JP4427318B2 - Film coated tablets - Google Patents

Description

  The present invention relates to a film-coated tablet.

Fursultiamine hydrochloride, sodium chondroitin sulfate, to produce tablets of compounding vitamin B ₁₂ compounds are required masking unpleasant odor and taste with the fursultiamine hydrochloride and chondroitin sodium sulfate, and vitamin B ₁₂ compound Needed to be stabilized. Therefore, in the prior art, for example, sugar-coated tablets are used to mask unpleasant odors and tastes of fursultiamine hydrochloride and chondroitin sodium sulfate, thereby stabilizing vitamin B ₁₂ by reducing water content. However, such sugar-coated tablets have the disadvantage that the tablets become large and difficult to take. Accordingly, a thin-layer sugar-coated tablet having a thin sugar-coated layer was invented, and it became possible to stabilize the drug by reducing the size of the tablet and reducing the water content (Patent Document 1). In this technique, to produce a tablet formulation fursultiamine hydrochloride, sodium chondroitin sulfate, vitamin B ₁₂ compound. As a result, the unpleasant odor and taste were actually reduced, and the stability of vitamin B ₁₂ was good. However, when the obtained thin-layer sugar-coated tablet was stored under high humidity, sodium chondroitin sulfate was hygroscopically expanded and cracked in the tablet. When cracks occur, the quality of appearance deteriorates and unpleasant odor and taste are not masked, which is a problem in formulation. Furthermore, it became fursultiamine hydrochloride, sodium chondroitin sulfate, tablets containing a combination of vitamin B ₁₂ compound and also clear that cause decay delay aging.
JP 2002-179559 A

  An object of the present invention is to provide a film-coated tablet which is free from cracks even under high humidity, can reduce unpleasant odor and taste, and is stable over time.

    As a result of intensive studies to achieve the above object, the present inventors have surprisingly found that coating with a film coating composition containing hydroxypropylmethylcellulose as a film base and talc as a lubricant under high humidity. Also found that a film-coated tablet can be produced without cracking, reducing unpleasant odor and taste, and stable over time. As a result, it was also found out that the drug content and disintegration time can be made stable over time, and the present invention has been completed. The present invention has been completed.

That is, the present invention
(1) A film layer containing fursultiamine hydrochloride, chondroitin sulfate sodium and vitamin B ₁₂ in the uncoated tablet, and containing 8% (w / w) or more of hydroxypropyl methylcellulose based on the uncoated tablet weight Film-coated tablets, characterized by being coated,
(2) The film-coated tablet according to (1), wherein the film layer containing hydroxypropylmethylcellulose is a film layer further containing talc,
(3) The film-coated tablet according to the above (1), wherein the vitamin B ₁₂ is cyanocobalamin, hydroxocobalamin acetate or mecobalamin,
(4) Provided is a film-coated tablet or the like as described in (1) above, wherein the moisture content is reduced to an equilibrium relative humidity of 40% or less.

  According to the present invention, it is possible to provide a film-coated tablet that is free from cracks even under high humidity, can reduce unpleasant odor and taste, and is stable over time.

In the film-coated tablet according to the present invention, hydroxypropylmethylcellulose is used as a film base. As a result, an unpleasant odor and taste of fursultiamine hydrochloride and sodium chondroitin sulfate can be effectively reduced, and a film coating agent that is stable over time can be obtained. The content of hydroxypropylmethylcellulose in the film layer is usually 50 to 95% (w / w), preferably 60 to 90% (w / w), more preferably 75 to 85% (w / w).
Furthermore, additives such as fillers, lubricants, masking agents, plasticizers, colorants and the like in amounts usually used for the film layer can be blended as necessary. Additives that can be used in the present invention include talc, precipitated calcium carbonate, magnesium stearate, calcium stearate, titanium oxide, macrogol 6000, copolyvidone, triacetin, triethyl citrate, glycerin, propylene glycol, riboflavin, yellow iron sesquioxide, Examples include iron sesquioxide and yellow No. 5 aluminum lake.
In order to blend in the film layer, generally, Macrogol 6000 is blended as a lubricant. In the film-coated tablet of the present invention, a lubricant other than Macrogol 6000 is used from the viewpoint of the temporal stability of the appearance. It is preferable to use a preservative. In particular, talc is preferable as the lubricant. By using talc as a lubricant, an unpleasant odor and taste possessed by fursultiamine hydrochloride and sodium chondroitin sulfate can be effectively reduced, and a film coating agent that is stable over time can be obtained. When talc is used as a lubricant, the amount usually used may be used, but the content of talc in the film layer is usually 3 to 30% (w / w), preferably 5 to 20% (w / W).

Film-coated tablets in the invention contains fursultiamine hydrochloride, sodium chondroitin sulfate, and vitamin B ₁₂ such as an active ingredient. Examples of the vitamin B ₁₂ class include cyanocobalamin, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, and mecobalamin. Moreover, the film coating tablet in this invention may contain the other active ingredient as needed. Examples of the active ingredient include vitamin B ₁ derivatives (fursultiamine hydrochloride, discetiamine hydrochloride, octothiamine, chicotiamine, bisbutiamine, bisbenchamine, benfotiamine, etc.), vitamin B ₁ (thiamine hydrochloride, thiamine nitrate, nitric acid). Bistiamine, thiamine disulfide, thiamine dicetyl sulfate, etc.), vitamin B ₂ (riboflavin, sodium riboflavin phosphate, riboflavin butyrate, etc.), vitamin B ₆ (pyridoxine hydrochloride, pyridoxal phosphate, etc.), vitamin C (ascorbic acid, ascorbine) Acid sodium, calcium ascorbate, etc.), vitamin E (d-α-tocopherol succinate, dl-α-tocopherol calcium succinate, d-α-tocopherol acetate, dl-α-tocopherol acetate, etc.), Cochin acid, nicotinamide, calcium pantothenate (e.g., calcium pantothenate type S (trade name)), biotin, .gamma.-oryzanol, orotic acid, glucuronolactone, glucuronic acid amide, vitamins such as Coix.
The amount of these active ingredients is not particularly limited, and the amount normally used for tablets may be used.

The production method of the film-coated tablet in the present invention includes granulation handbook (edited by Japan Powder Industrial Technology Association, Ohm Co., Ltd.), prescription design of orally administered preparation (Professor Mitsuru Hashida, Professor, Graduate School of Pharmaceutical Sciences, Kyoto University) ), Compression methods for powders (powder engineering / preparation and particle design division, published by Nikkan Kogyo Shimbun), and a general method may be used, and there is no particular limitation.
Uncoated applying a film coating in the present invention include, for example, granulated and sieved using fursultiamine hydrochloride, sodium chondroitin sulfate, and the active ingredient of the vitamin B _12, etc., excipients, and a binder, obtained An uncoated tablet can be obtained by mixing a disintegrating agent and a lubricant with the obtained granulated powder and making a tablet. As these excipients, binders, disintegrants and lubricants, those conventionally used for tablet production may be used.

The film coating of the uncoated tablet can be obtained by spraying the uncoated tablet with a film coating solution containing hydroxypropylmethylcellulose as a base. The uncoated tablet may be sub-coated if desired. The film coating solution is obtained by suspending and dissolving hydroxypropylmethylcellulose and the above-mentioned additive blended if necessary in water at the above ratio. The spraying of the film coating solution may be performed by a known method such as using a commercially available film coating machine.
The film coating is preferably performed so that the film layer is 8% (w / w) or more, preferably 10% (w / w) or more based on the weight of the uncoated tablet.
These production conditions may be the same as those used in the production of ordinary film-coated tablets.
The film-coated tablet of the present invention thus obtained may be administered in the same manner as a normal tablet.
EXAMPLES Hereinafter, although an Example etc. demonstrate this invention further in detail, this invention is not limited to this.

412.0 g of fursultiamine hydrochloride, 2973 g of chondroitin sulfate sodium salt and 411.6 g of powdered reduced maltose water candy 411.6 g were put into a fluidized bed granulator (FD-5S, Paulek) and sprayed with 525.2 g of 0.04% cyanocobalamin aqueous solution. Further, fluidized bed granulation was performed by spraying 1400 g of a 6% hydroxypropylcellulose (HPC-L) aqueous solution. The obtained granulated powder was sized with a sizing machine (Power Mill, Showa Chemical Machinery) to obtain a sized powder. This is the T group sized powder. On the other hand, 73.5 g of pyridoxine hydrochloride, 3500 g of glucosamine hydrochloride (pulverized product, particle size of 180 μm, 100% passage), and 245.0 g of powdered reduced maltose water candy were charged into a fluidized bed granulator (FD-5S, Powrec), and 6% hydroxy Fluidized-bed granulation was performed by spraying 1983 g of an aqueous propylcellulose (HPC-L) solution. The obtained granulated powder was sized with a sizing machine (Power Mill, Showa Chemical Machinery) to obtain a sized powder. This is designated as group B sized powder.
The obtained T group sized powder 3658 g, B group sized powder 3600 g, croscarmellose sodium 288.0 g, and magnesium stearate 38.4 g were mixed in a mixer (tumbler mixer, Showa Chemical Machinery) to obtain. The mixed powder was tableted with a rotary tableting machine using a 9.5 mm diameter mortar and an R radius of 8 mm in curvature radius so that the weight per tablet was 395 mg and the thickness was 6.0 mm, and an uncoated tablet was obtained. It was.
Using the coating solution prepared by dissolving and suspending 574.5 g of hydroxypropylmethylcellulose (TC-5 MW), 72 g of talc, 72 g of titanium oxide, and 1.5 g of yellow iron sesquioxide in 6480 g of purified water, Film coating tablets were obtained by coating with a machine (Dria Coater DRC-500, Powrec) at 10% (w / w) based on the weight of the uncoated tablet.

393.0 g of fursultiamine hydrochloride, 2880.0 g of sodium chondroitin sulfate, and 768.4 g of powdered reduced maltose water candy are put into a fluidized bed granulator (FD-5S, Pauleck), and 166.2 g of 0.13% cyanocobalamin aqueous solution is added. After spraying, fluidized bed granulation was performed by spraying 680.5 g of a 6% hydroxypropylcellulose (HPC-L) aqueous solution. The obtained granulated powder was sized with a sizing machine (Power Mill, Showa Chemical Machinery) to obtain a sized powder. This is the T group sized powder. On the other hand, 72 g of pyridoxine hydrochloride, 3600 g of glucosamine hydrochloride (pulverized product, particle size of 180 μm, 100% passage) and 256.5 g of powdered reduced maltose water candy were mixed with a 6% hydroxypropyl cellulose (FD-5S, Paulek) in a fluidized bed granulator (FD-5S, Paulek). HPC-L) Fluidized bed granulation was performed by spraying 2026 g of aqueous solution. The obtained granulated powder was sized with a sizing machine (Power Mill, Showa Chemical Machinery) to obtain a sized powder. This is designated as group B sized powder.
The obtained T group sized powder 3515 g, B group sized powder 3488 g, croscarmellose sodium 214.8 g and magnesium stearate 36.27 g were mixed in a mixer (tumbler mixer, Showa Chemical Machinery) to obtain The mixed powder was tableted with a rotary tableting machine using a 9.5 mm diameter mortar and an R radius of 8 mm in curvature radius so that the weight per tablet was 390 mg and the thickness was 6.0 mm, and an uncoated tablet was obtained. It was.
Using a coating solution obtained by dissolving and suspending 398.9 g of hydroxypropyl methylcellulose (TC-5 MW), 50 g of talc, 50 g of titanium oxide, and 1.1 g of riboflavin in 4500 g of purified water, Coater DRC-500 (Paurek) was coated at 8% (w / w) based on the weight of the uncoated tablet to obtain film-coated tablets.

412.0 g of fursultiamine hydrochloride, 2973 g of chondroitin sulfate sodium salt and 411.6 g of powdered reduced maltose water candy were sprayed with a fluidized bed granulator (FD-5S, Paulek) with 525.2 g of 0.04% cyanocobalamin aqueous solution, Furthermore, fluidized-bed granulation is carried out by spraying 1400 g of 6% hydroxypropyl cellulose (HPC-L) aqueous solution. The obtained granulated powder is sized with a particle sizer (Power Mill, Showa Chemical Machinery) to obtain a sized powder. This is the T group sized powder. On the other hand, 73.5 g of pyridoxine hydrochloride, 3500 g of lactose, and 245.0 g of powdered reduced maltose water candy are sprayed with 1983 g of a 6% hydroxypropylcellulose (HPC-L) aqueous solution in a fluidized bed granulator (FD-5S, Pauleck). Thus, fluidized bed granulation is performed. The obtained granulated powder is sized with a particle sizer (Power Mill, Showa Chemical Machinery) to obtain a sized powder. This is designated as group B sized powder.
The obtained T group sized powder 3658 g, B group sized powder 3600 g, croscarmellose sodium 288.0 g, and magnesium stearate 38.4 g were mixed in a mixer (tumbler mixer, Showa Chemical Machinery) to obtain The resulting mixed powder is tableted with a rotary tableting machine using a 9.5 mm diameter mortar and a curvature radius of 8 mm so that the weight per tablet is 395 mg and the thickness is 6.0 mm. Obtained.
Using the coating solution prepared by dissolving and suspending 574.5 g of hydroxypropylmethylcellulose (TC-5 MW), 72 g of talc, 72 g of titanium oxide, and 1.5 g of yellow iron sesquioxide in 6480 g of purified water, A film coating tablet was obtained by coating with a machine (Dria Coater DRC-500, Powrec) in an amount of 10% based on the weight of the uncoated tablet.

Comparative Example 1

The mixed powder of Example 2 was tableted with a rotary tabletting machine using a mortar with a diameter of 8.5 mm and an R facet with a curvature radius of 6.5 mm so that the weight per tablet was 260 mg and the thickness was 5.1 mm. , Got an uncoated tablet.
3042 g of the obtained uncoated tablet was dissolved in 225 g of hydroxypropylmethylcellulose (TC-5 MW) and 25 g of talc in 2250 g of purified water and suspended in a coating machine (Doria Coater DRC-500, Paulek). 4% (w / w) coating based on the weight of the uncoated tablet, and further, 1215 g of purified white sugar, 540 g of talc, 112.5 g of titanium oxide, 112.5 g of crystalline cellulose (Avicel PH-F20), 270 g of gum arabic powder Using a coating solution dissolved and suspended in 2250 g of purified water, coating was performed with a coating machine (Dria Coater DRC-500, Paulek) at 40% (w / w) based on the weight of the uncoated tablet. Furthermore, using a coating solution in which 998.3 g of purified sucrose and 1.7 g of riboflavin were dissolved in 2333 g of purified water, the coating machine (Doria Coater DRC-500, Powrec) was used with 10% of the uncoated tablet weight ( w / w) Coating was performed to obtain a thin-layer sugar-coated tablet.

Test example 1

Each of the 60 tablets produced in Example 1, Example 2 and Comparative Example 1 was stored open in a glass bottle for 2 months under conditions of 25 ° C. and 75% RH. The number of broken tablets was counted and the rate of broken tablets was calculated.
The results are shown in Table 1.

Test example 2

Film-coated tablets with the same composition as Example 1 and different equilibrium relative humidity (ERH) were produced (Example 4, Example 5, Comparative Example 2). The tablets of Example 3, Example 4, Example 5, and Comparative Example 2 were stored in a glass bottle at 50 ° C. and 2 M sealed, and the drug residual rate (cyanocobalamin, fursultiamine hydrochloride) and disintegration time (JP 14 amended General Test Method) Disintegration test).
The results are shown in Table 2.

平衡相対湿度（ＥＲＨ）４０％以下のフィルムコーティング錠は、５０℃で保存した際に、薬物含量の低下、崩壊遅延も少なかった。すなわち、平衡相対湿度（ＥＲＨ）４０％以下に低水分化したフィルムコーティング錠は、安定であった。

Film-coated tablets with an equilibrium relative humidity (ERH) of 40% or less had little decrease in drug content and delay in disintegration when stored at 50 ° C. That is, the film-coated tablet whose moisture content was reduced to 40% or less of equilibrium relative humidity (ERH) was stable.

Claims (2)

Fursultiamine hydrochloride during uncoated contain chondroitin sulfate sodium and vitamin B ₁₂ compound, relative to the uncoated tablet weight, of 8% (w / w) or more, is coated with the film layer formulation of hydroxypropyl methylcellulose, A film-coated tablet characterized by having a low moisture content at an equilibrium relative humidity of 40% or less . The film-coated tablet according to claim 1, wherein the vitamin B ₁₂ is cyanocobalamin, hydroxocobalamin acetate or mecobalamin.