JP2011162531A - Fexofenadine-including, film-coating oral pharmaceutical preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a fexofenadine oral pharmaceutical preparation with a stability-improved film coating relating to the film-coating oral pharmaceutical preparation including fexofenadine or a physiologically allowable salt of the same (hereinafter simply described as "fexofenadine"). <P>SOLUTION: The fexofenadine oral pharmaceutical preparation is a granulated product produced from a fexofenadine bulk drug or such as a filler wherein the surfaces of plain tablets have film coating layers substantially including no plasticizer. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a film-coated oral preparation containing fexofenadine or a physiologically acceptable salt thereof (hereinafter simply referred to as “fexofenadine”). More specifically, the present invention relates to a fexofenadine oral preparation coated with a film coating composition containing substantially no plasticizer. More specifically, the present invention includes fexofenadine tablets coated with a film coating composition that is substantially free of polyethylene glycol.

  Fexofenadine is useful as an antihistamine disclosed in US Pat. No. 4,254,129 and US Patent Application Publication No. 2002-0193603, and is widely used as a therapeutic agent. However, fexofenadine is known to be unstable to heat, humidity and light and to have a bitter taste. Tablets already on the market are film-coated and are thought to be intended to compensate for the above drawbacks. In the tablet, a normal coating composition, that is, a plasticizer typified by polyethylene glycol is used. This seems to be based on the idea that plasticizers such as polyethylene glycol do not interact with active ingredients in conventional pharmaceuticals.

Conventionally, it is well known to use a plasticizer for film coating. The following are known as tablet film coating compositions containing polyethylene glycol as a plasticizer.
Patent Document 1 relates to a film coating of a solid dispersion, which is a film coating method using an aqueous coating liquid as a coating liquid. The aqueous coating liquid contains a water-soluble polymer compound, and has high water solubility. Polyethylene glycol is described as a specific example of the molecular compound. It is a technology aimed at shielding the unpleasant taste and odor of the active ingredient, and improving stability against light and moisture.
Patent Document 2 relates to a fast-dissolving film-coated tablet excellent in storage stability of mosapride citrate, and describes polyethylene glycol as a specific example of a coating formulation component.
Patent Document 3 relates to a film-coated tablet having a highly glossy surface without being subjected to sugar coating, and specifically describes polyethylene glycol as a coating composition.

On the other hand, patent document 4 is known regarding the coating of fexofenadine.
The coating preparation described in Patent Document 4 is an oral preparation of fexofenadine having a film coating containing polyethylene glycol, which is a plasticizer having a constitution different from that of the present invention.
Accordingly, it is a fexofenadine oral preparation coated with a film using a coating composition that does not contain polyethylene glycol, which is a substantially plasticizer characteristic of the present application, and is stable against heat, light, etc. No conventional fexofenadine oral preparation has sex.

  JP 2008-81512 A   Japanese Patent Publication No. WO60111638   JP 2008-201713 A   Japanese Patent No. 4105762

  The present inventors have examined a film-coated oral preparation of fexofenadine. It has been found that the stability to heat and light is extremely reduced. Conventionally, there has been no report that plasticizers such as polyethylene glycol have an adverse effect on fexofenadine or cause a change in the composition, so this is a completely new finding. The present invention is based on this finding, and therefore the object of the present invention is to provide a fexofenadine oral preparation with a film coating that does not decrease stability. In particular, it includes providing heat and light stable fexofenadine tablets.

As a result of intensive studies from the above results, the present inventors have developed a good oral fexofenadine formulation. That is, the present inventors completed the present invention by discovering that a fexofenadine oral preparation coated with a film using a coating composition containing no plasticizer such as polyethylene glycol is stable to heat and light.
That is, the present invention is as follows.
1) An oral formulation of fexofenadine coated with a film coating composition containing substantially no plasticizer.
2) The fexofenadine oral preparation according to 1), wherein the plasticizer is polyethylene glycol.
3) The film coating composition is selected from methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, carboxyvinyl polymer, polyvinyl alcohol (partially saponified product), polyvinyl alcohol methyl acrylate methacrylate copolymer and polyvinyl alcohol polyethylene glycol graft copolymer. The fexofenadine oral preparation according to 1) to 2), which contains one or more kinds.
4) The fexofenadine oral preparation according to 1) to 3), further comprising titanium dioxide and / or iron oxide.
5) Fexofenadine tablets coated with a film coating composition substantially free of polyethylene glycol.

  According to the present invention, a fexofenadine-containing film-coating oral preparation having improved stability, particularly stability to heat and light, can be obtained. Therefore, the fexofenadine-containing film coating oral preparation of the present invention is extremely useful as a pharmaceutical product. That is, according to the film-coated oral preparation of the present invention, fexofenadine is hardly decomposed and can be stored in a stable state. In particular, tablets do not cause any trouble in production and have no bitterness when taken. Therefore, not only can a high-quality pharmaceutical product be supplied, it has the advantage that an excellent pharmaceutical product can be provided in improving the patient's QOL (Quality of Life).

Hereinafter, the present invention will be further described in detail.
The oral preparation of fexofenadine of the present invention has a film coating layer substantially free of a plasticizer such as polyethylene glycol on the surface of a granulated product or uncoated tablet produced with a fexofenadine drug substance or excipient. It is a fexofenadine oral formulation.

  Examples of the fexofenadine oral preparation of the present invention include tablets, capsules, powders, fine granules, granules, and lozenges. The fexofenadine oral preparation of the present invention is preferably a tablet. In particular, a fexofenadine tablet having a film coating using a coating composition substantially free of polyethylene glycol is preferred.

  In the film coating composition of the present invention, a general coating base can be used on the condition that it does not contain a plasticizer such as polyethylene glycol. The type of the coating base is not particularly limited and can be appropriately selected by those skilled in the art. Such coating bases include, for example, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (partially saponified product), polyvinyl alcohol methyl acrylate methacrylate copolymer and polyvinyl alcohol polyethylene glycol graft copolymer, hydroxyethyl cellulose Cellulose-based water-soluble coating base such as methylhydroxyethylcellulose, cellulose-based enteric coating agent such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, methacrylic acid copolymer, shellac, etc. Other enteric film coating agents Etc., and the like. In the present invention, it is preferable to use hydroxypropylmethylcellulose. The proportion of the film base in the coating layer is preferably about 5 to about 99.5% by weight, preferably about 30 to about 98% by weight, more preferably about 50 to about 93% by weight.

  Examples of the plasticizer of the present invention include polyethylene glycol, phthalated esters such as acetylated monoglyceride, butyl phthalyl butyl glycolate, dibutyl tartrate, diethyl phthalate, glycerin, propylene glycol, triacetin, citrate, tripropioin. , Diacetin, acetyl monoglyceride, castor oil, triethyl citrate, polyhydric alcohol, glycerol, acetate ester, glycerol triacetate, acetyl triethyl citrate, dioctyl azelate, epoxidized tarate, triisooctyl trimellitic acid, trimellitic acid tri 2-ethylhexyl, di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate, etc. Kill. The present invention requires that these plasticizers be coated without being used in the film coating composition.

  In addition to the coating base, additives such as lubricants, taste improvers, colorants, and sugars can be added to the coating base. Examples of the lubricant include talc and magnesium stearate. When talc is used as the lubricant, it is preferably added so that the weight in the film coating composition is 2 to 10%, particularly preferably 5 to 7%. The colorant can be appropriately selected according to the purpose, and examples thereof include pigments such as titanium oxide. When adding a titanium oxide, it is preferable to add so that it may become 10 to 60% as a weight in a film coating composition, and 20 to 40% is especially preferable. Examples of the taste improving agent include sugar alcohols such as sorbitol and erythritol. Examples of the saccharide include monosaccharides, disaccharides, polysaccharides, and sugar alcohols, and examples include sucrose, sorbitol, lactose, erythritol, mannitol, and xylitol. In addition, as a film coating composition, additives used in normal pharmaceutical production such as a gelling agent, a surfactant, and a fragrance can be added.

  In the present invention, the uncoated tablet to which film coating is applied can be obtained by a general method using fexofenadine, which is an active ingredient. Pharmaceutical additives include pharmaceutically acceptable carriers such as excipients, binders, disintegrants, disintegration aids, lubricants, fluidizing agents, brighteners, foaming agents, moisture-proofing agents, surfactants. , Stabilizers, emulsifiers, antioxidants, fillers, preservatives, preservatives, sweeteners, flavoring agents, cooling agents, flavoring agents / fragrances, fragrances, coloring agents, etc. A commonly used one can be used.

  The film coating preparation in the present invention may be produced by a general method, and can be orally administered using any standard film coating apparatus well known in the art. Can be coated. As a coating method used in the present invention, a method known per se, for example, a pan coating method, a fluid coating method, a rolling coating method and the like are used. For example, it can be produced by coating an uncoated tablet with at least one layer of a coating agent, followed by drying and, if necessary, coating. The coating can be layered, and the components of each layer can be changed depending on the purpose.

  The amount of the film coating composition in the present invention coated on the tablet can be the same as in the case of normal film coating. Specifically, a film coating amount of about 3 to 10 mg can be used per uncoated tablet, and about 5 to 8 mg is more preferable. The thickness of the film layer is not particularly limited as long as it can effectively reduce the light-shielding property or the bitterness of the drug, but the lower limit is usually 1 μm or more, preferably 5 μm or more, more preferably 10 μm or more, particularly preferably. Is 20 μm or more, and the upper limit is 1000 μm or less, preferably 500 μm or less, more preferably 200 μm or less, and particularly preferably 100 μm or less.

  In addition, the present inventors have confirmed that the tablet coated with the film coating of the present invention is a tablet that is easy to take even for patients who have difficulty in swallowing without feeling slimy or sticky when taken.

  Hereinafter, the present invention will be described more specifically with reference to Examples, Comparative Examples, and Test Examples, but the present invention is not limited thereto.

Example 1
(1) Production of uncoated tablet 120.0 g of fexofenadine hydrochloride, 52.0 g of crystalline cellulose (Avicel pH101) and 120.0 g of pregelatinized starch were combined in a blender and mixed. To the powder mixture, 90 g of purified water was added and mixed. The obtained wet granules were dried.
The dried granules were screened on a 30 mesh screen. To the granule, 81.0 g of crystalline cellulose (Avicel PH102) and 24.0 g of sodium croscarmellose were added. After mixing these components, 3 g of magnesium stearate was added and mixed. This mixed powder was compression-molded into tablets.
(2) Production of film-coated tablet Production example of coated tablet using uncoated tablet obtained in (1) A film-coated tablet was produced by the following procedure. Film coating solution: 28.4 g of hydroxypropylmethylcellulose (TC-5S), 18.9 g of hydroxypropylmethylcellulose (TC-5R), 5.1 g of Povidone (USP), 20.2 g of titanium dioxide (USP), pink oxidation An aqueous suspension was prepared containing 0.25 g of iron mixture, 0.4 g of yellow iron oxide mixture, 7.3 g of silicon dioxide (M7), and about 920 g of purified water. This solution was sieved with a No. 200 sieve to obtain a film coating solution.
Film-coated tablets: Film coating is performed by putting uncoated tablets into Hi-Coater LABO (Freund Sangyo Co., Ltd.) and spraying the film coating solution until the coating is 5-8 parts by weight with respect to 200 parts by weight of uncoated tablets. I got a tablet.

Example 2
Using fexofenadine hydrochloride having a smaller amount of related substances than in Example 1, uncoated tablets similar to those in Example 1 were produced to obtain film-coated tablets containing no plasticizer.
Film coating solution: 28.4 g of hydroxypropylmethylcellulose (TC-5S), 18.9 g of hydroxypropylmethylcellulose (TC-5R), 5.1 g of Povidone (USP), 20.2 g of titanium dioxide (USP), pink oxidation An aqueous suspension was prepared containing 0.25 g of iron mixture, 0.4 g of yellow iron oxide mixture, 7.3 g of silicon dioxide (M7), and about 920 g of purified water. This solution was sieved with a No. 200 sieve to obtain a film coating solution.
Film-coated tablets: Film coating is performed by putting uncoated tablets into Hi-Coater LABO (Freund Sangyo Co., Ltd.) and spraying the film coating solution until the coating is 5-8 parts by weight with respect to 200 parts by weight of uncoated tablets. I got a tablet.

Example 3
Using the uncoated tablet obtained in Example 2, a film-coated tablet containing no plasticizer was obtained.
Film coating solution: An aqueous suspension containing 60 g of hydroxypropylmethylcellulose (TC-5R), 20 g of titanium dioxide (USP), 0.25 g of pink iron oxide mixture, 0.4 g of yellow iron oxide mixture and about 920 g of purified water is prepared. did. This solution was sieved with a No. 200 sieve to obtain a film coating solution.
Film-coated tablets: Film coating is performed by putting uncoated tablets into Hi-Coater LABO (Freund Sangyo Co., Ltd.) and spraying the film coating solution until the coating is 5-8 parts by weight with respect to 200 parts by weight of uncoated tablets. I got a tablet.

Comparative Example 1
A film-coated tablet containing polyethylene glycol 400 was obtained using the uncoated tablet obtained in Example 1.
Film coating solution: 28.4 g of hydroxypropylmethylcellulose (TC-5S), 18.9 g of hydroxypropylmethylcellulose (TC-5R), 5.1 g of Povidone (USP), 20.2 g of titanium dioxide (USP), pink oxidation An aqueous suspension was prepared containing 0.25 g of iron mixture, 0.4 g of yellow iron oxide mixture, 7.3 g of silicon dioxide (M7), 39.4 g of polyethylene glycol 400 and about 920 g of purified water. This solution was sieved with a No. 200 sieve to obtain a film coating solution.
Film-coated tablets: Film coating is performed by putting uncoated tablets into Hi-Coater LABO (Freund Sangyo Co., Ltd.) and spraying the film coating solution until the coating is 5-8 parts by weight with respect to 200 parts by weight of uncoated tablets. I got a tablet.

Comparative Example 2
A film-coated tablet containing polyethylene glycol 6000 was obtained using the uncoated tablet obtained in Example 1.
Film coating solution: 28.4 g of hydroxypropylmethylcellulose (TC-5S), 18.9 g of hydroxypropylmethylcellulose (TC-5R), 5.1 g of Povidone (USP), 20.2 g of titanium dioxide (USP), pink oxidation An aqueous suspension was prepared containing 0.25 g of iron mixture, 0.4 g of yellow iron oxide mixture, 7.3 g of silicon dioxide (M7), 39.4 g of polyethylene glycol 6000 and about 920 g of purified water. This solution was sieved with a No. 200 sieve to obtain a film coating solution.
Film-coated tablets: Film coating is performed by putting uncoated tablets into Hi-Coater LABO (Freund Sangyo Co., Ltd.) and spraying the film coating solution until the coating is 5-8 parts by weight with respect to 200 parts by weight of uncoated tablets. I got a tablet.

Test example

Test example 1
Blending Test A blending change test between fexofenadine hydrochloride and each component (polyethylene glycol 6000, polyethylene glycol 400) was performed. That is, fexofenadine hydrochloride and various components were blended in a glass container at a ratio of 1: 1 by weight ratio, and a storage test was conducted at 60 ° C. for 2 weeks after sealing. When blended, it was in suspension or contact. As a comparative example, only fexofenadine hydrochloride was placed in a glass container, and after a tight seal, a storage test at 60 ° C. for 2 weeks was similarly conducted. After two weeks, the amount of related substances produced (total amount of related substances) was measured.
Method for measuring related substances Prepare this product as powder, take an amount corresponding to 25 mg of fexofenadine hydrochloride according to the displayed amount, add acetonitrile / sodium dihydrogen phosphate buffer solution (3: 5) to make 25 mL, and shake. . This solution is centrifuged, and the supernatant is used as a sample solution. Pipet 1 mL of this solution and add the mobile phase to make exactly 100 mL. Pipet 1 mL of this solution, add the mobile phase to make exactly 10 mL, and use this as the standard solution. Test 20 μL of the sample solution and standard solution by liquid chromatography under the following conditions. The peak area of each solution is measured by the automatic integration method.
Test conditions Detector: UV absorption photometer (measurement wavelength: 220 nm)
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 25 cm is packed with 5 μm of phenylated silica gel for liquid chromatography.
Column temperature: constant temperature around 26 ° C. Mobile phase: 300 mL of acetonitrile and 3 mL of triethylamine are added to 500 mL of sodium dihydrogen phosphate buffer.
Flow rate: Adjust so that the retention time of fexofenadine is about 9 minutes.
Area measurement range: The sample solution is about 6 times the retention time of fexofenadine, and the standard solution is about 2 times the retention time of fexofenadine.

表１から明らかなように、フェキソフェナジンはポリエチレングリコールと接触させると、多くの分解物（類縁物質）が生成されることが判明した。result

As is apparent from Table 1, when fexofenadine was brought into contact with polyethylene glycol, it was found that many decomposition products (related substances) were produced.

Test example 2
Stability test The uncoated tablet of Example 1, Examples 1 and 2, and Comparative Examples 1 and 2 were stored under each condition, and a purity test (test method according to Test Example 1) was performed after sampling.
Storage conditions: Storage conditions are 60 ° C. and 60 ° C. (RH 75%), 61,000 × hr and 1.201 × hr in open conditions.

result

  From the results of Table 2, it was confirmed that Comparative Example 1 containing polyethylene glycol 400 as a plasticizer was worse in stability than Example 1 containing no plasticizer at 60 ° C. in light. On the other hand, Comparative Example 2 containing polyethylene glycol 6000 was found to be less stable than Example 1 at 60 ° C., but the stability to light was not different from Example 1.

  As is apparent from Table 3, Examples 2 and 3 using fexofenadine hydrochloride having good purity were found to exhibit excellent stability.

According to the present invention, a fexofenadine-containing film coating oral preparation with improved stability can be provided.

Claims (5)

  An oral formulation of fexofenadine coated with a film coating composition substantially free of plasticizer.   The oral preparation of fexofenadine according to claim 1, wherein the plasticizer is polyethylene glycol.   The film coating composition is selected from methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, carboxyvinyl polymer, polyvinyl alcohol (partially saponified product), polyvinyl alcohol methyl acrylate methacrylate copolymer and polyvinyl alcohol polyethylene glycol graft copolymer. Or the fexofenadine oral formulation of Claim 1 thru | or 2 containing 2 or more types.   Furthermore, titanium dioxide and / or iron oxide are contained, The fexofenadine oral formulation of Claim 1 thru | or 3 characterized by the above-mentioned.   A fexofenadine tablet coated with a film coating composition substantially free of polyethylene glycol.