JP5828280B2 - Tablet and production method thereof - Google Patents

Description

  The present invention relates to a tablet containing acetaminophen.

  Acetaminophen is an excellent drug as an antipyretic analgesic, but has a bitter taste and needs to be masked in order to improve the dosage. As a masking method for unpleasant taste, a method of adding a sweetener or a corrigent, a matrix method of dispersing a drug in a carrier by spray-drying a liquid in which a gastric or water-insoluble polymer is suspended or dissolved, A coating method in which a nucleus containing a drug is coated with a film containing a gastric polymer or a water-insoluble polymer is mainly known.

  However, even if the coated particles are coated (masked) with acetaminophen, if they are tableted to prepare a tablet, the coating film may be destroyed and bitterness may be felt when taken, achieving the desired masking effect. The result will be poorly taken. In particular, orally disintegrating tablets and chewable tablets disintegrate in the oral cavity after ingestion, and thus can be taken without water, but the above bitter taste is very easily felt. In view of the above, there has been a demand for a tablet that can suppress the bitter taste of acetaminophen during taking even if the tablet is prepared by tableting.

JP 2000-7556 A

  This invention is made | formed in view of the said situation, and it aims at providing the manufacturing method of the tablet containing acetaminophen which is excellent in the acetaminophen bitterness masking effect in taking. As another problem, improvement of disintegration property in the mouth, and a problem of the production method include suppression of the adhesion of the preparation to the equipment during tableting.

  As a result of intensive studies to achieve the above object, the present inventors have used (A) acetaminophen-containing coated particles and (B) granulated particles having a particle diameter of 150 to 600 μm containing sugar alcohol and starch. It was found that a tablet excellent in acetaminophen bitterness masking effect during administration can be obtained by making the tablet to be used. Moreover, it discovered that it was excellent also in the disintegration property in a mouth by adjusting the mixing | blending mass ratio of the sugar alcohol: starch in (B) particle | grains.

  And by mixing the said (A) component and the (B) component and tableting, while obtaining the said tablet, adhesion of the formulation to the equipment at the time of tableting which is the subject at the time of manufacture, especially a wrinkle It has been found that it can be suppressed, and has led to the present invention.

Accordingly, the present invention provides the following tablets and tablet production methods.
[1]. A tablet comprising (A) acetaminophen-containing coated particles and (B) granulated particles having a particle diameter of 150 to 425 μm containing mannitol and starch.
[2]. (B) a sugar alcohol in the component: mixing mass ratio of the starch, 96: 4-75: 25 [1] The tablet according.
[3]. (A) The tablet according to [1] or [2], wherein the compounding amount of the particles is 20 to 70% by mass in the tablet, and (B) the compounding amount of the particles is 40 to 75% by mass in the tablet .
[4]. (A) The tablet in any one of [1]-[3] whose average particle diameter of a component is 50-600 micrometers.
[ 5 ]. The tablet according to any one of [1] to [4], further comprising (C) a fragrance and / or a sweetener.
[ 6 ]. The tablet according to any one of [1] to [ 5 ], which is an orally disintegrating tablet.
[ 7 ]. (A) A manufacturing method of a tablet in which acetaminophen-containing coated particles and (B) granulated particles having a particle diameter of 150 to 425 μm containing mannitol and starch are mixed, and the mixture is tableted.

  ADVANTAGE OF THE INVENTION According to this invention, the tablet containing an acetaminophen excellent in the acetaminophen bitterness masking effect in taking can be obtained. Moreover, the tablet containing acetaminophen which is excellent also in the disintegration property in the mouth can be obtained by adjusting the blending mass ratio of (B) sugar alcohol: starch in the particles. Furthermore, the manufacturing method of the tablet containing an acetaminophen which can suppress adhesion of the formulation to the equipment at the time of tableting, especially a wrinkle can be provided.

Hereinafter, the present invention will be described in detail.
The tablet of the present invention comprises (A) acetaminophen-containing coated particles and (B) granulated particles having a particle diameter of 150 to 600 μm containing sugar alcohol and starch.

(A) Acetaminophen-containing coated particles (A) The acetaminophen-containing coated particles are not particularly problematic as long as they are coated with acetaminophen, but are preferably coated with a water-insoluble coating agent. Note that “water-insoluble” indicates that the amount dissolved in 10,000 mL of water is 1 g or less than 1 mL. The coating agent that forms the coating film contains a water-insoluble coating component, and can further contain a plasticizer and an antacid.

The average particle child size acetaminophen particles as the core is preferably in a range of from 50 to 600, the range of 100~400μm is more preferable. When the average particle child size is less than 50 [mu] m, the particles are easily granulation proceeds by aggregation of particles occurs because fine, coating becomes uneven, there is a possibility that the taste-masking is poor, whereas, greater than 600μm However, there is no problem with the bitterness masking property, but the roughness becomes strong, and there is a possibility that the doseability may deteriorate.

In the present invention, the average particle and child sizes, 1000μm, 850μm, 500μm, 355μm , 250μm, 150μm, 75μm, 45μm, sieve with a 20μm inner diameter 75mm, and a sample amount 10 g, Japanese Pharmacopoeia "Powder particle size measuring Method ”The particle diameter is 50% of the cumulative mass when the test is conducted based on the second method and measured. Moreover, 50% particle size of the cumulative mass when measured using a laser type scattering diffractometry particle size distribution analyzer (BECKMAN COULTER, Inc.) for an average particle child size by the above measurement method was 100μm or less It was defined as an average particle size of the child.

  Examples of water-insoluble coating components include ethyl cellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, carboxymethyl ethyl cellulose, carboxyvinyl polymer, cellulose acetate phthalate, shellac, purified shellac, methacrylic acid copolymer LD, methacrylic acid copolymer L, Listed products such as methacrylic acid copolymer S, Japanese pharmacopoeia such as acrylate / methyl methacrylate copolymer emulsion, Japanese pharmacopoeia, food additives and the like can be used. These can be used individually by 1 type or in combination of 2 or more types. Of these, ethyl cellulose is preferred from the viewpoint of usability and odor. The amount of the water-insoluble coating component is not particularly limited, but is preferably in the range of 30 to 60% by mass in the coating agent.

  The plasticizer is presumed to have a function of imparting appropriate spreadability to the solution containing the coating agent and facilitating film formation. Examples of the plasticizer include those described in official documents such as standards for pharmaceutical additives such as triacetin and triethyl citrate (Pharmaceutical Daily Inc.). These can be used individually by 1 type or in combination of 2 or more types. Among these, triacetin and triethyl citrate are preferable in view of film formability, and triacetin is more preferable in terms of taste. Although the quantity of a plasticizer is not specifically limited, The range of 5-15 mass% in a coating agent is preferable.

  It is preferable to add an antacid to the coating film from the viewpoint of controlling solubility. As antacids, synthetic hydrotalcite, magnesium hydroxide, dry aluminum hydroxide gel, aluminum hydroxide gel, magnesium alumina hydroxide, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / magnesium carbonate mixed Examples thereof include dry gels, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation products, and the like. These can be used individually by 1 type or in combination of 2 or more types. Of these, synthetic hydrotalcite and magnesium hydroxide are preferable, and synthetic hydrotalcite is more preferable. Although the quantity of an antacid is not specifically limited, 10-80 mass% is preferable in a coating agent, More preferably, it is 30-60 mass%. If the amount of the antacid in the coating agent is too small, the dissolution property in the stomach and the rapid release property may be lowered, and if it is too much, the film forming property may be lowered.

  The amount of the coating agent is not particularly limited, but the mass ratio of coating agent / acetaminophen is preferably in the range of 0.05 to 0.35, and more preferably in the range of 0.15 to 0.25. If the value is too small, the coating film becomes thin, and if the value is too large, the coating film becomes thick.

The average particle child size (A) acetaminophen-containing coated particles is preferably 50 to 600, 100-400 are more preferred.

  (A) Although the compounding quantity of particle | grains is not specifically limited, 20-70 mass% in a tablet is preferable. The amount of acetaminophen is preferably 100 to 300 mg / tablet.

  (A) Although the manufacturing method of particle | grains is not specifically limited, The core acetaminophen particle | grain can be obtained by coating with the coating component containing a coating component and the plasticizer and an antacid agent as needed. The coating with the coating agent is generally wet coating, but is not limited thereto. In the case of wet coating, for example, a dispersion liquid in which a coating agent is dispersed in an arbitrary dispersion medium (hereinafter, also referred to as a coating agent dispersion liquid) is sprayed on acetaminophen particles serving as a nucleus. Preferred examples of the dispersion medium for the coating film composition include hydrophilic solvents such as water and ethanol.

  The method for spraying the coating agent dispersion is not particularly limited, but it is preferable to use a coating apparatus having a fluidized bed because the coating agent can be uniformly attached to the surface of the core acetaminophen particles. Thereby, it is possible to perform an excellent coating that is uniform and has less unevenness in elution. Moreover, the strength of the coating film to be formed is high, and the possibility of breaking by tableting or chewing is reduced.

  An apparatus as shown below can be used for coating fine particles. There are multiplex capable of stirring rolling fluidized bed coating, CF granulator capable of centrifugal rolling bed coating, flow coater capable of fluidized bed coating, GPCG, and Spirer flow. In particular, in an apparatus capable of the Wurster method (for example, a GPCG Wurster specification machine), efficient fine particle coating is possible. The Wurster method is a system in which a spray liquid is sprayed onto the core particle powder from the bottom of the fluidized bed toward the top.

(B) Granulated particles having a particle diameter of 150 to 600 μm containing sugar alcohol and starch (B) By blending the particles, (A) destruction of the acetaminophen-containing coated particles during tableting can be suppressed. In the case of sugar alcohol alone, disintegration in the mouth decreases, and in the case of starch alone, a high tableting pressure is required to maintain hardness, and (A) the acetaminophen-containing coated particles are easily destroyed, resulting in a bitter taste masking effect. Is inferior.

  Examples of the sugar alcohol include mannitol, erythritol, xylitol, and the like, which can be used alone or in combination of two or more. Of these, mannitol is preferred.

  Examples of the starch include starches such as corn starch and rice starch, and starch derivatives such as sodium carboxymethyl starch and hydroxypropyl starch. These can be used alone or in combination of two or more. Of these, corn starch is preferred.

  The blending mass ratio of the sugar alcohol: starch in the component (B) is preferably 98: 2 to 50:50, more preferably 96: 4 to 75:25, from the balance of bitterness masking effect, disintegration in the mouth, and ingestion. 95: 5 to 85:15 are more preferable. When the ratio of starch is high, the bitterness masking effect may be insufficient.

  (B) Although the compounding quantity of particle | grains is not specifically limited, 30-80 mass% in a tablet is preferable, 40-75 mass% is more preferable, 50-70 mass% is further more preferable. (B) When the compounding quantity of particle | grains is less than 30 mass%, cushioning property is insufficient and sufficient bitterness masking property may not be obtained. Moreover, from the point of sufficient masking effect, 50 mg or more is preferable with respect to 100 mg of acetaminophen, and 200 mg or more is more preferable. Although an upper limit is not specifically limited, It is 600 mg or less.

(B) the particle element size of the particles is 150～600Myuemu, preferably 150～425Myuemu, more preferably 150～355Myuemu, more preferably 150 to 250 [mu] m. Those grain child size in this range can be obtained by sieving. (B) When something particle element diameter of the particles is less than 150 [mu] m, adhesion to the equipment occurs during tableting, whereas exceeding 600 .mu.m, bitterness masking effect becomes insufficient.

(B) Although the manufacturing method of particle | grains is not specifically limited, For example, the wet granulation method etc. can be selected. Specifically, after mixing sugar alcohol, starch, and optional components as required, an aqueous solution containing a binder such as polyvinyl alcohol, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. is sprayed in a fluidized bed granulator. However, it can be obtained by wet granulation. Examples of the fluidized bed granulator include a GPCG series, WSG / WST / WH series from POWREC Co., Ltd., a flow coater, a spiral flow, etc. from Freund Sangyo Co., Ltd. Although it does not specifically limit as a drying method after granulation, For example, in the case of a fluidized granulation method, it can dry, blowing 40-100 degreeC warm air in a fluidized tank. Since the obtained granulated particles to obtain the desired particle element size, subjected to an appropriate sieve.

  In addition, as for content of the sugar alcohol and starch in (B) particle | grains, 90-98 mass% is preferable in (B) particle | grains. Moreover, 0.01-10 mass% is preferable for content of the binder in the said aqueous solution.

  The tablet of the present invention may further contain (C) a fragrance and / or a sweetener. By blending the component (C), the masking effect is improved. The component (C) can be blended in the particles (A) and (B), but is preferably blended separately from the particles (A) and (B).

  Although it does not specifically limit as a fragrance | flavor, Peach, grapefruit, apple, etc. are mentioned, It can use individually by 1 type or in combination of 2 or more types. Among them, peach is preferable. 0.5-2 mg is preferable with respect to 100 mg of acetaminophen, and 1.0-1.2 mg is more preferable.

  Examples of the sweetener include aspartame, sucralose, acesulfame potassium, saccharin, saccharin sodium, trehalose, thaumatin and the like, and these can be used alone or in combination of two or more. Of these, sucralose is preferable. The sweetener is preferably 1.0 to 5.0 mg and more preferably 2.0 to 3.0 mg with respect to 100 mg of acetaminophen.

  In the tablet of the present invention, in addition to the above components, other tablet components such as an excipient, a disintegrant imparting disintegration, and a lubricant may be used singly or in combination, as long as the effects of the present invention are not impaired. An appropriate amount can be blended by appropriately combining species or more.

  As the excipient, a commonly used excipient can be used. For example, crystalline cellulose, ethyl cellulose, cellulose such as low-substituted hydroxypropyl cellulose and derivatives thereof, starch and derivatives thereof such as corn starch, potato starch, hydroxypropyl starch, sugars such as lactose and mannitol, sugar alcohols, and the like. The content of the excipient may be in the range of 0 to 20% by mass, preferably 0 to 10% by mass with respect to the tablet. Regarding the excipient content, too much cellulose and its derivatives will lead to a decrease in disintegration in the mouth, too much starch and its derivatives will lead to a reduction in bitterness, and too much sugar and sugar alcohol will cause disintegration in the mouth. This leads to a decrease in property and adhesion.

  Although a disintegrating agent does not need to be contained in a tablet, disintegrating from the inside of a tablet can be obtained by mix | blending a disintegrating agent, and the disintegrating property of the whole tablet can be improved. Examples of the disintegrant include crospovidone (polyvinylpyrrolidone), carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl starch sodium, croscarmellose sodium, hydroxypropyl starch, and the like. . Of these, crospovidone is preferred. However, in the present invention, when the disintegrating agent is used to improve the disintegration property in the mouth, if the blending amount is increased, there is a possibility that a decrease in hardness or deterioration of appearance may occur due to storage. In addition, since disintegration is obtained by the present invention, the content of the disintegrant is preferably 5% by mass or less, more preferably 3% by mass or less, more preferably 3% by mass or less in the tablet in order to prevent a decrease in hardness and appearance deterioration due to the above storage. It is also possible to have a composition that does not contain an agent.

  As the lubricant, a commonly used lubricant can be used. For example, magnesium stearate, sucrose fatty acid ester, sodium stearyl fumarate, polyethylene glycol, talc, stearic acid and the like can be mentioned. The content of the lubricant is preferably 0.1 to 1% by mass relative to the tablet.

  In addition, the orally disintegrating tablet of the present invention includes stabilizers such as sodium edetate and benzoic acid, pigments such as titanium oxide, iron sesquioxide, and food yellow No. 5, malic acid, tartaric acid, citric acid, succinic acid, An acidulant such as fumaric acid can also be blended.

  The tablet of the present invention is prepared by, for example, mixing (A) acetaminophen-containing coated particles and (B) granulated particles having a particle diameter of 150 to 600 μm containing sugar alcohol and starch, and tableting the mixture. Can be obtained at The molding pressure (tablet pressure) at the time of tableting is appropriately selected so as to achieve the target tablet hardness, preferably 0.1 to 1.2 t, and more preferably 0.1 to 1.0 t. The tablet hardness varies depending on the tablet size, but is preferably about 3 kgf (tablet hardness measuring instrument (manufactured by Yamato Scientific Co., Ltd.)) or more. According to the present invention, a good masking effect can be obtained by using granulated particles having a specific particle diameter containing sugar alcohol and starch. Furthermore, by adjusting the ratio of starch, the tableting pressure required to obtain a suitable hardness can be kept low (1.0 t or less), and as a result, a better masking effect can be obtained.

  The mass of the tablet is preferably 20 to 2000 mg / tablet although it depends on the diameter and shape of the tablet. Among these, in the case of a tablet having a diameter of 11.0 mm, 200 to 700 mg / tablet is preferable from the viewpoint of disintegration and tablet moldability. The shape of the tablet is not particularly limited, but may be a round shape, a caplet shape, a donut shape, an oblong shape or the like, a laminated tablet, a dry-coated tablet, etc. A secant line may be attached. In addition, the packaging of the orally disintegrating tablet is not particularly limited, but PTP (Press Through Package) may be packaged to prevent moisture.

  The tablet of the present invention is preferably an orally disintegrating tablet because it is excellent in masking effect and also excellent in disintegration. An orally disintegrating tablet refers to a tablet that is composed only of saliva in the oral cavity, disintegrates the tablet in the oral cavity by shearing or chewing with the tongue and upper jaw, and swallows the saliva dispersion of disintegrated particles.

EXAMPLES Hereinafter, although an Example , a reference example, and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. In the following examples, unless otherwise specified, “%” in the composition represents mass%, and the ratio represents mass ratio.

[Preparation Example 1: Preparation of acetaminophen-containing particles]
Acetaminophen (manufactured by Tyco Healthcare Japan Co., Ltd.) having a bitter and unpleasant taste was used. First, ethyl cellulose aqueous dispersion, triacetin, and synthetic hydrotalcite are added in a predetermined amount at a ratio of 4: 1: 4 in the amount of solid content to purified water in an amount to adjust the total solid content concentration of the coating liquid to 20% by mass, Stir well to obtain a coating solution. Next, using a fluidized bed granulator multiplex MP-01 Wurster use (manufactured by POWREC), 800 g of acetaminophen particles are added, and the above air flow rate is 65 ° C. and the exhaust temperature is 25 to 40 ° C. The coating solution prepared in (1) was sprayed so that the total solid content was 160 g. This was dried at an air supply temperature of 80 ° C. for 40 minutes to obtain masking particles. The average particle child size was 200～250Myuemu.

  The following table shows the blending amount in one tablet when 120 mg of acetaminophen-containing particles are blended per tablet (coating agent / acetaminophen = 0.2).

[Preparation Example 2: (B) Preparation of Sugar Alcohol and Starch Containing Particle Diameter 150-600 μm (Mannitol / Starch Granulated Particles-1)]
3240 g of D-mannitol and 360 g of corn starch are mixed, put into Spiraflow SFC-5 type (manufactured by Freund), and sprayed with 2400 g of a 6% aqueous solution of hydroxylpropylcellulose at an intake temperature of 90 ° C. and an exhaust temperature of 36-45 ° C. did. Then, sieving the resulting granules to obtain particles of desired particle child size.

  The following table shows the blending amount in one tablet when 322.7 mg of mannitol / starch granulated particles are blended per tablet (D-mannitol: corn starch = 90: 10).

[Preparation Example 3: Preparation of (B) Sugar Alcohol and Starch-containing Particle Size 150-600 μm (Mannitol / Starch Granulated Particles)]
By adjusting the amount in the same manner as in Preparation Example 2, particles of D-mannitol: corn starch = 80: 20 were obtained.

[Examples 1 to 4, Reference Example 1 , Comparative Examples 1 to 4]
Using the particles obtained in the above preparation example, each component having the composition shown in Tables 3 to 5 is sufficiently mixed, and magnesium stearate (which is sieved using a sieve having an opening of 500 μm) is put into the mixture. The mixture was lightly mixed to obtain granules for tableting. Usuki was 11.0mm, using a sumi-square flat plate, twelve stands and the rotating disk rotation speed was 30rpm, and tableted with the tableting pressure shown in the table with a rotary tableting machine, containing acetaminophen A round tablet having an amount of 100 mg / tablet, a mass of 450 mg, and 11 mm was obtained. Note that Comparative Example 3 could not be molded.

[Bitter taste masking test]
Seven panelists included one tablet in their mouths, and evaluated the bitterness intensity felt when they were dissolved by applying shear with their tongue and upper jaw, and the average value was calculated.
<Evaluation point>
5: Feels no bitterness 4: Feels bitter taste 3: Feels bitter taste 2: Feels bitter taste 1: Very feels bitterness The results are shown by the following criteria based on the average value obtained above.
<Standard>
◎: 4.5 or more ○: 4 or more and less than 4.5 Δ: 3 or more and less than 4 ×: less than 3

[Elution rate]
The dissolution test based on the Japanese Pharmacopoeia paddle method was conducted. It carried out using the buffer solution of pH6.8 which assumed the pH of the saliva as an alternative of the elution property in the saliva in the oral cavity. The elution rate (%) indicates the ratio of the amount of the eluted component to 100% when the amount of the component contained in one sample is 100%. When the coating of the coated particles (A) is broken, the drug elution rate increases and bitterness is produced, which is an index for bitterness evaluation.
A result is shown on the following reference | standard from the elution rate (%) 30 minutes after obtained above.
<Standard>
A: Less than 35% B: 35% or more and less than 45% Δ: 45% or more and less than 60% ×: 60% or more In this evaluation, if the elution rate after 30 minutes is less than 60%, the above bitterness masking test The evaluation score is 3 or more. From the results of Examples and Reference Examples , there was a correlation between the bitter taste masking result and the mouth elution rate result.

[Mouth disintegration]
Seven panelists included one tablet in their mouths, and evaluated the disintegration property when dissolved by applying shear with the tongue and upper jaw in the following three stages. Evaluation criteria: Acceptable if the tablet disintegrates.
<Standard>
○: Easily disintegrating △: Disintegrating ×: Difficult to disintegrate The tablets obtained in Examples and Reference Examples are only saliva in the oral cavity, and can be disintegrated in the oral cavity by shearing or chewing with the tongue and upper jaw, It was suitable as an orally disintegrating tablet.

[Adhesion]
After mixing 720 g of acetaminophen-containing granules, 1914 g of mannitol granulated product, sucralose, peach flavor, pulverized menthol / corn starch, and sieving the lubricant magnesium stearate using a sieve with an opening of 500 μm A fixed amount is added and lightly mixed to form granules for tableting. The mortar was 11.0 mm in diameter, and a Sumi angle flat was used to make a single-layer tablet with a 12-spindle rotary disk rotation speed of 30 rpm so that the content of acetaminophen was 100 mg / tablet using a rotary tableting machine. , Observe the state of the board and candy when all the powder is tableted.
The results are shown by the following criteria (if no powder adheres visually, it was judged that no soot was attached).
<Standard>
○: No powder adhesion X: Powder adhesion is observed

The tablets of Examples and Reference Examples were evaluated after storage at 50 ° C. for 2 weeks. As a result, there was no bitterness and the disintegration property in the mouth was good. The tablets of Examples and Reference Examples have excellent solubility under gastric conditions (pH 1.2), suppress elution of acetaminophen in the oral cavity, and exhibit excellent dissolution in the stomach. It was possible to achieve both performance and efficacy.

Claims (7)

A tablet comprising (A) acetaminophen-containing coated particles and (B) granulated particles having a particle diameter of 150 to 425 μm containing mannitol and starch. (B) a sugar alcohol in the component: mixing mass ratio of the starch, 96: 4-75: tablet of claim 1 wherein 25. The tablet according to claim 1 or 2, wherein (A) the compounding amount of the particles is 20 to 70% by mass in the tablet, and (B) the compounding amount of the particles is 40 to 75% by mass in the tablet . The tablet according to any one of claims 1 to 3, wherein the (A) component has an average particle size of 50 to 600 µm. Furthermore, (C) A fragrance | flavor and / or a sweetener are contained, The tablet of any one of Claims 1-4 characterized by the above-mentioned. It is an orally disintegrating tablet, The tablet of any one of Claims 1-5 . (A) A manufacturing method of a tablet in which acetaminophen-containing coated particles and (B) granulated particles having a particle diameter of 150 to 425 μm containing mannitol and starch are mixed, and the mixture is tableted.