropyl methylcellulose and binder is 75% (w / w) or more.In this case, it is preferred to use hydroxypropyl cellulose as binder.

[0031] Finally, the obtained second mixture is compressed into tablets. The conditions for the compression are not particularly limited, but for example, the tablet is compressed using a rotary tablet press HT-GS18SS-U (manufactured by Hata Iron Works Co., Ltd.) under the following conditions: punch size: diameter 8 mm (curvature radius: 6.5 mm), compression pressure: 7 to 10 kN, and rotation speed: 35 rpm.

[0032] In addition, the above-mentioned tablet of the present invention is not limited to one manufactured by such a tablet manufacturing method of the present invention, but it is preferable that the tablet is manufactured by the tablet manufacturing method of the present invention.

[0033] The present invention will be described in more detail below with reference to experimental examples, but the present invention is not limited to these.

[0034] <Experimental Example 1> First, lactoferrin (derived from milk), whey protein concentrate, lactoperoxidase, maltitol 42.48mg / 3 tablets, and tricalcium phosphate 3.75mg / 3 tablets were weighed out to a total weight of 1.2kg and mixed to obtain a first mixture (total ratio: 446.25mg / 3 tablets, total weight: 1.2kg).Then, the first mixture was dried in a fluidized bed granulation dryer FLOW COATER FLO-5A (manufactured by Freund Corporation) at an intake temperature of 90℃, an exhaust temperature of 39.7-62.3℃, and an air volume of 0.8m. 3 The powder was granulated by spraying 500 mL of water onto the flowing powder at a spray air pressure of 0.2 MPa under the conditions of 10 ...

[0035] Next, hydroxypropyl methylcellulose was weighed out at a ratio of 112.5 mg / 3 tablets, tricalcium phosphate at 11.25 mg / 3 tablets, calcium stearate at 7.5 mg / 3 tablets, crystalline cellulose at 75 mg / 3 tablets, milk calcium at 22.5 mg / 3 tablets, and hydroxypropyl cellulose at 75 mg / 3 tablets, with a total weight of 800 g, and mixed with the obtained granules to obtain a second mixture (total amount: 750 mg / 3 tablets, total weight 800 g). The physical properties of the second mixture are as shown in Table 1.

[0036] The second mixture was compressed into tablets using a rotary tablet press HT-GS18SS-U (Hata Steel Works, Ltd.) under the following conditions: punch size: diameter 8 mm (curvature radius: 6.5 mm), compression pressure: 7-10 kN, and rotation speed: 35 rpm, to produce approximately 2,000 uncoated tablets of 250 mg and diameter 8 mm. The resulting tablets each contain 68.336% (w / w) of lactoferrin, whey protein, and hydroxypropyl methylcellulose in total.

[0037] The following physical properties of the obtained tablets were measured.

[0038] ·Moisture content The weight loss at 80°C was measured as the moisture content using an electronic moisture meter MA35M (manufactured by Sartorius Japan Co., Ltd.).

[0039] Bulk density The measurements were made in accordance with the provisions of the Japanese Industrial Standards (JIS) using a bulk density measuring device (manufactured by Tsutsui Rikagaku Kikai Co., Ltd.).

[0040] ·Particle size For the second mixture before tableting, JIS sieves (standard number: JIS Z8801, No. 30, No. 42, No. 60, No. 83, No. 100, No. 140, No. 200) are stacked in order with the smaller number on top, and 10 g of sample is provided on the top No. 30 sieve. Then, all are set in an electromagnetic sieve vibrator AS200 Control (Recce), and run for 1 minute with a vibration intensity of 1.5 mm / g, and the amount remaining on each sieve is measured. Particle size% = 100 x amount remaining on each sieve (g) / 10g It was calculated as:

[0041] Weight (average of 10 tablets) Measurements were performed using an electronic balance QUINTIX513-1S (manufactured by Sartorius Japan Co., Ltd.).

[0042] Tablet thickness (average of 10 tablets) The measurement was performed using a digital thickness gauge M0-10 (manufactured by Monotaro).

[0043] Hardness (average of 10 tablets) In accordance with the tablet hardness regulations of the Japanese Pharmacopoeia, the lateral hardness was measured using a Kiya hardness tester KHT-20N (manufactured by Fujiwara Seisakusho Co., Ltd.).

[0044] Disintegration time (average of 6 tablets) The measurements were carried out in accordance with the provisions of the disintegration test method prescribed in the Japanese Pharmacopoeia using a PTZ AUTO 2EZ (Pharma Test).

[0045] The results are shown in Table 1.

[0046] [Table 1]

[0047] <Comparative Experiment Example 1> When the same ingredients as in Experimental Example 1 were mixed in a formulation and compressed directly into tablets without going through the steps of obtaining the first mixture and granules, the fluidity and compressibility were poor, and tablets with sufficient hardness were not obtained (hardness: 4 to 7 kgf). In addition, the weight fluctuated greatly, and the target weight of 250 mg per tablet could not be achieved.

[0048] The embodiments disclosed herein should be considered to be illustrative and not restrictive in all respects. The scope of the present invention is defined by the claims, not the above description, and is intended to include all modifications within the meaning and scope of the claims.

Claims

1. A tablet containing lactoferrin, lactoperoxidase, whey protein and hydroxypropyl methylcellulose in a total amount of 65% (w / w) or more, and having a hardness of 10 kgf or more in the uncoated form.

2. 2. The tablet according to claim 1, further comprising a binder, wherein the total of lactoferrin, lactoperoxidase, whey protein, hydroxypropyl methylcellulose and the binder is 75% (w / w) or more.

3. 3. The tablet of claim 2, wherein the binder is hydroxypropyl cellulose.

4. The tablet according to claim 1, which has both gastric and enteric properties.

5. Mixing lactoferrin, lactoperoxidase and whey protein to obtain a first mixture; granulating the first mixture to obtain a granule; A step of mixing the granules with hydroxypropyl methylcellulose so that the total amount of lactoferrin, lactoperoxidase, whey protein, and hydroxypropyl methylcellulose is 65% (w / w) or more to obtain a second mixture; and compressing the second mixture into a tablet.

6. The method for producing tablets according to claim 5, wherein in the step of obtaining the second mixture, hydroxypropyl methylcellulose and a binder are mixed with the granulated material so that the total amount of lactoferrin, lactoperoxidase, whey protein, hydroxypropyl methylcellulose and the binder is 75% (w / w) or more.

7. The method for producing a tablet according to claim 6, wherein the binder is hydroxypropyl cellulose.

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