HK1179172A - Orally disintegrating tablet - Google Patents

Description

Orally disintegrating tablet

Technical Field

The present invention relates to an intraorally disintegrating tablet containing an organic acid as a disintegration accelerator.

Background

Orally disintegrating tablets containing organic acids such as ascorbic acid and citric acid are known. Specific examples thereof include orally disintegrating tablets containing ascorbic acid as an active ingredient (patent documents 1 to 3) and orally disintegrating tablets containing ascorbic acid as an active ingredient as a dissolving agent added to ensure absorbability (patent documents 4 and 5), but nothing is described or suggested about the contribution of ascorbic acid to disintegration in the orally disintegrating tablets. As a technique for achieving the disintegration property, a technique of containing ascorbic acid and citric acid as a foamable disintegrating agent which requires a combination of carbonate is known (patent document 6).

On the other hand, the orally disintegrating tablets have been studied for the purpose of simultaneously achieving an orally disintegrating property, a masking property of unpleasant taste or irritating sensation such as bitterness derived from an active ingredient, and an elution property realized in the intestinal tract (an elution property controlled to be equal to that of a general tablet, a controlled elution property such as sustained release property, etc.).

As an example thereof, there is known an intraorally disintegrating tablet obtained by coating core particles containing an active ingredient with a substance obtained by further mixing a water-insoluble polymer such as ethyl cellulose or an enteric polymer such as a methacrylic acid copolymer with a disintegrant such as croscarmellose sodium or a water-permeable ingredient such as hypromellose, and compression-molding the resulting particles together with the ingredient such as the disintegrant (patent documents 7 and 8).

However, although this method is excellent in the masking property such as bitterness and the dissolution property in the intestinal tract, the disintegration property immediately after production is poor, and there is a problem in that a good-quality preparation can be stably supplied.

Documents of the prior art

Patent document

Patent document 1, Japanese patent laid-open No. 2009-161495

Patent document 2 Japanese patent No. 3884056

Patent document 3 Japanese patent laid-open publication No. 2002-121133

Patent document 4 Japanese patent application laid-open No. 2003-512402

Patent document 5 Japanese laid-open patent publication No. 2002-316923

Patent document 6 Japanese patent application laid-open No. Hei 5-500956

Patent document 7 Japanese patent laid-open publication No. 2003-504324

Patent document 8, Japanese patent laid-open No. 2008-214334.

Disclosure of Invention

Technical problem to be solved by the invention

The purpose of the present invention is to provide an intraorally disintegrating tablet which has a bitterness-masking property and a good elution property and which constantly maintains a good intraorally disintegrating property from immediately after production.

Technical means for solving technical problems

As a result of intensive studies in view of the above-mentioned problems, the present inventors have found that a preparation prepared by coating a core particle containing an active ingredient with a water-insoluble polymer or an enteric polymer and compression-molding the resulting particle together with an organic acid such as ascorbic acid and citric acid has a masking property such as bitterness and a good elution property, and maintains a good intraoral disintegration property constantly from immediately after production, and have completed the present invention.

That is, the present invention is an intraorally disintegrating tablet formed by coating core particles containing an active ingredient with a coating layer containing a water-insoluble polymer and/or an enteric polymer, and compression-molding the resulting particles together with an organic acid.

Effects of the invention

The present invention provides an intraorally disintegrating tablet which has a bitterness-masking property and a good elution property and which constantly maintains a good intraorally disintegrating property immediately after production.

Detailed Description

The present invention relates to an intraorally disintegrating tablet, which is formed by coating core particles containing an active ingredient with a coating layer containing a water-insoluble polymer and/or an enteric polymer, and compression-molding the resulting particles together with an organic acid.

The intraorally disintegrating tablet in the present invention means a tablet which can be taken by disintegrating in the oral cavity within 60 seconds, preferably within 30 seconds, by saliva in the oral cavity or by taking a small amount of water.

The hardness of the intraorally disintegrating tablet of the present invention is preferably 29N or more, and more preferably 49N or more. For the preferable dissolution property of the tablet of the present invention, the dissolution rate after 60 minutes evaluated by the japanese pharmacopoeia paddle method at 50 rpm using Mcllvaine buffer solution of ph6.0 is 80% or more.

The core particle in the present invention may contain a fluidizing agent such as light anhydrous silicic acid, talc, stearic acid or a metal salt thereof, in addition to the active ingredient.

The size of the core particle in the present invention is usually 1 to 50 μm, preferably 3 to 30 μm, as a median diameter measured by a laser diffraction method.

The core particle in the present invention is coated with a coating agent containing a water-insoluble polymer, an enteric polymer or a mixture thereof. Examples of the water-insoluble polymer include ethyl cellulose, aminoalkyl methacrylate copolymer RS, and ethyl acrylate/methyl methacrylate copolymer, and examples of the enteric polymer include methacrylic acid/ethyl acrylate copolymer, methacrylic acid/methyl methacrylate copolymer, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate. The coating agent may contain, in addition to these, a plasticizer such as polyethylene glycol, triethyl citrate, acetylated monoglyceride, triacetin, polysorbate 80, or propylene glycol, an anti-agglomerating agent such as talc, titanium oxide, stearic acid or a metal salt thereof, a sucrose fatty acid ester, or sodium stearyl fumarate, a disintegrating agent such as croscarmellose sodium, low-substituted hydroxypropyl cellulose, or crosslinked polyvinylpyrrolidone, and an elution rate adjusting substance such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, or polyvinylpyrrolidone.

The methacrylic acid copolymer used in the present invention is not particularly limited, and examples thereof include a methacrylic acid copolymer LD (for example, trade name: オイドラギット L30D55, エボニック Co., Ltd.), a methacrylic acid copolymer L (for example, trade name: オイドラギット L100, エボニック Co., Ltd.), a methacrylic acid copolymer S (for example, trade name: オイドラギット S100, エボニック Co., Ltd.), and the like.

The content (coating rate) of the coating layer containing the water-insoluble polymer or the enteric polymer is usually 2 to 100% by weight, preferably 5 to 80% by weight, and more preferably 10 to 60% by weight, based on the core particle.

Examples of the organic acid used in the present invention include ascorbic acids such as ascorbic acid, sodium ascorbate, potassium ascorbate, and ascorbic acid 2 glucoside, citric acid and citrate (collectively referred to as "citric acids", the same applies hereinafter), fumaric acid and fumarate (fumaric acids), malic acid and malate (malic acids), and tartaric acid and tartrate (tartaric acids), and among them, ascorbic acids and citric acids are preferable.

The content of these organic acids is usually 0.5 to 20% by weight, preferably 1 to 10% by weight, and more preferably 2 to 5% by weight, based on the weight of the tablet.

The tablet of the present invention may contain additives generally used in tablets within a range not particularly affecting bitterness-masking property, enteric property, disintegratability, and the like. Examples of the additives include excipients, binders, lubricants, and flavoring agents.

The orally disintegrating tablet of the present invention is particularly preferably an orally disintegrating tablet in which a core particle containing an active ingredient is coated with a layer containing a water-insoluble polymer and/or an enteric polymer, and the resulting particle, a granule obtained by coating the particle containing a disintegrant with a disintegrant, and an organic acid are compression-molded together.

The active ingredient in the tablet of the present invention is not particularly limited, and examples thereof include 2- (3-cyano-4-isobutoxyphenyl) -4-methyl-5-thiazolecarboxylic acid (hereinafter sometimes referred to as "compound I").

The intraorally disintegrating tablet of the present invention can be produced without difficulty using a conventional production machine or a production machine with a little change. For example, the particles are prepared by coating the active ingredient with a coating layer containing a water-insoluble polymer or an enteric polymer, and then compression-molding the particles together with particles of ascorbic acid compounds or citric acid compounds and 1 or more pharmaceutically acceptable additives.

Examples

[ example 1] (with ascorbic acid outside the particles)

15.1g of polysorbate 80 (sun light ケミカルズ) was added to 522.8g of purified water, and after mixing, 35.3g of talc (Nixing pharmaceutical) and 12.6g of croscarmellose sodium (FMC) were added and sufficiently stirred (solution 1). Separately, 427g of pure water was dissolved in 1.4g of sodium hydroxide (Wako pure chemical industries, Ltd.) to give a solution, which was added to 380.3g of methacrylic acid copolymer LD (エボニック Co., Ltd.; オイドラギット L30D 55) and stirred (solution No. 2). Adding the 2 nd solution into the 1 st solution to suspend the solution, and sieving the solution to prepare a coating dispersion.

300g of Compound I and 15g of light anhydrous silicic acid (フロイント, trade name; アドソリダー 101) were charged into a seed coating/seeding apparatus (パウレック, MP-01 SFP), and the above coating dispersion was sprayed to obtain drug-containing particles.

870g of D-mannitol (trade name: マンニット P, manufactured by Tokyo Kaisha Kogyo Co., Ltd.), 40g of light anhydrous silicic acid (trade name: フロイント, manufactured by Kogyo Kaisha Kogyo Co., Ltd.; アドソリダー 101) and 45g of crosslinked polyvinylpyrrolidone (ISP, trade name: ポリプラスドン XXL-10) were charged into a fluidized bed granulator (パウレック, MP-01), and 144g of pure water was sprayed to obtain granules. 45g of crospovidone was put into the granules, and powder coating was performed to prepare disintegrant-coated granules.

To 108.5g of the disintegrant-coated granule, 36.2g of drug-containing particles, 3.0g of ascorbic acid (Wutian chemical industry), and 2.3g of calcium stearate (Japanese oil and fat) were added, mixed, and then compression-molded using a rotary tablet press (Utsu iron house, see HT-AP6 SS-U). The molding conditions were 250mg of the tablet weight, a straight line (a horizontal pestle) having a diameter of 8mm, and the tablet was compressed so that the hardness became about 78.5N.

[ example 2 ] (citric acid outside the particles)

Tablets were prepared by the same method as in example 1 except that the ascorbic acid of example 1 was replaced with citric acid.

[ example 3 ] (with sodium ascorbate in the outside of the granule)

Tablets were prepared by the same method as in example 1 except that ascorbic acid in example 1 was replaced with sodium ascorbate.

[ example 4 ] (with ascorbic acid 2 glucoside outside the granule)

Tablets were prepared by the same method as in example 1 except that ascorbic acid of example 1 was replaced with ascorbic acid 2 glucoside.

[ comparative example ] (No ascorbic acid, citric acid, sodium ascorbate, ascorbic acid 2 glucoside outside the granule)

15.1g of polysorbate 80 (sun light ケミカルズ) was added to 522.8g of purified water, and after mixing, 35.3g of talc (Nixing pharmaceutical) and 12.6g of croscarmellose sodium (FMC) were added and sufficiently stirred (solution 1). Separately, 427g of pure water was dissolved in 1.4g of sodium hydroxide (Wako pure chemical industries, Ltd.) to obtain a solution, which was added to 380.3g of methacrylic acid copolymer LD (エボニック Co., Ltd.; オイドラギット L30D 55) and stirred (solution No. 2). Adding the 2 nd solution into the 1 st solution to suspend the solution, and sieving the solution to prepare a coating dispersion.

Then, the above coating dispersion was sprayed with compound I and light anhydrous silicic acid in the same manner as in example, to obtain drug-containing particles. Further, disintegrant-coated granules were prepared by the same method as in examples.

To 112.4g of disintegrant-coated granule, 35.3g of drug-containing particles and 2.3g of calcium stearate (Japanese oil and fat) were added and mixed, followed by compression molding using a rotary tablet machine (examined and ironed culture vessel, see Utilia, Ltd., HT-AP6 SS-U) under the same molding conditions as in examples.

[ test example ]

The tablets of examples 1 to 4 and comparative example were evaluated for intraoral disintegration time and masking property immediately after production. The masking property evaluation method was performed by 2 healthy adult males, and the masking property of the disintegrated main drug stimulus was evaluated by placing the tablet on the tongue according to the following criteria:

0: has obvious shielding effect and can not feel stimulation completely

1: has shielding effect and hardly senses irritation

2: having a masking effect but feeling a stimulus

3: the masking effect is weak, and the stimulus is strongly felt (acceptable)

4: without masking effect, the stimulus is strongly felt (unacceptable)

The results are shown in Table 1.

[ Table 1]

In the comparative example, even in the formulation containing the disintegrant, the disintegration was significantly delayed and the masking property was reduced. However, in examples 1 to 4, the addition of the organic acid improved the disintegration property and the masking property.

Industrial applicability

The present invention is used for producing an intraorally disintegrating tablet.

Claims (6)

1. An orally disintegrating tablet is obtained by coating core particles containing an active ingredient with a layer containing a water-insoluble polymer and/or an enteric polymer, and compression-molding the resulting particles together with an organic acid.

2. The tablet according to claim 1, wherein the content of the organic acid is 1 to 10% by weight.

3. The tablet according to claim 1 or 2, wherein the organic acid is an ascorbic acid and/or a citric acid.

4. The tablet according to any one of claims 1 to 3, wherein the water-insoluble polymer and/or the enteric polymer is a methacrylic acid copolymer.

5. A tablet according to any one of claims 1 to 3, wherein the water-insoluble polymer and/or the enteric polymer is ethyl cellulose.

6. An orally disintegrating tablet is obtained by coating a core particle containing an active ingredient with a layer containing a water-insoluble polymer and/or an enteric polymer, and compression-molding the resulting particle, a granule obtained by coating a particle containing a disintegrant with a disintegrant, and an organic acid.