JP6716862B2 - Solid formulation - Google Patents

Description

The present invention relates to a solid preparation that can be taken without water.

The solid preparation that can be taken without water is an excellent preparation that is easy to take even for people with low swallowing ability such as children and the elderly, and has the advantage that it can be taken in any situation without water ( Patent Document 1).
Various studies have been conducted so far to obtain an orally disintegrating tablet. For example, an orally disintegrating tablet containing starch powder and gelatinized starch, a water-soluble excipient containing mannitol, sodium stearyl fumarate and a medicinal ingredient (patent document 1), a sugar having low moldability and a sugar having high moldability. It has been reported that an orally-dissolving compression-molded product (Patent Document 2), which contains swollen and rapidly disintegrates and dissolves in the oral cavity.
However, in Patent Document 1, when starch powder and gelatinized starch are used, sticking to a manufacturing apparatus is likely to occur and handling in manufacturing is difficult. Further, in the method of Patent Document 2, since a moistening/drying step after tableting at low pressure is an essential condition for producing an orally disintegrating tablet, the number of manufacturing steps is large and the operation is complicated.
Further, a compression molding composition has been reported in which the hardness required for carrying is maintained by coating a saccharide with an aluminometasilicate, and which exhibits rapid disintegration in the oral cavity (Patent Document 3). However, it has been found that when a medicinally active ingredient is coated with alumino-metasilicate, an interaction occurs and the appearance stability is poor, and there is a problem in commerciality.

The physical properties of the pharmaceutically active ingredient contained in the formulation may greatly affect the productivity. For example, when compounding a medicinal active ingredient known to cause adhesion to a machine wall or a die during granulation or tableting, as an additive for granulation or a tableting aid to prevent these adhesions. Measures such as increasing the amount of lubricants such as talc and magnesium stearate are made. However, although effective in preventing adhesion, it causes further problems such as delayed collapse and capping. Moreover, since it is known that changes such as solidification and discoloration occur over time, there is room for further improvement (Patent Document 4).

Further, a tablet having improved irritation and adhesion during production has been reported by spray granulating a powder containing a pharmaceutically active ingredient with a binder solution in which light anhydrous silicic acid is dispersed (Patent Document 5). ). However, the tablet obtained in Patent Document 5 has a problem in rapid disintegration required for a formulation to be taken without water.

JP, 2004-83579, A Japanese Patent Publication No. 7-74153 JP 2002-308760 A Japanese Patent No. 2841267 JP 2000-239185 A

16th Revised Japanese Pharmacopoeia Manual Hirokawa Shoten Co., Ltd. Page A-33-34

An object of the present invention is to provide a solid preparation which has moderate hardness and rapid disintegration and is excellent in stability of the preparation and which can be taken without water. Another object of the present invention is to provide a manufacturing method capable of suppressing adhesion even when a medicinally active ingredient having poor manufacturability that causes adhesion to a manufacturing device or the like is mixed during manufacturing.

The present inventors have conducted various studies in order to achieve the above-mentioned object, and a powder containing a pharmaceutically active ingredient is spray-granulated with a solution in which silicon dioxide is dispersed, and a sugar alcohol. It was found that the contained solid preparation has appropriate hardness and rapid disintegration and is excellent in stability of the preparation. Furthermore, they have found that it is possible to suppress discoloration of the preparation and to prevent the preparation from adhering to manufacturing equipment during the manufacture, and thus completed the present invention.

That is, the present invention is
(1) A powder containing an active pharmaceutical ingredient (a), which is spray-granulated with a solution in which silicon dioxide is dispersed, and (b) a sugar alcohol, which is characterized by containing without water. Possible solid formulations,
(2) The solid preparation according to (1), wherein the solid preparation that can be taken without water is an orally disintegrating tablet or a chewable tablet.
(3) The solid preparation according to (1), wherein the silicon dioxide is light anhydrous silicic acid.
(4) The solid preparation according to (1) or (3), wherein the silicon dioxide has an average particle size of 0.0001 to 20 μm.
(5) The solid preparation according to (1), wherein the sugar alcohol is at least one selected from the group consisting of mannitol, erythritol, and xylitol.
(6) The solid preparation according to (1), wherein the pharmaceutically active ingredient is at least one selected from the group consisting of antipyretic analgesics, antihistamines, central nervous system stimulants, and vitamins.
(7) The solid preparation according to (1) or (6), wherein the pharmaceutically active ingredient is at least one selected from loxoprofen or a salt thereof, ibuprofen, caffeine and ascorbic acid.
(8) The solid preparation according to (1) or (5), wherein the sugar alcohol content is 10 to 80% by mass based on the total mass of the solid preparation.
(9) A method for producing a solid preparation containing a sugar alcohol, which can be taken without water, characterized by spray granulating a powder containing a pharmaceutically active ingredient with a solution in which silicon dioxide is dispersed,
Is.

According to the present invention, it has a desired moderate hardness and rapid disintegration, and in the disintegration test or the oral disintegration test according to the Japanese Pharmacopoeia, the disintegration time is 60 seconds or less, more preferably 50 seconds or less, and particularly preferably 30. Within seconds, a solid formulation is obtained. Furthermore, it has a suitable strength that does not damage during the distribution process, the tablet hardness is 0.5 MPa or more in terms of tensile strength, and a solid preparation with excellent appearance stability that suppresses discoloration of the preparation is obtained. can get. Further, according to the manufacturing method of the present invention, it is possible to suppress the adhesion to manufacturing equipment or the like during manufacturing.

Hereinafter, the solid preparation of the present invention that can be taken without water and the method for producing the same will be described.

The pharmaceutically active ingredient of the present invention is not particularly limited as long as it is an ingredient to be used in medicine, for example, antitussive expectorant, bronchodilator, central stimulant, antihistamine, hypnotic sedative, antispasmodic agent, Gastrointestinal agents, antacids, nourishing tonics, antipyretic analgesics, vitamins, antiemetics, bactericidal ingredients, crude drugs and the like. For example, dihydrocodeine or a salt thereof, tipepidine or a salt thereof, dextromethorphan or a salt thereof, dimemorphan or a salt thereof, noscapine, methylephedrine or a salt thereof, aminophylline, diprophylline, theophylline, guaifenesin, carbocysteine, ambroxol or a salt thereof, Bromhexine or a salt thereof, methoxyphenamine or a salt thereof, trimethoquinol or a salt thereof, chlorpheniramine or a salt thereof, carbinoxamine or a salt thereof, loratadine, fexofenadine or a salt thereof, mequitazine, promethazine or a salt thereof, phenylephrine, tranexam. Acids, pseudoephedrine or salts thereof, belladonna total alkaloids, scopolamine or salts thereof, dimenhydrinate, papaverine, diphenhydramine or salts thereof, bromvalerylurea allylisopropylacetylurea, aluminum hydroxide gel, magnesium oxide, magnesium silicate, aluminum silicate, Synthetic hydrotalcite, magnesium hydroxide, sodium hydrogen carbonate, magnesium carbonate, magnesium aluminometasilicate, calcium hydrogen phosphate, aminoacetic acid, sofalcone, omeprazole, ursodesoxycholic acid, peppermint oil, lemon oil, menthol, aceto Aminophen, loxoprofen or a salt thereof, ibuprofen, etenzamid, aspirin, salicylamide, meclizine or a salt thereof, caffeine, ascorbic acid, riboflavin, domperidone, cetylpyridinium chloride, fungal extract, rhubarb, borei, fennel, shukusha, ryokyou , Koboku, Pheasant, Turmeric, Keihi, Ginger, Peony, Fern, Engosaku, Chazenshi and the like. In particular, when using a component having physicochemical properties such as adhesion to a manufacturing device that causes trouble in the manufacturing process, the present invention is highly meaningful. Examples of such pharmaceutically active ingredient include loxoprofen or a salt thereof, ibuprofen, ascorbic acid, caffeine and the like.
The content of the pharmaceutically active ingredient is preferably 0.05% by mass to 80% by mass, more preferably 0.1% by mass to 70% by mass, based on the total mass of the solid preparation.

In the present invention, the silicon dioxide to be dispersed in the granulation solvent at the time of spray granulation is not particularly limited as long as it is commonly used in the pharmaceutical industry. Examples thereof include light anhydrous silicic acid, heavy anhydrous silicic acid, and hydrous silicon dioxide, with light anhydrous silicic acid being preferred. The average particle size of silicon dioxide is preferably 0.0001 to 20 μm.

Examples of the spray granulation solvent used in the present invention include water, alcohols such as ethanol, and one or a mixed solvent of two or more thereof. From the viewpoint of the effect of the present invention, the content of silicon dioxide in the spray granulation solvent is preferably in the range of 0.001 part by mass to 0.1 part by mass with respect to 1 part by mass of the powder to be granulated. In addition to the solvent, the spray granulation solvent may contain sugar alcohol or low-substituted hydroxypropylcellulose in addition to the silicon dioxide of the present invention, but preferably does not contain other components. In particular, it is not preferable from the viewpoint of the effect of the present invention to manufacture by including a binder such as hypromellose or hydroxypropyl cellulose in the spray granulation solvent.

The sugar alcohol of the present invention is not particularly limited as long as it is commonly used as a drug, but mannitol, erythritol, xylitol, maltitol and sorbitol are preferable, and mannitol is more preferable. The sugar alcohol of the present invention may be added to the powder before granulation together with the pharmaceutically active ingredient of the present invention, or may be added to the granulation solvent for spray granulation soot formation. It is also possible to add a powder after mixing the sugar alcohol to the granulated product after granulation. From the viewpoint of the effect of the present invention, the content of the sugar alcohol of the present invention is preferably 10 to 85% by mass, more preferably 25 to 80% by mass, based on the entire final preparation.

Furthermore, the content of silicon dioxide in the spray granulation solvent is preferably 0.001 parts by mass to 10 parts by mass, more preferably 0.001 parts by mass to 5.0 parts by mass, relative to 1 part by mass of the pharmaceutically active ingredient. More preferably 0.005 to 5.0 parts by mass.
When the pharmaceutically active ingredient is loxoprofen, the content of silicon dioxide in the spray solvent is preferably 0.01 to 0.7 parts by mass with respect to 1 part by mass of loxoprofen. Similarly, in the case of ibuprofen, 0.005 to 0.3 parts by mass is preferable with respect to 1 part by mass of ibuprofen, and in the case of ascorbic acid, 0.01 to 0.5 parts by mass with respect to 1 part by mass of ascorbic acid. Is preferable, and in the case of caffeine, 0.01 to 0.5 parts by mass is preferable with respect to 1 part by mass of caffeine.

Further, the production method of the present invention requires a step of spray granulating a powder containing a pharmaceutically active ingredient in a solution in which silicon dioxide is dispersed, a fluidized bed granulation method, a stirring granulation method, a vacuum rolling granulation method. Method, vacuum stirring granulation method and the like can be used, but it is preferable to use the fluidized bed granulation method from the viewpoint of the effect of the present invention.

Further, in the solid preparation of the present invention, it does not prevent blending of silicon dioxide other than in the spray granulation solvent. It may be added to the powder before granulation, or may be added after the granulation. From the viewpoint of tablet physical properties and compression moldability, the upper limit of the content of silicon dioxide in the total mass of the final preparation is 10 parts by mass.

Examples of the solid preparation of the present invention that can be taken without water include orally disintegrating tablets, chewable tablets, and granules.

The orally disintegrating tablet of the present invention means a tablet in which the disintegration time in the oral cavity under normal chewing conditions is extremely fast. In addition, the chewable tablet of the present invention means a tablet that is taken by chewing. The orally disintegrating tablet or the chewable tablet is easy to take, and for example, it is a suitable dosage form for administration to children, the elderly, and busy business persons who are difficult to take ordinary tablets.
The size and shape of the orally disintegrating tablet or chewable tablet of the present invention are not particularly limited, and may be split tablets having score lines.

Orally disintegrating tablets, when producing chewable tablets, to the granulated product obtained by spray granulation with a solution of the silicon dioxide of the present invention, appropriately add the powdered additive components, tableting, etc. It is obtained by performing general compression molding of. As the tableting device, a device generally used for tablet molding is used, and for example, a single shot tableting machine, a rotary tableting machine or the like is used.
The production of the granules is not particularly limited, and for example, they may be produced by one granule containing all of them at the same time, or may be produced by grouping the granules into two granules or three or more granules. Good.

The solid preparation which can be taken without water of the present invention, other known excipients, disintegrating agents, binders, disintegrating agents, acidulants, effervescent agents, sweetening agents, as long as the effects of the present invention are not impaired. Flavors, flavors, lubricants, colorants, antioxidants, surfactants, plasticizers and the like may be added.

Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples and the like. When the tablet was produced, it was produced under the following equipment and conditions so that the tensile strength was 0.5 MPa or more.

Examples 1, 3-4, Comparative Examples 1-4
Equipment: Desktop simple tablet molding machine (Product name: HANDTAB; Ichihashi Seiki)
Tableting pressure: 3-10 kN
Example 2
Equipment: Small rotary tablet machine (Product name: VELA5; Kikusui Seisakusho)
Tableting pressure: 5-7kN
Examples 5-6
Equipment: Desktop simple tablet molding machine (Product name: Tabflex; Okada Seiko)
Tableting pressure: 600-800kgf

(Comparative Example 1)
The ingredients shown in the mixing powder in Table 1 were weighed and mixed into a uniform powder, while a solution in which the ingredients shown in the granulating solvent in Table 1 were also dissolved and dispersed was prepared, and a fluidized bed granulator (trade name) : MP-01; Paulec Co., Ltd.) to produce a granulated product by spray granulation. The granules thus obtained were weighed and mixed with the components added to the rear powder shown in Table 1 and then tableted to give tablets having a tablet diameter of 9.5 mm.

(Comparative example 2)
The ingredients shown in the mixing powder in Table 1 were weighed and mixed into a uniform powder, while a solution in which the ingredients shown in the granulating solvent in Table 1 were also dissolved and dispersed was prepared, and a fluidized bed granulator (trade name) : MP-01; Paulec Co., Ltd.) to produce a granulated product by spray granulation. The granules thus obtained were weighed and mixed with the components added to the rear powder shown in Table 1 and then tableted to give tablets having a tablet diameter of 9.5 mm.

(Comparative example 3)
The ingredients shown in the mixed powder in Table 1 were weighed and mixed into a uniform powder, while a solution in which the ingredients shown in the granulation solvent in Table 1 were also dissolved and dispersed was prepared and spray granulated using a mortar. A granulate was produced. The granules thus obtained were weighed and mixed with the components added to the rear powder shown in Table 1 and then tableted to give tablets having a tablet diameter of 9.5 mm.

(Example 1)
The ingredients shown in the mixing powder in Table 1 were weighed and mixed into a uniform powder, while a solution in which the ingredients shown in the granulating solvent in Table 1 were also dissolved and dispersed was prepared, and a fluidized bed granulator (trade name) : MP-01; Paulec Co., Ltd.) to produce a granulated product by spray granulation. The granules thus obtained were weighed and mixed with the components added to the rear powder shown in Table 1 and then tableted to give tablets having a tablet diameter of 9.5 mm.

(Example 2)
The ingredients shown in the mixed powder of the granulated product a in Table 1 were weighed and mixed to form a uniform powder, while a solution in which the ingredients shown in the granulation solvent in Table 1 were dissolved and dispersed was prepared to prepare a fluidized bed. A granulated product a was produced by spray granulation using a granulator (trade name: MP-01; Powrex Co., Ltd.). Similarly, the granulated material b was manufactured. The granulated product a and the granulated product b were mixed and homogenized, and then the powdered additive components shown in Table 1 were weighed and mixed, and then tableted to obtain tablets having a tablet diameter of 9.5 mm.

(Example 3)
The ingredients shown in the mixed powder in Table 1 were weighed and mixed into a uniform powder, while a solution in which the ingredients shown in the granulation solvent in Table 1 were also dissolved and dispersed was prepared and spray granulated using a mortar. A granulate was produced. The granules thus obtained were weighed and mixed with the components added to the rear powder shown in Table 1 and then tableted to give tablets having a tablet diameter of 9.5 mm.

The formulations of Examples 1 to 3 and Comparative Examples 1 to 3 are shown in Table 1.

<Evaluation Method 1> Examples 1 to 3 and Comparative Examples 1 to 3
(1) Hardness test The hardness of the tablets of Examples 1 to 3 and Comparative Examples 1 to 3 was measured three times using a Schleuniger tablet hardness meter (manufactured by Schleuniger). The obtained results were calculated using the following [Equation 1], the tensile strength was calculated, and the average value was calculated.

F: Tablet hardness (N)
D: Tablet diameter (mm)
t: Tablet thickness (mm)

As shown in Table 2, it was found that the tablets of Examples 1 to 3 and Comparative Examples 1 to 3 all had a tensile strength of 0.5 MPa or more and were tablets having an appropriate strength.

(2) Evaluation of Presence or Absence of Adhesion during Manufacturing Process Adhesion of the tablets of Examples 1 to 3 and Comparative Examples 1 to 3 to the wall of the granulator during granulation, and the mortar of the tableting machine during tableting, Adhesion to the punch and the turntable was observed according to the following evaluation criteria.
<Evaluation criteria>
Significant adhesion: ++
Some adhesion: +
No adhesion: −

(3) Disintegration test (Japanese Pharmacopoeia disintegration tester)
According to the disintegration test method described in the 16th revision of the Japanese Pharmacopoeia, the disintegration times of the tablets of Examples 1 to 3 and Comparative Examples 1 to 3 were measured 3 times each, and the average value was obtained.

Table 3 shows (2) the presence or absence of adhesion during the manufacturing process, and (3) the result of the disintegration test.

As shown in Table 3, the granules obtained by spray granulating a powder containing a pharmaceutically active ingredient with a solution in which light anhydrous silicic acid is dispersed and a solid preparation containing mannitol are attached to a device in a granulation step. However, the disintegration time also showed rapid disintegration within 50 seconds (Examples 1 to 3).
On the other hand, when the light anhydrous silicic acid was blended only in the mixed powder without including the granulated product spray-granulated with the solution in which the light anhydrous silicic acid was dispersed, the adhesion to the equipment was remarkable and the disintegration time was 60 seconds or more. (Comparative example 1). Further, even in the case of a preparation containing a granulated product in which light anhydrous silicic acid is dispersed in a solution and spray-granulated with a granulating solvent, if sugar alcohol is not contained in the preparation, adhesion to a device was confirmed ( Comparative Examples 2-3). It was also found that the inclusion of hypromellose, which is a binder, in the spray granulation solvent increased the disintegration time and increased the adherence to the device (compared with Comparative Examples 2 and 3).

(Example 4)
The ingredients shown in the mixed powder in Table 4 were weighed and mixed to form a uniform powder, while a solution in which the ingredients shown in the granulation solvent in Table 4 were dissolved and dispersed was prepared and spray granulated using a mortar. A granulate was produced. The granules thus obtained were weighed and mixed with the components added to the rear powder shown in Table 4 and then tableted to give tablets having a tablet diameter of 9.5 mm.

(Comparative Example 4)
The ingredients shown in the mixed powder in Table 4 were weighed and mixed to form a uniform powder, while a solution in which the ingredients shown in the granulation solvent in Table 4 were dissolved and dispersed was prepared and spray granulated using a mortar. A granulate was produced. The granules thus obtained were weighed and mixed with the components added to the rear powder shown in Table 1 and then tableted to give tablets having a tablet diameter of 9.5 mm.

The formulations of Example 4 and Comparative Example 4 are shown in Table 4.

<Evaluation Method 2> Example 4 and Comparative Example 4
(1) Hardness test and (3) Disintegration test were performed in the same manner as in Evaluation method 1.
(4) Appearance evaluation The tablets of Example 4 and Comparative Example 4 were stored in a tightly sealed state, and the appearance after storage for 2 weeks at 65° C. was observed by two specialized panelists, and relative comparison with the product immediately after production was performed. In accordance with the following evaluation criteria.
<Evaluation criteria>
Significant discoloration:++
Slightly discolored: +
No discoloration: −
The results of the tensile strength, the collapse test, and the appearance evaluation are shown in Table 5 below.

As shown in Table 5, it was found that the tablets of Example 4 and Comparative Example 4 all had a tensile strength of 0.5 MPa or more and were tablets having an appropriate strength. The disintegration time was 60 seconds or less in both Example 4 and Comparative Example 4, but the tablet of Comparative Example 4 produced by dispersing magnesium aluminometasilicate in a spray granulation solvent may have a significantly discolored formulation. Do you get it.

(Example 5)
The ingredients shown in the mixed powder in Table 6 were weighed and mixed to form a uniform powder, while a solution in which the ingredients shown in the granulation solvent in Table 6 were also dissolved and dispersed was prepared, and a fluidized bed granulator (trade name) : MP-01; Paulec Co., Ltd.) to produce a granulated product by spray granulation. The granules thus obtained were weighed and mixed with the components added to the rear powder shown in Table 1 and then tableted to give tablets having a tablet diameter of 8 mm.

(Example 6)
The ingredients shown in the mixed powder in Table 6 were weighed and mixed to form a uniform powder, while a solution in which the ingredients shown in the granulation solvent in Table 6 were also dissolved and dispersed was prepared, and a fluidized bed granulator (trade name) : MP-01; Paulec Co., Ltd.) to produce a granulated product by spray granulation. The granules thus obtained were weighed and mixed with the components added to the rear powder shown in Table 1 and then tableted to give tablets having a tablet diameter of 8 mm.

The formulations of Examples 5-6 are shown in Table 6.

<Evaluation method 3> Examples 5 to 6
(1) The hardness test and (2) the evaluation of the presence or absence of adhesion during the manufacturing process were performed in the same manner as the evaluation method 1.

(5) Oral disintegration test Two healthy adult panelists contained the tablets of Examples 5 and 6 in their mouths, without chewing in the oral cavity, and measuring the time until the tablets completely disintegrate in the oral cavity, The average value is shown.
Table 7 shows the tensile strength, the presence or absence of adhesion during the manufacturing process, and the result of the oral disintegration test.

As shown in Table 7, even when the powder contained ascorbic acid or anhydrous caffeine as a pharmaceutically active ingredient, it did not adhere to the device during the manufacturing process, and the oral disintegration time was excellent within 20 seconds. A formulation was obtained.

ADVANTAGE OF THE INVENTION According to this invention, the solid formulation which is excellent in manufacturability, has desired moderate hardness, is excellent in formulation stability, and rapidly disintegrates or dissolves in the oral cavity and can be taken without water can be provided.

Claims (6)

Loxoprofen or its salt, ibuprofen, powder containing a pharmaceutically active ingredient which is at least one selected from caffeine and ascorbic acid , spray granulated with a solution in which silicon dioxide is dispersed, characterized by sugar sugar, A method for producing a solid preparation which can be taken without containing water. The method for producing a solid preparation according to claim 1, wherein the solid preparation that can be taken without water is an orally disintegrating tablet or a chewable tablet. The method for producing a solid preparation according to claim 1, wherein the silicon dioxide is light anhydrous silicic acid. The method for producing a solid preparation according to claim 1 or 3, wherein the average particle diameter of silicon dioxide is 0.0001 to 20 µm. The method for producing a solid preparation according to claim 1, wherein the sugar alcohol is at least one selected from the group consisting of mannitol, erythritol, and xylitol. The method for producing a solid preparation according to claim 1 or 5, wherein the content of the sugar alcohol is 10 to 80% by mass based on the total mass of the solid preparation.