JP5744412B2 - Furosemide formulation - Google Patents

Description

  The present invention relates to a furosemide preparation, and more particularly to a solid furosemide preparation that suppresses coloration that occurs over time.

Furosemide (chemical name 5- (aminosulfonyl) -4-chloro-2-[(2-furanylmethyl) amino] benzoic acid) is one of the loop diuretics and the lumen of the thick ascending limb of Henle's loop By suppressing the Na ⁺ · K ⁺ · 2Cl ⁻ cotransport carrier in the side membrane, it is a drug that suppresses reabsorption of NaCl and K ⁺ and exhibits a fast-acting and powerful diuretic action.

  This furosemide is known to be colored with respect to light, and preparations containing furosemide are already on the market, but in the uncoated tablet state, coloring occurs over time. However, recently, even when a tablet containing furosemide is stored in a light blocking container such as an automatic separator, it is confirmed that it is colored in the same manner as when colored against light (non-patent document). 1).

  The coloring of such furosemide preparations is a phenomenon in which coloring is not desirable for commercial purposes, and the cause of this coloring has been found and development of means for preventing the coloring has been required.

“Medical Pharmacy”, Vol. 35, No. 6, p. 395-402, Reiko Teraoka and 4 others, “Effects of colored PTP packaging materials on the photostability of furosemide tablets” (published on June 10, 2009 by the Japan Medical Pharmaceutical Association)

  The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a solid preparation containing furosemide and prevented from being colored.

  In order to solve the above-mentioned problems, the present inventors have extensively studied the factors considered to be the cause of coloring in the furosemide-containing solid preparation, and as a result, the coloring component is a very small amount of furosemide hydrolyzate. It was revealed. Furthermore, as a result of research on the means for preventing this coloration, it was confirmed that the above coloration can be prevented by coating a solid preparation containing furosemide with a film containing a water-soluble polymer and an oxidized metal. The headline and the present invention were completed.

  That is, the present invention is a furosemide preparation obtained by coating the surface of a solid preparation containing furosemide with a coating agent containing a water-soluble polymer and an oxidized metal.

  Since the furosemide preparation of the present invention does not color over time, a special container is not required, and a one-dose package in which a plurality of drugs are packaged in a single bag is possible. can do.

  The furosemide preparation of the present invention is prepared by coating the surface of a solid preparation containing furosemide with a coating agent containing a water-soluble polymer and an oxidized metal.

  Examples of the solid preparation containing furosemide include tablets, granules, fine granules, and powders, with tablets being preferred. The amount of furosemide contained in the solid preparation is not particularly limited, but is preferably 1 to 50% by mass (hereinafter simply referred to as “%”), more preferably 2.5 to 30%.

  This solid preparation can be produced by a conventional method except that it contains furosemide. That is, a known excipient and furosemide may be mixed to form a solid formulation composition, which may be formulated according to a conventional method. Examples of excipients used include, for example, sugar alcohols such as lactose, mannitol, xylitol, sorbitol, erythritol, purified white sugar, crystalline cellulose, powdered cellulose, dextran, dextrin, glucose, powdered sugar, corn starch, potato starch And rice starch.

  If necessary, conventionally known optional components such as various lubricants, solubilizers, buffers, adsorbents, binders, suspending agents, antioxidants, fillers, pH adjusters, A dispersing agent, a disintegrating agent, a disintegrating aid, a moisture proofing agent, a preservative, a solvent, a solubilizing aid, a fluidizing agent, and the like can be added. Among these, examples of the disintegrant include carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl methylcellulose, crystalline cellulose, hydroxypropyl starch, partially pregelatinized starch, and crospovidone. Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, carmellose sodium, polyvinyl alcohol, polyvinylpyrrolidone and the like. Examples of the fluidizing agent include hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, talc, magnesium aluminate metasilicate, and the like. Examples of the lubricant include stearic acid, calcium stearate, magnesium stearate, hydrogenated oil, sucrose fatty acid ester, stearyl alcohol fumarate, talc, macrogol and the like.

  In order to prepare a tablet (plain tablet) using the composition for a solid preparation, the composition may be granulated if necessary and then compression molded by a conventional method.

  What is necessary is just to implement by the method used normally as a method of granulating. Specific examples include fluidized bed granulation, stirring granulation, extrusion granulation, Wurster granulation, or a combination thereof. Note that other methods are not particularly problematic as long as they do not hinder the compression molding of the next step.

  Any compression molding method can be used as long as it can form tablets. Specific examples include a rotary tableting machine and a single-shot tableting machine, but are not limited thereto.

  The solid preparation thus prepared is then coated with a coating agent containing a water-soluble polymer and an oxidized metal.

  Examples of the water-soluble polymer blended in the coating agent include hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, methylcellulose, polyvinylpyrrolidone and the like, among which hydroxypropylmethylcellulose is preferable. Examples of the oxidized metal include titanium oxide, yellow iron sesquioxide, and iron sesquioxide. Among these, titanium oxide is preferable.

  The coating agent is prepared by dissolving or suspending the water-soluble polymer and the oxidized metal in a solvent of purified water, ethyl alcohol, propanol, methylene chloride, methanol, or a mixed solution thereof. The amount of the water-soluble polymer in the film-forming component excluding this solvent is about 50 to 90%, preferably 60 to 70%. The amount of oxidized metal is about 1 to 40%, preferably 5 to 30%.

  In addition, other additives can be added to the coating agent as long as the effects of the present invention are not impaired. Specifically, a plasticizer, a brightener, a colorant, and the like can be added. Examples of the plasticizer may include macrogol, triethyl citrate, glycerin, glycerin fatty acid ester, triacetin, castor oil, polysorbate, propylene glycol, and the like. In addition to the oxidized metal described above as a colorant, for example, yellow No. 5, yellow No. 4 aluminum lake, blue No. 1, red No. 2 and other lake pigments, copper chlorophyll, phenol red, methylene blue, Beta carotene, caramel and the like can be contained. Further, as the brightener, for example, cetanol, hydrogenated oil, white beeswax, stearic acid, calcium stearate, magnesium stearate, macrogol and the like can be contained.

  These coating liquids can be adjusted immediately before the coating is performed, but commercially available adjusted coating liquids can also be used. Specific examples include Opadry (Nippon Colorcon).

The method for coating the solid preparation with a coating agent may be a known method, and for example, methods such as fluidized bed granulation, drip-type coating, pan coating and the like can be appropriately used. The ratio of the solid preparation and the coating agent used in the coating varies depending on the specific form of the solid preparation. In the case of a tablet, about 1 to 20 parts, preferably 3 parts of the coating agent is used per 100 parts of the solid preparation. Or it may be about 10 parts.

  In addition, after coating a film containing a water-soluble polymer and an oxidized metal, it is possible to impart sustainability or maintain gastric and enteric properties within a range that does not impair the effects of the invention. . It is also possible to form sugar-coated tablets using sugar after coating.

  EXAMPLES Next, although an Example is given and this invention is demonstrated in more detail, this invention is not restrict | limited at all by these Examples.

Example 1
Preparation of furosemide formulation (tablets):
A pharmaceutical composition was prepared according to the following formulation, and granulated with a fluidized bed granulator. The resulting granule was used and a tablet was used to make a diameter of 6.1 mm and a thickness of 2 An uncoated tablet with a diameter of 9 mm and a weight of 90 mg was prepared. A coating agent having the following composition was suspended in purified water on the obtained uncoated tablets and sprayed in a doria coater so that the dried film was 7 mg per tablet to prepare a film coating agent.

<Prescription formulation>
Component name Compounding amount (mg)
Furosemide 20.0
Lactose hydrate 19.0
Corn starch 19.5
Crystalline cellulose 18
Light anhydrous silicic acid 0.9
Partially pregelatinized starch 9
Alphalated starch 1.8
Light anhydrous silicic acid 0.9
Magnesium stearate 0.9
Total 90.0

<Coating agent formulation>
Component name Compounding amount (mg)
Hydroxypropylmethyl 4.5
Cellulose ^{* 1}
Macrogol 6000 0.7
Titanium oxide 1.8
Carnauba low amount
Total 7
* 1 Viscosity: 6.0 mPa / s

Test example 1
Anti-coloring test (1):
For the uncoated tablet (diameter 6.1 mm, thickness 2.9 mm) prepared in Example 1, its film-coated tablet, and the drug substance (furosemide) molded into a tablet of the same size as described above with an oil press, Thus, the presence or absence of coloring was evaluated.

  First, 5 tablets each of the above-mentioned uncoated tablet, film-coated tablet and tablet-form drug substance were taken and placed in a petri dish. For these, air was blown for 2 weeks with a blower (fan). Next, the color difference (ΔE) on the air contact surface was examined using a spectrocolorimeter (SE-2000; manufactured by Nippon Denshoku Industries Co., Ltd.). Note that as the reference value of ΔE, the value of each tablet at the start of the test was used. Moreover, the test result was made into the average value of 5 tablets each. The results are shown in Table 1.

<Test conditions>
Temperature 25 ℃ Dark room Wind 5.4m / sec
Test period 1 week or 2 weeks

<Result>

  As is clear from this result, it was found that the color difference of the tablet coated with film coating was less than that of the uncoated tablet containing furosemide.

Test example 2
Anti-coloring test (2):
Since the coloration is simply hidden by the film coating, and the uncoated tablet may be colored, the internal coloration state of the film-coated tablet after receiving a blast for 2 weeks in Test Example 1 was examined. It was.

  In the investigation, the coating film was peeled off from the film-coated tablet to obtain an uncoated tablet, and then ΔE was confirmed using a spectrocolorimeter (SE-2000). The reference value for ΔE was the value obtained when the coated film of the film-coated tablet immediately after production was removed. About the test result, the average value of the repetition frequency 3 in the measurement of 1 tablet was used. As a result, it was found that ΔE of the uncoated tablet in the film coating agent subjected to the anti-coloring test was 0.68, which was hardly colored.

Since the furosemide preparation of the present invention does not color with time, it can be used as a highly commercial drug.

Claims (4)

Furosemide preparations, in which the surface of a solid preparation containing furosemide is film-coated with a coating agent containing a water-soluble polymer and an oxidized metal ( however, the coating agent contains a polyvinyl alcohol-polyether graft copolymer) Except what you do ).   The furosemide preparation according to claim 1, wherein the solid preparation is a tablet, granule, fine granule or powder.   The furosemide preparation according to claim 1 or 2, wherein the water-soluble polymer is hydroxypropylmethylcellulose.   The furosemide preparation according to any one of claims 1 to 3, wherein the oxidized metal is titanium oxide.