JP2001316249A - Tablet-type medicinal composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a tablet-type medicinal composition having a proper strength. SOLUTION: This tablet-type medicinal composition is produced by formulating the following components (A) to (C): (A) a medicine; (B) one or more kinds of compounds selected from the group consisting of inorganic salts and inorganic oxides having poor solubility in water; and (C) saccharides and/or sugar alcohols where particles of an amount of >=50 mass % based on the total mass of the component C have a particle diameter of 20-300 μm.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a tablet-type pharmaceutical preparation which suppresses breakage of tablets during a packaging process and during transportation.

[0002]

2. Description of the Related Art After tableting, tablets are passed through a powdering machine to remove adhering powder, stored in a predetermined storage container, or supplied to a filling machine for packaging.
For this reason, in many cases, individual tablets are repeatedly dropped, rubbed, and collided. The tablet strength in the manufacturing process is often performed relatively early within a certain period, and the strength immediately after manufacturing often becomes a problem. On the other hand, a consumer removes a tablet from a packaging container by applying a force such as compression or shearing to the tablet when removing the tablet from the package. However, such a problem concerning the removal from the packaging / container on the consumer side is a problem including the stability of the preparation, and is a problem that must be guaranteed for a long time.
Since the strength of the tablet is a problem at the most fragile part, it is considered that the force from the side in the case of a circular tablet, the bending strength determines the strength as a tablet when the thickness is smaller than the diameter direction . For a tablet that is extremely long in one direction, it can be said that the bending strength toward the center of the tablet determines the strength. Further, as a partial weak point, when the angle of the intersection of the side surface and the plane of the tablet is small, the weak point of this portion is likely to occur. This is particularly problematic when the central portion of the tablet is concave. Further, the capping which is one of the tableting obstacles also has a biased distribution of the internal residual stress in the capping, which is the weakest point against the shearing force in the direction perpendicular to the side surface such as the peeling of the tablet. Furthermore, these weaknesses can be said to increase the problem as the size of the tablet increases. Such a problem not only lowers the quality of the tablet, but also causes variations in the content of the physiologically active ingredient and troubles in manufacturing equipment. Useability is reduced, and a composition that can solve these problems is desired.

In response to these requirements, water-soluble polymers such as hydroxypropylcellulose, polyvinylpyrrolidone and methylcellulose are directly added to physiologically active ingredients and excipients, followed by dry granulation, or water or an appropriate solvent. A tablet is prepared by adding the above-mentioned water-soluble polymer dissolved in the above to a composition obtained by mixing a physiologically active ingredient and an excipient, kneading or wet granulating, drying and adding an appropriate additive. However, in the former method, the disintegration greatly changes due to moisture absorption immediately after production or over time, so it is inconvenient to stably release the physiologically active ingredient. In the latter case, there is a problem with respect to a physiologically active ingredient having poor water stability. Addition of a dry binder such as crystalline cellulose is also conceivable. In this case, however, it often occurs that the tablet strength is reduced by adding a lubricant such as magnesium stearate to the formulation powder. In this case, it is known that the longer the mixing time is, the more the strength is reduced, and it is necessary to appropriately set the mixing time. This is related to the scale at the time of production, and therefore, it is necessary to set an appropriate condition for setting the mixing time.

[0004]

SUMMARY OF THE INVENTION The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a tablet-type pharmaceutical composition having an appropriate strength without performing complicated steps.

That is, according to the present invention, a drug selected from the group consisting of a granular drug, a sugar and / or a sugar alcohol having a specific particle size, and inorganic salts and inorganic oxides which are hardly soluble in water. By blending more than one compound into a tablet, it has been found that the compound has appropriate strength as a tablet. Accordingly, the present invention provides the following (A) to (C) components: (A) a drug; (B) one or more compounds selected from the group consisting of inorganic salts and inorganic oxides that are hardly soluble in water; (3) A tablet-type pharmaceutical composition characterized in that 50% or more based on the total mass of the component (C) contains sugars and / or sugar alcohols having a particle size of 20 to 300 µm.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. (A) Component The drug used in the tablet-type pharmaceutical composition of the present invention is granular,
The drug may be in the form of a powder or a granule, and the drug in the form of a powder or granule can be used alone or in combination. The preferred particle size of the drug used in the tablet-type pharmaceutical composition of the present invention is 1 to 1500 µm, and the more preferred size is 50 to 500 µm. The crystal form of the drug is not particularly limited. Specific examples of the drug used in the tablet-type pharmaceutical composition of the present invention include aspirin, acetaminophen, ibuprofen, ascorbic acid, riboflavin, thiamine nitrate, pyridoxine hydrochloride, lactylphenetidine, sazapyrine, salicylamide, sodium salicylate, aspirin Aluminum, Bromvalerylurea, Ethenzamide, Isotipedil hydrochloride, Diphenhydramine hydrochloride, Dipheterol hydrochloride, Triprolidine hydrochloride, Tripelenamine hydrochloride, Tondiamine hydrochloride, Phenetazine, Methdilazine hydrochloride, Diphenhydramine salicylate, Carbinoxamine diphenyldisulfonate, Alimezine tartrate, Dimamine diphenylphenate Pyralin, mebuhydroline napadylate, promethazine methylene disalicylate Carbinoxamine maleate, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, Jifeteroru phosphoric acid, hydrochloric Akuroramido, hydrochloric Cloperastine, citric acid pentoxyverine, tipepidine citrate,
Sodium dibnate, dextromethorphan hydrobromide, dextromethorphan phenolphthalin salt, tipepidine fendizoate cloperastine hibenzate, codeine phosphate, dihydrocodeine phosphate, noscapine hydrochloride, noscapine, dl-methylephedrine hydrochloride, dl -Methylephedrine saccharin salt, potassium guaiacol sulfonate, guaifenesin, sodium benzoate caffeine, anhydrous caffeine, allyl isopropylacetyl urea, bromvalerylurea, vitamin B
And its derivatives, their salts, vitamin B2 and their derivatives, and their salts, vitamin C and its derivatives, and their salts, hesperidin and its derivatives, and their salts. Of these, acetaminophen, ascorbic acid, etenzamid, ibuprofen, riboflavin, thiamine nitrate, pyridoxine hydrochloride,
Aspirin is preferred, and acetaminophen, ibuprofen and aspirin are more preferred. The content of the drug in the tablet-type pharmaceutical composition of the present invention is preferably 10 to
It is 90% by mass, more preferably 20 to 80% by mass.
In the present specification, a simple expression “%” means “% by mass”.

Component (B) The water-insoluble inorganic salts and inorganic oxides of the present invention include, for example, the following components: magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, oxide Magnesium, dihydroxyaluminum amino acetate (aluminum glycinate),
Aluminum hydroxide gel, dried aluminum hydroxide gel, mixed dried gel of aluminum hydroxide and magnesium carbonate, co-precipitated product of aluminum hydroxide and sodium hydrogen carbonate, co-precipitated product of aluminum hydroxide, calcium carbonate and magnesium carbonate, water Coprecipitated products of magnesium oxide and potassium aluminum sulfate, magnesium carbonate, magnesium aluminate metasilicate, magnesium aluminate silicate, anhydrous calcium phosphate, precipitated calcium carbonate, calcium phosphate hydrate, magnesium oxide and the like.
Among the above, a calcium compound is particularly preferred.

The preferred particle size of the inorganic salts and inorganic oxides which are hardly soluble in water in the present invention is in the range of 0.5 to 100 μm, more preferably 0.5 to 50 μm, particularly preferably 0.5 to 20 μm. is there. It is preferable that the content in this range is at least 50%, more preferably at least 70%, particularly preferably at least 80%, based on the total mass of the component (B). In this range, the strength and solubility of the tablet are particularly good. The proportion of the poorly water-soluble inorganic salts and inorganic oxides used in the present invention to the whole preparation is 1 to 50%. More preferably, 1.5
-30%, particularly preferably 2-10%. The component (B) may be used alone or in combination of two or more.

(C) Component As the saccharides and / or sugar alcohols used in the present invention, considering the use of the solid preparation of the present invention, saccharide components used as pharmaceutical additives and food additives are preferably used. Specific examples include monosaccharides such as glucose and fructose; disaccharides such as sucrose, lactose and maltose; sugars such as oligosaccharides; and sugar alcohols such as sorbitol, xylitol, erythritol and mannitol. it can. Among them, disaccharides and sugar alcohols are preferable, and among them, lactose, sorbitol, xylitol, erythritol and mannitol are preferable. These sugars and sugar alcohols can be used alone or in an appropriate combination of two or more. In the present invention, the component (C) has a particle size of 20 to 300 μm at 50% by mass or more based on the total mass of the component (C). More preferred particle size is
It is 30 to 250 μm, particularly preferably 50 to 200 μm. Further, those having a particle size in the above range are preferably 70% or more, and particularly preferably 80% or more. Also,
The content of the fine powder having a size of 0.5 μm or less is preferably 5% or less, and particularly preferably 1% or less. In addition, 5
It is particularly preferred that the amount of powder having a particle size of 00 μm or more is 10% or less, preferably 5% or less. When the fine powder and the coarse powder are in the above range, it is particularly preferable in physical properties such as impact strength and solubility.

The saccharides or sugar alcohols used in the present invention can be recrystallized after synthesis, and then pulverized into particles having an appropriate particle size before use. Further, in order to increase the tablet strength and to easily maintain the disintegration property, it is preferable to use the composition after forming porous particles by spray drying or the like. The content of the saccharide and / or sugar alcohol used in the present invention in the preparation is preferably 15 to 70%, particularly preferably 20 to 60%, and most preferably 25 to 50%. In the present invention, the ratio between the average particle diameter of the inorganic salts and inorganic oxides that are hardly soluble in water and the average particle diameter of the saccharides and sugar alcohols is preferably 2: 1 to 1: 1.
1:20. More preferably, 1: 1 to 1: 1
5, particularly preferably 1: 2 to 1:10.

When granulating or compressing, the composition of the present invention may contain, if necessary, additives usually used, such as a lubricant,
A binder, a coating agent, an excipient, a disintegrant, a disintegration aid and the like can be used alone or in combination of two or more kinds as long as the effect of enhancing the tablet strength is not hindered. Specific examples of the optional additive include the following components.

Examples of the lubricant include gum arabic, cacao butter, carnauba wax, glycerin, liquid paraffin, crystalline cellulose, sucrose fatty acid ester, stearyl alcohol, stearic acid, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, fumaric acid, beeswax. , Magnesium stearate, silicone oil, hardened castor oil, talc and the like. As the binder, hydroxypropylcellulose (degree of substitution 53.
4-77.5%), methylcellulose, gelatin, polyvinylpyrrolidone, partially pregelatinized starch and the like.
Examples of the coating agent include glycerin, liquid paraffin, silicone resin, stearic acid, gelatin, corn oil, polyvinyl alcohol, macrogol, and methacrylic acid copolymer.

As the excipient, gum arabic, ethyl cellulose, kaolin, cocoa butter, citric acid or a salt thereof,
Examples include crystalline cellulose, stearic acid or a salt thereof, dextran, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol and the like. Disintegrators include cellulose or derivatives thereof, starch and derivatives thereof, and the like.
Examples of the disintegration aid include cellulose or a derivative thereof, stearic acid, and hydroxypropyl cellulose. In addition, dyes, fragrances, and the like can be appropriately added as long as the effects of the present invention are not impaired.

The tablet-type pharmaceutical composition of the present invention may be in various forms, such as a circular tablet whose form is a perfect circle when viewed from the top, or an oval, triangle, square, hexagon, or lens. Alternatively, it may be a deformed tablet having a disk shape or the like. The dimensions of the tablet-type pharmaceutical composition of the present invention refer to the diameter when the form viewed from the top is a perfect circle, and the length of the longest part of the tablet when the form is elliptical, triangular or square. I do. The size of the tablet-type pharmaceutical composition of the present invention is preferably 10 mm or more, more preferably 11 to 15 mm, and still more preferably 15 to 20 mm. When the tablet-type pharmaceutical composition of the present invention is a deformed tablet, the length of the shortest portion of the tablet is preferably 2 mm or more, more preferably 5 to 8 mm, and still more preferably 5 to 10 mm. By setting the size of the pharmaceutical composition of the present invention within the above range, the addition of an inorganic substance significantly improves the bonding strength, and the strength is greatly improved. The method for producing the tablet-type pharmaceutical composition of the present invention is not particularly limited, such as a wet or dry indirect compression method and a direct compression method. The tablet-type pharmaceutical composition of the present invention includes tablets for internal use such as uncoated tablets, chewable tablets, and effervescent tablets; oral tablets such as troches, buccal tablets, and sublingual tablets; parenteral tablets such as tablets for injection; It may be a tablet or the like.

[0014]

EFFECT OF THE INVENTION The tablet-type pharmaceutical composition of the present invention has improved strength, and remarkable improvements in impact resistance in the packaging step and prevention of tablet breakage during transportation are recognized. In addition, regarding the storage of tablets for a long period of time, they can be prepared as solid preparations with little change over time in tablet strength.

[0015]

EXAMPLES The present invention will be described below in detail with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples. [Example 1, Comparative Examples 1 to 3] (Example 1) Tablets having the composition shown in Table 1 below were prepared by the following method.

Table 1 [Composition] mg / tablet Acetaminophen 120 Ascorbic acid 60 Partially pregelatinized starch 25 Lactose anhydride 150 Precipitated calcium carbonate 25 Carmellose 19 Yellow No. 5 aluminum lake 0.4 Fragrance 0.4 Magnesium stearate 2. 2 total 402.0

Acetaminophen 600 g (particle size: 75
４425 μm, average particle size: 350 μm), ascorbic acid 300 g (particle size: 106-355 μm, average particle size: 2)
20 μm), 95 g of carmellose (particle size: 53 to 212)
μm, average particle size: 120 μm) and partially pregelatinized starch 1
25 g were weighed, and each was put into a V-type mixer (V-5; Tokuju Seisakusho) and mixed for 15 minutes. Next, 750 g of fractionated anhydrous lactose powder, which had been previously pulverized with a hammer mill (Atomizer; Fuji Paudal) and collected on a sieve having a particle size of 45 to 180 μm (average particle size of 120 μm), had a particle size of 1 to 50 μm.
125 g of 10 μm precipitated calcium carbonate (average particle diameter: 5 μm; as determined by a particle size distribution measurement using a high pressure passage filling method) was charged into the mixer, and mixed for another 20 minutes. Next, a part of the mixed powder was placed in a plastic bag, and 2 g of yellow No. 5 aluminum lake and 2 g of fragrance were added to make the mixture uniform. Then, 11 g of magnesium stearate was added and mixed for 5 minutes. The resulting powder is tableted at a tableting pressure of 1 t, 1.2 t, and 1.5 t using a rotary tableting machine (L-41; Hata Iron Works) to obtain a circular tablet having an average mass of 402 mg and a diameter of 10 mm. Was.

(Comparative Example 1) 45% of the powder having a particle diameter of 20 to 300 μm was added to the total weight of anhydrous lactose powder,
20% for those with a thickness of ~ 500 μm, 3
5% anhydrous lactose powder (average particle size 120 μm) 7
Comparative Example 1 was obtained in the same manner as in Example 1 except that 50 g was used. (Comparative Example 2) The particle size was 2 with respect to the total mass of the anhydrous lactose powder.
Except for using anhydrous lactose powder (average particle diameter 200 μm) containing 45% of 0 to 300 μm, 35% of 350 to 500 μm, and 20% of 15 μm or less.
Comparative Example 2 was obtained in the same manner as in Example 1. (Comparative Example 3) 600 g of acetaminophen (particle size: 75)
４425 μm, average particle size: 350 μm), ascorbic acid 300 g (particle size: 106-355 μm, average particle size: 2)
20 μm), 95 g of carmellose (particle size: 53 to 212)
μm, average particle size: 120 μm) and partially pregelatinized starch 1
25 g was taken in a V-type mixer (V-5; Tokuju Seisakusho) and mixed for 15 minutes. Then, it was previously pulverized with a hammer mill (Atomizer; Fuji Paudal Co., Ltd.).
The fractionated anhydrous lactose powder collected on a 180 μm
5 g was charged and mixed for another 20 minutes. Next, a part of the mixed powder was placed in a plastic bag, and 2 g of yellow No. 5 aluminum lake and 2 g of fragrance were added to make the mixture uniform. Then, the mixture was put again in the mixer and mixed for another 10 minutes. Then, 11 g of magnesium stearate was added and mixed for 5 minutes. The resulting powder is tableted at a tableting pressure of 1 t, 1.2 t, and 1.5 t using a rotary tableting machine (L-41; Hata Iron Works) to obtain a circular tablet having an average mass of 402 mg and a diameter of 10 mm. Was.

The strength of the tablets obtained in Example 1 and Comparative Examples 1 to 3 was evaluated. Hardness and friability were measured as indices of strength. Hardness is Monsanto type hardness meter (TH-203C)
P; Toyama Sangyo). The friability was measured using a friability tester (tablet friability tester; Kayagaki Rika Kogyo). The friability was determined by the following formula by taking 20 tablets and performing the rotation at 45 revolutions per minute for 5 minutes. Friability (%) = (Tablet mass before test (20 tablets) −Tablet mass after test (20 tablets)) / Tablet mass before test (20 tablets) × 100

[0019]

[Table 2] As shown in Example 1, when lactose having a specific particle size was used in combination with precipitated calcium carbonate, good hardness was exhibited. Also,
The impact resistance of the tablets was also found to be good, as indicated by the friability. In addition, although the hardness and the friability were slightly improved even when the tableting pressure in Comparative Examples 1 to 3 was increased to 1 to 1.5 t, the effect as in Example 1 was not recognized. Example 2 Tablets having the composition shown in Table 3 below were prepared by the following method.

[0020]

[Table 3]

1250 g of ethenzamide (particle size: 53 to 2)
950 g of mannitol obtained by previously pulverizing with a pulverizer (Atomizer; manufactured by Fuji Paudal Co., Ltd.), passing through a sieve and fractionating particles having a particle diameter of 45 to 180 μm (50 μm, average particle diameter: 230 μm) ( Average particle size: 105 μm) 200 g of calcium phosphate having a particle size of 0.2 to 8 μm (average particle size: 5 μm), 120 g of carmellose (particle size: 53 to
(212 μm, average particle size: 120 μm) and 350 g of crystalline cellulose were placed in a stirring mixer (FS-10J; manufactured by Fukae Industry Co., Ltd.) and mixed for 10 minutes. Next, 100 g of the mixed powder was placed in a plastic bag, 0.2 g of fragrance was added, and the mixture was uniformly dispersed. Then, the mixture was returned to the stirring mixer and mixed for another 5 minutes. Next, 28 g of magnesium stearate was added and mixed for 2 minutes. A rotary tableting machine (12UH
(K; Kikusui Seisakusho) at a tableting pressure of 1 to 2 tons to obtain round tablets having a diameter of 11 mm and an average mass of 580 mg. (Comparative Example 4) Comparative Example 4 was obtained in the same manner as in Example 2 except that 950 g of mannitol having a particle diameter of 300 µm to 600 µm was used. About Example 2 and Comparative Example 4,
The comparison was performed using the same apparatus as in Example 1 and Comparative Example 1.

[0022]

[Table 4]

As shown in Example 2, when mannitol having a particle diameter of 45 to 180 μm and calcium phosphate were used in combination, good hardness and friability were obtained. When mannitol having a particle size exceeding 180 μm is used, although the hardness and the friability are slightly improved even when the tableting pressure is increased,
The effect as in Example 2 in which mannitol having a particle diameter of 45 to 180 μm and calcium phosphate were used in combination was not observed.
Further, even when the tableting pressure was increased, no effect was observed in improving the hardness or reducing the friability. Example 3 Tablets having the composition shown in Table 5 below were prepared by the following method.

[0024]

[Table 5]

750 g of ibuprofen (particle size: 425 to
750 g of erythritol obtained by previously pulverizing with a pulverizer (atomizer; manufactured by Fuji Paudal Co.), passing through a sieve and collecting particles having a particle diameter between 45 and 180 μm. 750 g of lactose treated in the same manner as erythritol (each average particle size: 106 μm)
m), 500 g of calcium phosphate (particle size; 0.3 to 9.
5 μm, average particle size 4.5 μm), 150 g of crosslinked polyvinylpyrrolidone and 400 g of crystalline cellulose were placed in a stirring mixer (FS-10J; manufactured by Fukae Kogyo KK) and mixed for 10 minutes. Next, take 100 g of this mixed powder in a plastic bag,
After 0.3 g of Red No. 104 was added and uniformly dispersed, the mixture was returned to the stirring mixer and mixed for another 5 minutes. Next, 57 g of magnesium stearate was added and mixed for 2 minutes.
The obtained mixed powder was tableted at a tableting pressure of 0.5 to 1.5 t using a rotary tableting machine (12UHK; Kikusui Seisakusho) to obtain a rod-shaped tablet having a major axis of 17 mm, a minor axis of 7 mm and an average mass of 336 mg. Obtained. 750 g of ibuprofen was previously pulverized with a pulverizer (Atomizer; manufactured by Fuji Paudal), passed through a sieve, and compared using the same apparatus as in Example 1 and Comparative Example 1.

[0026]

[Table 6] Example 4 Tablets having the composition shown in Table 7 below were prepared by the following method.

[0027]

[Table 7]

15 g of riboflavin, thiamine nitrate 55
g, pyridoxine hydrochloride (30 g) and magnesium silicate (average particle size: 6.1 μm) (75 g) in a V-type blender (V-1).
(Type 0; Tokuju Seisakusho). This and pulverized by a pulverizer (Atomizer; manufactured by Fuji Paudal Co., Ltd.) in advance, and 450 g of lactose treated in the same manner as 300 g of xylitol obtained by fractionating particles having a particle diameter of 45 to 180 μm through a sieve. , 150 g of carmellose), 195 g of crystalline cellulose and 35 g of hydroxypropyl starch were placed in a stirring mixer (FS-10J; manufactured by Fukae Kogyo KK) and mixed for 10 minutes. Next, 100 g of the mixed powder was placed in a plastic bag, 1 g of a fragrance was added, and the mixture was uniformly dispersed. Then, the mixture was returned to the stirring mixer and further mixed for 5 minutes. Next, 36 g of magnesium stearate was added and mixed for 2 minutes. The obtained mixed powder was tableted at a tableting pressure of 0.5 to 1.5 t using a rotary tableting machine (12UHK; Kikusui Seisakusho), and the diameter was 7 mm.
Round tablets with an average mass of 200 mg were obtained. Example 4 was compared using the same device as in Example 1 and Comparative Example 1.

[0029]

[Table 8] As described above, a tablet composition having improved strength is obtained by blending one or more components selected from inorganic salts and inorganic oxides that are hardly soluble in water and sugar and / or sugar alcohols having a specific particle size. Can be.

Claims (4)

[Claims] 1. A tablet-type pharmaceutical composition comprising the following components (A) to (C): (A) drug; (B) a group consisting of inorganic salts and inorganic oxides which are hardly soluble in water. And (C) at least 50%, based on the total mass of the component (C), of sugars and / or sugar alcohols having a particle size of 20 to 300 μm. 2. 50% based on the total mass of component (B)
The tablet-type pharmaceutical composition according to claim 1, wherein the above has a particle size of 0.5 to 100 µm. 3. A method for producing a tablet-type pharmaceutical composition, which comprises tableting a mixture containing the following components (A) to (C): (A) a drug; (B) a poorly water-soluble inorganic material. At least one compound selected from the group consisting of salts and inorganic oxides; and (C) sugars and / or sugar alcohols having a particle size of 20 to 300 µm at least 50% based on the total mass of the component (C). 4. The tablet-type pharmaceutical composition according to claim 1, wherein the longest portion of the tablet has a size of 10 mm or more.