JP2016020330A - Solid preparations - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a solid preparation which has proper hardness, can dissolve rapidly, has excellent formulation stability, and can be taken without water; and also to provide a production method which can inhibit adhesion even in the case where the formulation contains a pharmaceutical active ingredient which has poor manufacturability which causes adhesion and the like to a manufacturing equipment when manufacturing.SOLUTION: The invention relates to a solid preparation, which can be taken without water, containing (a) a granulated material obtained by spray-granulation of powders containing medical active ingredients with the solution in which silicon dioxide is dispersed; and (b) a sugar alcohol.SELECTED DRAWING: None

Description

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

A solid formulation that can be taken without water is an excellent formulation that is easy to take even for people with low swallowing ability, especially children and the elderly, and has the merit that it can be taken even in situations where there is no water, regardless of the scene. Patent Document 1).
So far, various studies have been made to obtain orally disintegrating tablets. For example, starch powder and gelatinized starch, water-soluble excipient containing mannitol, orally disintegrating tablet containing sodium stearyl fumarate and medicinal ingredients (Patent Document 1), low moldability saccharide and high moldability saccharide In-oral dissolution type compression-molded product having a rapid disintegration property and solubility in the oral cavity (Patent Document 2) and the like have been reported.
However, in Patent Document 1, when starch powder and starch that has been gelatinized are used, sticking to a manufacturing apparatus or the like is likely to occur, and handling in manufacturing is difficult. Moreover, in the method of patent document 2, since the humidification / drying process after tableting at low pressure is an indispensable condition in order to manufacture an orally disintegrating tablet, the number of manufacturing processes increases and the operation is complicated.
Moreover, the composition for compression molding which maintains the hardness required for carrying by coating saccharides with a metasilicate aluminate, and shows a rapid disintegration property in the oral cavity is reported (patent document 3). However, it has been found that when an active pharmaceutical ingredient is coated with metasilicate aluminate, interaction occurs and appearance stability is poor, and there is a problem in merchantability.

  In addition, the active pharmaceutical ingredients contained in the preparation may greatly affect manufacturability depending on their physical properties. For example, when blending active pharmaceutical ingredients known to cause adhesion to the machine wall or mortar during granulation or tableting, as an additive for granulation or tableting aid, Devises such as increasing the amount of lubricants such as talc and magnesium stearate. However, although it is effective in preventing adhesion, it causes further problems such as decay delay and capping. Further, 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 by spray granulating a powder containing an active pharmaceutical ingredient with a binder solution in which light anhydrous silicic acid is dispersed has been reported (Patent Document 5). ). However, the tablet obtained by patent document 5 has a subject in the rapid disintegration required for the formulation 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 Amendment Japanese Pharmacopoeia Manual Yodogawa Shoten Co., Ltd. A-33-34

  An object of the present invention is to provide a solid preparation that can be taken without water, having moderate hardness and rapid disintegration, and excellent in the stability of the preparation. Another object of the present invention is to provide a production method capable of suppressing adhesion even when a pharmaceutical active ingredient having poor manufacturability that causes adhesion or the like to production equipment during production is blended.

  The inventors of the present invention conducted various studies to achieve the above object. As a result, a granulated product obtained by spray granulating a powder containing an active pharmaceutical ingredient with a solution in which silicon dioxide was dispersed, and a sugar alcohol were obtained. It has been found that the contained solid preparation has an appropriate hardness and rapid disintegration and is excellent in the stability of the preparation. Further, the present inventors have found that the preparation can be produced without causing discoloration of the preparation and causing no adhesion to production equipment during production, thereby completing the present invention.

That is, the present invention
(1) (a) a granulated product obtained by spray granulating a powder containing an active pharmaceutical ingredient with a solution in which silicon dioxide is dispersed; and (b) a sugar alcohol, which is used 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 average particle size of silicon dioxide is 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 active pharmaceutical ingredient is at least one selected from the group consisting of an antipyretic analgesic component, an antihistamine, a central nervous stimulant, and a vitamin.
(7) The solid preparation according to (1) or (6), wherein the active pharmaceutical ingredient is at least one selected from loxoprofen or a salt thereof, ibuprofen, caffeine and ascorbic acid,
(8) The solid formulation according to (1) or (5), wherein the sugar alcohol content is 10 to 80% by mass relative to the total mass of the solid formulation,
(9) A method for producing a solid preparation that can be taken without water containing a sugar alcohol, characterized by spray granulating a powder containing a pharmaceutically active ingredient with a solution in which silicon dioxide is dispersed;
It is.

  According to the present invention, it has a desired moderate hardness and rapid disintegration. In the disintegration test or oral disintegration test by the Japanese Pharmacopoeia, the disintegration time is within 60 seconds, more preferably within 50 seconds, and particularly preferably 30. Within seconds, a solid formulation is obtained. Furthermore, it has an appropriate strength that is not damaged in 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. can get. Moreover, according to the manufacturing method of this invention, it became possible to suppress adhesion to manufacturing equipment etc. at the time of manufacture.

  Hereinafter, the solid preparation which can be taken without water of the present invention and the production method thereof will be described.

The pharmaceutical active ingredient of the present invention is not particularly limited as long as it is a component that can be used in medicine. For example, antitussive expectorant, bronchodilator, central stimulant, antihistamine, hypnotic sedative, antispasmodic, Gastrointestinals, antacids, nourishing tonics, antipyretic analgesics, vitamins, antiemetics, bactericides, herbal medicines 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, diprofylline, theophylline, guaifenesin, carbocysteine, ambroxol or a salt thereof, Bromhexine or salt thereof, methoxyphenamine or salt thereof, trimethquinol or salt thereof, chlorpheniramine or salt thereof, carbinoxamine or salt thereof, loratadine, fexofenadine or salt thereof, mequitazine, promethazine or salt thereof, phenylephrine, tranexam Acid, pseudoephedrine or salt thereof, belladonna total alkaloid, scopolamine or salt thereof, dimenhydrinate, papaverine, diphenhydramine or salt thereof Bromvaleryl urea Allyl isopropyl acetyl urea, aluminum hydroxide gel, magnesium oxide, magnesium silicate, aluminum silicate, synthetic hydrotalcite, magnesium hydroxide, sodium bicarbonate, magnesium carbonate, magnesium metasilicate magnesium phosphate, calcium hydrogen phosphate, Aminoacetic acid, sofalcone, omeprazole, ursodeoxycholic acid, peppermint oil, lemon oil, menthol, acetaminophen, loxoprofen or a salt thereof, ibuprofen, etenzamide, aspirin, salicylamide, meclizine or a salt thereof, caffeine, ascorbic acid , Riboflavin, Domperidone, Cetylpyridinium chloride, Rohto extract, Diou, Borei, Fennel, Shukusha, Ryokyo, Koboku, Pheasant, Con, cinnamon, ginger, peony, licorice, Corydalis, Shazenshi and the like. In particular, when using a component having physicochemical properties such as adhesion to a manufacturing device that hinders the manufacturing process, it is highly meaningful to implement the present invention. Examples of such pharmaceutically active ingredients 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 and more preferably 0.1% by mass to 70% by mass with respect to the total mass of the solid preparation.

  In the present invention, the silicon dioxide dispersed in the granulating solvent when spray granulating is not particularly limited as long as it is generally used in the pharmaceutical industry. For example, light anhydrous silicic acid, heavy anhydrous silicic acid, hydrous silicon dioxide and the like can be mentioned, and light anhydrous silicic acid is preferable. The average particle diameter 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 more mixed solvents thereof. The content of silicon dioxide in the spray granulation solvent is preferably in the range of 0.001 to 0.1 parts by mass with respect to 1 part by mass of the granulated powder from the viewpoint of the effect of the present invention. In addition to the silicon dioxide of the present invention, sugar alcohol or low-substituted hydroxypropylcellulose may be blended in the spray granulation solvent, but it is preferable not to blend other components. In particular, it is not preferable from the viewpoint of the effect of the present invention to produce a binder such as hypromellose or hydroxypropylcellulose in a spray granulation solvent.

  The sugar alcohol of the present invention is not particularly limited as long as it is generally used as a pharmaceutical product, but is preferably mannitol, erythritol, xylitol, maltitol, sorbitol, and more preferably mannitol. The sugar alcohol of the present invention may be blended with the active pharmaceutical ingredient of the present invention in the powder before granulation, or may be blended in a granulation solvent for spray granulation, It is also possible to add powder after mixing the sugar alcohol to the granulated product after granulation. 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, from the viewpoint of the effect of the present invention.

Furthermore, the content of silicon dioxide in the spray granulation solvent is preferably 0.001 to 10 parts by mass, more preferably 0.001 to 5.0 parts by mass with respect to 1 part by mass of the active pharmaceutical ingredient. 0.005 mass part-5.0 mass parts is further more preferable.
When the pharmaceutical 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. In the case of caffeine, it is preferably 0.01 to 0.5 parts by mass with respect to 1 part by mass of caffeine.

  In addition, the production method of the present invention requires a step of spray granulating a powder containing an active pharmaceutical ingredient in a solution in which silicon dioxide is dispersed. The fluidized bed granulation method, the stirring granulation method, the vacuum rolling granulation However, it is desirable to use the fluidized bed granulation method in view of the effect of the present invention.

  Further, in the solid preparation of the present invention, it does not preclude blending silicon dioxide other than in the spray granulation solvent. You may mix | blend in the powder before granulation, and may add later after granulation. The upper limit of the content of silicon dioxide in the total mass of the final preparation is 10 parts by mass from the viewpoints of tablet physical properties and compression moldability.

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

The orally disintegrating tablet of the present invention means a tablet having a very fast disintegration time in the oral cavity under normal chewing conditions. In addition, the chewable tablet of the present invention means a tablet that is chewed and taken. Orally disintegrating tablets or chewable tablets are easy to take, and are suitable for administration to, for example, children, elderly people, 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 a split tablet having a score line.

When producing an orally disintegrating tablet or chewable tablet, add a suitable additive to the granulated product obtained by spray granulation with a solution in which the silicon dioxide of the present invention is dispersed, tableting, etc. It is obtained by performing the general compression molding. As the tableting device, a device generally used for tablet formation is used, and for example, a single-shot tableting machine, a rotary tableting machine, or the like is used.
The production of the granule is not particularly limited. For example, it may be produced by one granule containing all at the same time, or it may be produced by grouping the granule into two granules or three or more granules. Also good.

  In the solid preparation that can be taken without water of the present invention, other known excipients, disintegrants, binders, disintegrants, sour agents, foaming agents, sweeteners, as long as the effects of the present invention are not hindered. A flavoring agent, a fragrance, a lubricant, a coloring agent, an antioxidant, a surfactant, a plasticizer, and the like may be blended.

  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. In addition, when manufacturing a tablet, it manufactured with the following apparatuses and conditions so that tensile strength might be 0.5 Mpa or more.

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

(Comparative Example 1)
The components shown in Table 1 were weighed and mixed to obtain a uniform powder, while a solution in which the components shown in Table 1 were dissolved and dispersed was prepared, and a fluidized bed granulator (trade name) : MP-01; Pauleck Co., Ltd.) to produce a granulated product by spray granulation. The resulting granulated product was weighed and mixed with the latter additive components shown in Table 1, and then tableted to obtain tablets with a tablet diameter of 9.5 mm.

(Comparative Example 2)
The components shown in Table 1 were weighed and mixed to obtain a uniform powder, while a solution in which the components shown in Table 1 were dissolved and dispersed was prepared, and a fluidized bed granulator (trade name) : MP-01; Pauleck Co., Ltd.) to produce a granulated product by spray granulation. The resulting granulated product was weighed and mixed with the latter additive components shown in Table 1, and then tableted to obtain tablets with a tablet diameter of 9.5 mm.

(Comparative Example 3)
The ingredients shown in Table 1 are weighed and mixed to form a uniform powder, while preparing a solution in which the ingredients shown in Table 1 are dissolved and dispersed, and spray granulation using a mortar. A granulated product was produced. The resulting granulated product was weighed and mixed with the latter additive components shown in Table 1, and then tableted to obtain tablets with a tablet diameter of 9.5 mm.

Example 1
The components shown in Table 1 were weighed and mixed to obtain a uniform powder, while a solution in which the components shown in Table 1 were dissolved and dispersed was prepared, and a fluidized bed granulator (trade name) : MP-01; Pauleck Co., Ltd.) to produce a granulated product by spray granulation. The resulting granulated product was weighed and mixed with the latter additive components shown in Table 1, and then tableted to obtain tablets with a tablet diameter of 9.5 mm.

(Example 2)
The components shown in the mixed powder of the granulated product a in Table 1 are weighed and mixed to obtain a uniform powder, and on the other hand, a solution in which the components shown in the granulating solvent in Table 1 are dissolved and dispersed is prepared. A granulated product a was produced by spray granulation with a granulator (trade name: MP-01; Pauleck Co., Ltd.). Similarly, granulated product b was produced. After the granulated product a and the granulated product b were mixed and made uniform, the powdered additive components shown in Table 1 were weighed and mixed, and then tableted to obtain tablets with a tablet diameter of 9.5 mm.

(Example 3)
The ingredients shown in Table 1 are weighed and mixed to form a uniform powder, while preparing a solution in which the ingredients shown in Table 1 are dissolved and dispersed, and spray granulation using a mortar. A granulated product was produced. The resulting granulated product was weighed and mixed with the latter additive components shown in Table 1, and then tableted to obtain tablets with a tablet diameter of 9.5 mm.

  Table 1 shows the formulations of Examples 1 to 3 and Comparative Examples 1 to 3.

<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 Schleunigel tablet hardness tester (manufactured by Schleunigel). The obtained results were calculated using the following [Equation 1], the tensile strength was calculated, and the average value was obtained.

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 had a tensile strength of 0.5 MPa or more, and had moderate strength.

(2) Evaluation of the presence or absence of adhesion during the manufacturing process The tablets of Examples 1 to 3 and Comparative Examples 1 to 3 adhered to the granulator wall during granulation, and the die of the tableting machine during tableting, The adhesion to the ridge and the rotating disk was observed according to the following evaluation criteria.
<Evaluation criteria>
Significant adhesion: ++
Slight 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 three times, and the average value was obtained.

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

As shown in Table 3, a granulated product 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 adhered to the device in the granulation process. The decay time also showed rapid decay within 50 seconds (Examples 1 to 3).
On the other hand, when the light anhydrous silicic acid is not included in the granulated product sprayed with a solution in which light anhydrous silicic acid is dispersed and the light anhydrous silicic acid is blended only in the mixed powder, the adhesion to the equipment is remarkable and the disintegration time is 60 seconds or more. (Comparative Example 1). In addition, even a formulation containing a granulated product obtained by dispersing light anhydrous silicic acid in a solution and spray granulating with a granulating solvent, adhesion to the device was confirmed if the formulation contained no sugar alcohol ( Comparative Examples 2-3). Moreover, it was found that when hypromellose as a binder was included in the spray granulation solvent, the disintegration time was delayed and the adhesion to the device increased (comparison with Comparative Examples 2 and 3).

Example 4
The components shown in Table 4 were weighed and mixed to obtain a uniform powder, while preparing a solution in which the components shown in Table 4 were dissolved and dispersed, and spray granulation using a mortar. A granulated product was produced. The resulting granulated product was weighed and mixed with the additive components shown in Table 4, and then tableted to obtain tablets with a tablet diameter of 9.5 mm.

(Comparative Example 4)
The components shown in Table 4 were weighed and mixed to obtain a uniform powder, while preparing a solution in which the components shown in Table 4 were dissolved and dispersed, and spray granulation using a mortar. A granulated product was produced. The resulting granulated product was weighed and mixed with the latter additive components shown in Table 1, and then tableted to obtain tablets with 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
The (1) hardness test and (3) disintegration test were performed in the same manner as in the evaluation method 1.
(4) Appearance evaluation The tablets of Example 4 and Comparative Example 4 were stored in a sealed state, and the appearance after storage for 2 weeks at 65 ° C. was observed by two specialized panelists. In accordance with the following evaluation criteria.
<Evaluation criteria>
Significant discoloration: ++
Slightly discolored: +
No discoloration:-
Table 5 shows the results of tensile strength, disintegration test, and appearance evaluation.

  As shown in Table 5, the tablets of Example 4 and Comparative Example 4 were all tablets having a tensile strength of 0.5 MPa or more and having moderate strength. In both Example 4 and Comparative Example 4, the disintegration time was within 60 seconds, but the tablet of Comparative Example 4 produced by dispersing magnesium aluminate metasilicate in a spray granulation solvent may cause the formulation to discolor significantly. I understood.

(Example 5)
The components shown in Table 6 were weighed and mixed to obtain a uniform powder, and on the other hand, a solution in which the components shown in Table 6 were dissolved and dispersed was prepared, and a fluidized bed granulator (trade name) : MP-01; Pauleck Co., Ltd.) to produce a granulated product by spray granulation. The resulting granulated product was weighed and mixed with the powdered ingredients shown in Table 1, and then tableted to obtain tablets with a tablet diameter of 8 mm.

(Example 6)
The components shown in Table 6 were weighed and mixed to obtain a uniform powder, and on the other hand, a solution in which the components shown in Table 6 were dissolved and dispersed was prepared, and a fluidized bed granulator (trade name) : MP-01; Pauleck Co., Ltd.) to produce a granulated product by spray granulation. The resulting granulated product was weighed and mixed with the powdered ingredients shown in Table 1, and then tableted to obtain tablets with a tablet diameter of 8 mm.

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

<Evaluation Method 3> Examples 5-6
(1) Hardness test and (2) Evaluation of the presence or absence of adhesion during the production process were performed in the same manner as in Evaluation Method 1.

(5) Oral disintegration test Two healthy adult panelists included the tablets of Examples 5 and 6 in their mouths, and measured the time until the tablets completely disintegrated in the oral cavity, without entanglement in the oral cavity. The average value was shown.
Table 7 shows the tensile strength, the presence or absence of adhesion during the production process, and the results of the oral disintegration test.

  As shown in Table 7, even when the powder contains ascorbic acid or caffeine anhydride as a pharmaceutical active ingredient, there is no adhesion to the device during the production process, and the oral disintegration time is excellent within 20 seconds. Preparations were obtained.

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

Claims (9)

  (A) a granulated product obtained by spray granulating a powder containing an active pharmaceutical ingredient with a solution in which silicon dioxide is dispersed; and (b) a solid that can be taken without water, comprising a sugar alcohol Formulation.   The 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 solid preparation according to claim 1, wherein the silicon dioxide is light anhydrous silicic acid.   The solid preparation according to claim 1 or 3, wherein the average particle diameter of silicon dioxide is 0.0001 to 20 µm.   The 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 solid preparation according to claim 1, wherein the active pharmaceutical ingredient is at least one selected from the group consisting of an antipyretic analgesic ingredient, an antihistamine, a central nervous stimulant, and a vitamin preparation.   The solid preparation according to claim 1 or 6, wherein the pharmaceutically active ingredient is at least one selected from loxoprofen or a salt thereof, ibuprofen, caffeine and ascorbic acid.   The solid preparation according to claim 1 or 5, wherein the sugar alcohol content is 10 to 80% by mass relative to the total mass of the solid preparation.   A method for producing a solid preparation which can be taken without water containing a sugar alcohol, characterized by spray granulating a powder containing an active pharmaceutical ingredient with a solution in which silicon dioxide is dispersed.