JP2003144528A - Multilayer tablet and manufacturing method thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a multilayer tablet in which interlayer debonding can be prevented and stability is excellent. SOLUTION: A method of suppressing the interlayer debonding of a multilayer tablet is characterized in that, in manufacturing a multilayer tablet, a crystalline cellulose having a bulk specific gravity of 0.10-0.25 g/ml is compounded in at least one layer and the amount of the cellulose to be compounded is 1-20 pts.wt. in the layer containing the cellulose having a bulk specific gravity of 0.10-0.25 g/ml. Also, the tablet contains the cellulose having a bulk specific gravity of 0.10-0.25 g/ml in at least one layer out of two or more layers.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for preventing delamination that occurs during the production of multilayer tablets.

[0002]

2. Description of the Related Art A multi-layer tablet is a tablet in which several kinds of prescription ingredients are compression-molded stepwise and contained in the same dosage form, and the following advantages can be considered. 1) It is possible to dispose the active ingredient which is incompatible with the composition on both sides of the layer which does not cause the composition change in the middle. 2) Separate coloring can be applied to each layer so that they can be easily identified. 3) By properly setting the content and blending amount of the components contained in two or more layers, the rapid-acting property, sustainability, etc. can be accurately controlled.

In the production of multi-layer tablets, frequent occurrence of delamination among the tableting problems is regarded as a problem. As a prior art for suppressing such problems, JP-A-5-163138 and JP-A-2000-336027 are known. The gazette is known. However, regarding the technique of JP-A-5-163138, the use of lactose is essential, but there is a problem of lactose intolerance, that is, there is a problem that some people cause watery stool or diarrhea by ingestion of lactose. The addition of lactose to the formulation is not preferred because it has been removed.

On the other hand, in the technique disclosed in Japanese Unexamined Patent Publication No. 2000-336027, the ratio of the average particle size of the powdery particles forming one layer to the average particle size of the powdery particles forming the other layer is 1 : 2 to 1:50, and it is necessary to adjust the particle size of the granules forming the respective layers in order to set such a ratio, which is not convenient as a manufacturing method. . In addition, JP-A 5-163
Neither the 138 publication nor the JP 2000-336027 publication has examined the bulk specific gravity of the crystalline cellulose to be used.

[0005]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a simple method for preventing delamination in a multilayer tablet.

The present inventor prevents delamination by using crystalline cellulose having a specific bulk specific gravity for at least one of the layers constituting a multilayer tablet. According to the method, it was found that a multilayer tablet having excellent stability can be obtained, and the present invention was completed.

That is, the present invention is as follows: 1. In the production of a multi-layer tablet, a method for suppressing peeling of a multi-layer tablet, which comprises blending at least one layer with crystalline cellulose having a bulk specific gravity of 0.10 to 0.25 g / ml. The amount of crystalline cellulose blended is such that the bulk specific gravity is 0.10.
~ 1-2 in a layer containing 0.25 g / ml of crystalline cellulose
2. The method for suppressing peeling of a multilayer tablet according to 1, wherein the content is 0 part by mass; The present invention relates to a multilayer tablet in which at least one of two or more layers contains crystalline cellulose having a bulk specific gravity of 0.10 to 0.25 g / ml.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is described in detail below.
The bulk specific gravity of the crystalline cellulose in the present invention is 0.
10 to 0.25 g / ml, preferably 0.10 to 0.20
g / ml, particularly preferably 0.10 to 0.18 g / ml is desirable. The bulk specific gravity of crystalline cellulose is 0.25
When it exceeds g / ml, the bonding force between the layers contacting each other is lowered, and it becomes impossible to prevent delamination. Further, if the bulk specific gravity of the crystalline cellulose is less than 0.10 g / ml, the fluidity of the powder at the time of tableting is lowered, and the variation in the weight of the resulting multilayer tablet becomes large. Therefore, the above range is preferable. .

The crystalline cellulose having a specified bulk specific gravity is preferably contained in the layer containing the crystalline cellulose in an amount of 1 to 20 parts by mass. The crystalline cellulose in the present invention can be added in the granulation step together with a lubricant such as vegetable oil and fat powder after spraying, drying and sieving, for example, when a fluidized bed granulation method is used. . Further, for the purpose of adjusting the particle size, bulk specific gravity, etc. of the resulting tableting powder, the crystalline cellulose of the present invention may be blended during granulation, and the blending method is not limited, and crystalline cellulose outside the scope of the present invention You may use together.

In a multi-layer tablet, two or more active ingredients that are incompatible may be arranged in separate layers, and a coloring component such as yellow vitamin B ₂ may be provided so that each layer can be easily identified. Can be added to each layer to give different coloring, and by combining the active ingredient with a component for controlling the fast-acting and sustaining properties of the active ingredient, the effect of many active ingredients can be controlled. It can be demonstrated in stages.

The kind of the active ingredient in the present invention is not particularly limited, and the herbal medicines, vitamins,
Includes minerals, herbs, and other active ingredients.

The herbal medicines include, for example, carrot (carrot of the family Araliaceae, dried Panax ginseng CA Mey.
atumsibiricum Red. rhizome), Ag (Aka leopard, equine donkey, Equus asinus L. boiled and buffed to remove dehaired skin), 杸 杝 子 (dried mature fruit of Solanaceae), anti-nosed (The viscera of the Viperaceae is taken out, peeled, stretched and dried for a long time), mountain herbs (San yak, dried roots of the yams of the yam family Anodontidae), large jujube (thus chinensis, corn butterflies and genus plants). Matured fruits), mulberry (soujin, matured fruits of mulberry family Moraceae), safflower (dried corolla, dried corolla of Asteraceae), cinnamon,
Otsukin (turmeric, ginger turmeric, dried tuberous root of turmeric), sonosumorin (sansonin, dried mature seeds of Ranunculiaceae paniculaceae), longan meat (flesh of long-spotted longan), skin (chinpi, tangerine citrus) Dried pericarp of persimmon), hippocampus (dry excluding the internal organs of mosquito, sycamore family Otatsu and variegated hippocampus), Cordyceps sinensis (Euphorbiaceae, Pleurotus communis, Cordyceps sinensis (Berk.) S
acc. fruiting bodies and sclerotia), 芦 巴 (fenugreek, fenugreek fenugreek seeds), and 茱 茸 (sausyuyu, dried fruits of the dogwood family sanshuyu) can be used. It can also be used as a mixture of crude drugs by Kampo prescription. These crude drugs are powdered extract powders obtained by pulverizing powders obtained by pulverizing the powders or extracting the powders with alcohol, hot water, etc., depending on the form or dosage form, and drying the extract. Can be used.

Examples of vitamins include thiamin hydrochloride.
Amine, thiamine nitrate, bisthiamine nitrate, dicetyamine hydrochloride
Dibenzoylthiamine, dibenzoylthiamine hydrochloric acid
Salt, thiamine cetyl sulfate, thiamine thiocyanate,
Thiamin naphthalene-1,5-disulfonate, thiami
Vitamin B such as lauryl sulfate₁, Riboflavin,
Vitamin B such as riboflavin sodium phosphate_TwoKind, salt
Vitamin B such as pyridoxine acid and pyridoxal phosphate
₆, Hydroxocobalamin hydrochloride, Hydroxocoba acetate
Such as lamin, cyanocobalamin, hydroxocobalamin, etc.
Vitamin B₁₂Kinds, folic acid, biotin, panthenol, bread
Bread such as calcium tothenate and sodium pantothenate
Nicotine such as tothenic acid, nicotinic acid, and nicotinic acid amide
Acids, ascorbic acid, sodium ascorbate,
Calcium ascorbate, stearin ascorbate
Vitamin Cs such as acid esters, methyl hesperidin, ru
Vitamin Ps such as Chin, Vitamin D₁, Vitamin D_Two,
Vitamin D_Three, Vitamin D _FourPowder of vitamin Ds such as
Products, vitamin K₁, Vitamin K_Two, Vitamin K_Three, Vita
Min K_Four, Vitamin K₅, Vitamin K₆, Vitamin K₇
Powdered products of vitamin K, such as palm oil carotene, duna
Riera carotene, cryptoxanthin, zeaxanthi
, Canthaxanthin, astaxanthin, β-apo-
Carotino such as 8'-carotenal, bixin and lycopene
Id-based compound powder, d-α-tocopherol, d-
β-tocopherol, d-γ-tocopherol, d-σ
-Vitamin Es such as tocopherol and tocotrienol
Powder products such as linoleic acid, linolenic acid, arachidonic acid, etc.
Examples thereof include powdered products of vitamin Fs.

As minerals, 12 kinds of minerals (calcium, magnesium, iron, zinc, selenium, chromium, manganese, copper, molybdenum) announced by the Ministry of Health and Welfare as nutritional requirements for the sixth revised Japanese in 2000. , Potassium, phosphorus, iodine). Such minerals may be inorganic minerals or organic minerals. The organic mineral in the present invention may be, for example, a mineral in which a metal such as zinc or copper is chemically bound to an amino acid which is a constituent component of protein, or an organic compound.

For example, as organic minerals, minerals such as zinc yeast, magnesium yeast, iron yeast, selenium yeast, chrome yeast, manganese yeast, copper yeast, molybdenum yeast, and iodine yeast are incorporated into yeast yeast cells. Commercially available products such as heme iron obtained by subjecting minerals and hemoglobin treated with enzymes to ultrafiltration or isochoric point precipitation and drying. On the other hand, as inorganic minerals, for example, commercially available products that can be used in foods such as dolomite, egg shell calcium, coral calcium, sea urchin shell calcium, petrified seaweed calcium, pearl calcium, bovine bone calcium, fish bone calcium, fish scale calcium, and milk calcium. Natural calcium and natural magnesium. For example, dolomite is obtained by roughly crushing rough dolomite, heat sterilizing it, and crushing it. Since the compounding ratio of calcium and magnesium is 2: 1, dolomite can be used to absorb calcium. A suitable composition is obtained.

As herbs, thistle extract,
Turmeric extract, mulberry leaf extract, Gymnema sylvestre extract, ginkgo leaf extract, eleuthero extract, blueberry extract, St. John's wort extract, saw palmetto fruit extract, pumpkin seed extract, beetroot tea extract, perilla seed extract, perilla leaf extract, rooibos tea extract, adlay barley. Extract, Echinacea extract, Merrilot extract, Pueraria Milifica powder, Chest tree extract, Pomegranate seed extract, Garcinia extract, Citrus aurantium extract, Clove extract, Centella asiatica extract,
Grape seed extract, red wine extract, millet extract,
Horsetail extract, Agaricus mushroom extract, Maitake extract, Garlic extract, Kidachi aloe extract, Propolis extract and the like can be mentioned. For these herbs, crushed products of fruits, seeds, leaves, etc., or extracts extracted from fruits, seeds, leaves, etc. with an aqueous ethanol solution are separated and concentrated, and additives such as excipients are added as necessary. It can be obtained by drying and drying, and a commercially available product can be used.

Other active ingredients include plant sterols, red yeast rice powder, soybean, soybean hypocotyl, soybean fermented product, soybean hypocotyl fermented product, red clover, kudzu, soybean extract, soybean hypocotyl extract, soybean fermentation. Extract, soybean hypocotyl fermentation extract, red clover extract, kudzu extract, glucosamine, chondroitin sulfate-containing mucopolysaccharide protein, collagen peptide, branched chain amino acid, chitosan, silk peptide, inositol, protein, bifidobacterial powder, lactic acid bacterial powder , Beer yeast, chlorella, spirulina, royal jelly powder, and the like, and commercially available products can be used.

In the multi-layered tablet of the present invention, different active ingredients may be blended in each layer, or the same active ingredient may be blended in each layer. Further, two or more kinds of the above active ingredients may be blended in one layer, and a layer not containing the above active ingredient may be provided.

In addition to the above active ingredients, the food composition of the present invention may contain inactive ingredients such as binders, excipients, disintegrants and lubricants.

The inactive ingredients used in the present invention include dextrin, wheat starch, rice starch, corn starch, potato starch, pregelatinized starch, partially pregelatinized starch, maltose, reduced lactose, reduced maltose, sorbitol, mannitol, erythritol. , Xylitol, sucrose, glucose, guar gum, xanthan gum, sodium alginate, gum arabic, tragacanth gum, pullulan, agar, gelatin,
Soybean dietary fiber, methyl cellulose, ethyl cellulose,
Hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, hydroxyethylcellulose, hydroxypropylstarch, polyvinylpyrrolidone, low-substituted hydroxypropylcellulose, carmellose , Carmellose calcium, Carmellose sodium, Croscarmellose sodium, Sodium carboxymethyl starch, Hardened vegetable oil, Vegetable oil and fat powder, Carnauba wax, Cocoa butter powder, Sucrose fatty acid ester, Stearic acid, Magnesium stearate, Aluminum stearate, Steer Calcium phosphate, silicon dioxide,
Examples thereof include talc, aluminum silicate, calcium hydrogen phosphate and the like.

The food composition of the present invention may be in the form of a multi-layered tablet, and may be, for example, a double-layered tablet or a multi-layered tablet having three or more layers by providing a layer having another purpose.
Further, they are manufactured according to a general manufacturing method without being influenced by their shape and weight.

For example, a mixture of the active ingredient and the crystalline cellulose as it is, or the active ingredient, the crystalline cellulose, an excipient, a binder, a disintegrating agent, a lubricant,
A mixture obtained by uniformly mixing other suitable additives is directly compression-molded to give a multilayer tablet. Alternatively, after the active ingredient is granulated by a suitable method as it is, the crystalline cellulose is added, and compression molding is carried out according to a conventional method to give a multilayer tablet, or the active ingredient and an excipient, a binder, a disintegrant, After uniformly mixing other suitable additives into granules by a suitable method, add suitable additives such as a lubricant and the crystalline cellulose, and compression-mold according to a conventional method to give a multilayer tablet. . Alternatively, compression-molded is a mixture of pre-produced granules, the active ingredient, the crystalline cellulose, and if necessary, an excipient, a binder, a disintegrating agent, a lubricant, and other suitable additives. Use multi-layered tablets.

The method for producing granules will be described below.
As a method of using the binder in the granulation step, there is a method of adding water or an aqueous solution of ethanol as a binder to the active ingredient or the mixture of the active ingredient and the inactive ingredient. The ethanol concentration of the aqueous ethanol solution used can be adjusted by the hygroscopicity of each powder, the average particle size, the bulk specific gravity, and the like. If necessary, a highly viscous solution in which the above-mentioned inactive component is dissolved can be used as a binding solution to make the working time of the granulation step efficient.

As the granulation method, a wet granulation method is suitable,
Specifically, the fluidized bed granulation method, the stirring granulation method, the extrusion granulation method, the crushing granulation method, the rolling granulation method and the like are effective. In the fluidized bed granulation method, the fluidized powder is granulated by spraying the binding liquid onto the fluidized powder in a fluidized bed granulator. In the stirring granulation method, powder is mixed, kneaded and granulated simultaneously in a closed structure by rotating a stirring blade at a high speed in a mixing tank while adding a binding solution. In the extrusion granulation method, the wet mass kneaded by adding the binding solution is forcedly extruded from a screen of an appropriate size by a screw type or basket type method to perform granulation. In the crushing and granulating method, the wet mass kneaded by adding the binding solution is sheared and ground by a rotary blade of a granulator, and the centrifugal force ejects it from the outer peripheral screen for granulation. In the rolling granulation method, the raw material powder that has been drawn to the outer wall by the centrifugal force of the rotating rotor rolls by the air blown up from the slit, and at this time the binding liquid sprayed from the spray gun creates a snowball type. Granulation is performed by growing spherical granules having a uniform particle size.

The granulated material can be dried by hot air heating type (shelf drying, vacuum shelf drying, fluidized bed drying), conduction heat transfer type (flat pan type,
Any method such as a shelf box type, a drum type) or freeze-drying can be used. In the hot air heating type, the material and hot air are brought into direct contact with each other, and at the same time, the evaporated water is removed. In the conductive heat transfer type, the material is indirectly heated through the heat transfer wall. In freeze-drying, the material is frozen at -10 ° C to -40 ° C and then warmed under high vacuum (2-0.1 Torr) to sublime and remove water.

[0025]

EXAMPLES Examples of the present invention will be shown below, but the present invention is not limited thereto. In the examples, a fluidized bed granulation method was used as the granulation method, and water was used as the binding liquid at that time. A fluidized bed drying method was adopted as the drying method.

[Example 1] Glucosamine 60 kg, riboflavin 5 kg, pyridoxine hydrochloride 5 kg, ascorbic acid 2
0 kg was put into a fluidized bed granulator (FLO120, manufactured by Freund Sangyo Co., Ltd.), and while being fluidized, water was sprayed to 5 parts by mass per 100 parts by mass of the mixed powder, and the loss on drying was 5%.
Drying was performed at 80 ° C. so as to be as follows. Furthermore, 1
After sieving with a vibrating sieve having a diameter of mm (1000D-2S, manufactured by Koei Sangyo Co., Ltd.), 14 kg of crystalline cellulose having a bulk specific gravity of 0.18 g / ml and 2 kg of vegetable oil and fat powder were added to the conical mixer ( Granules A were obtained by mixing for 7 minutes at a rotation speed of 15 rpm by Takagi Electric Co., Ltd.).

Next, 75 kg of collagen peptide, 15 kg of dextrin and 2 kg of soybean polysaccharide were added to a fluid bed granulator (FLO).
120, manufactured by Freund Sangyo Co., Ltd.), water was sprayed while being mixed so as to be 5 parts by mass with respect to 100 parts by mass of the mixed powder, and then dried at 80 ° C. so that the loss on drying was 5% or less. It was Furthermore, a vibrating screener with a diameter of 1 mm (1000D
-2S, manufactured by Koei Sangyo Co., Ltd.), and then 2 kg of vegetable oil and fat powder is added to the conical mixer (manufactured by Takagi Electric Co., Ltd.).
Granules B were obtained by mixing for 7 minutes at a rotation speed of 15 rpm.

In the next step, a rotary tableting machine (53
U, manufactured by Hatakko Kogyo Co., Ltd.), first, the above granule A is tableted at a pressure of 100 kg / cm ² as a first layer, and then the above granule B is tableted as a second layer at a pressure of 300 kg / cm ^2. After tableting, the tablet was further tableted at a pressure of 500 kg / cm ² to obtain a bilayer tablet.

[Example 2] 75 kg of collagen peptide,
2 kg of the soybean fermented extract was put into a fluidized bed granulator (FLO120, manufactured by Freund Sangyo Co., Ltd.), and while being fluidized, water was sprayed to 5 parts by mass per 100 parts by mass of the mixed powder,
Drying was performed at 80 ° C. so that the loss on drying was 5% or less. Furthermore, after sieving with a vibrating screener with a diameter of 1 mm (1000D-2S, manufactured by Koei Sangyo Co., Ltd.), the bulk specific gravity is 0.23 g / ml.
15 kg of crystalline cellulose and 2 kg of vegetable oil and fat powder are added to a conical mixer (manufactured by Takagi Electric Co., Ltd.) for 15 r.
Granules C were obtained by mixing for 7 minutes at a rotation speed of pm.

In the next step, a rotary tableting machine (53
U, manufactured by Hatakko Kogyo Co., Ltd.), the granules A produced according to Example 1 are tableted at a pressure of 100 kg / cm ² as a first layer, and then the granules C are used as a second layer of 300 kg / cm ²
After tableting at a pressure of, the tablet was further tableted at a pressure of 500 kg / cm ² to obtain a bilayer tablet.

[Comparative Example 1] A bilayer tablet was obtained in the same manner as in Example 1 except that the bulk specific gravity of the crystalline cellulose blended in the first layer was 0.39 g / ml.

[Comparative Example 2] A bilayer tablet was obtained according to the formulation and the manufacturing method of Example 2 except that corn starch was blended in place of the crystalline cellulose blended in Example 2.

100 tablets of each of the bilayer tablets of Examples 1 and 2 and Comparative Examples 1 and 2 were taken, placed in a tablet friability tester, and tested at a rotation speed of 25 rpm for 30 minutes.
The number of peeled tablets of each two-layer tablet was investigated. The results are shown in Table 1.

[0034]

[Table 1]

As shown in Table 1, in Examples 1 and 2, delamination did not occur even in the severe tablet friability test of 30 minutes at a rotation speed of 25 rpm. On the other hand, in Comparative Example 1, delamination of 62 tablets out of 100 tablets was observed, and in Comparative Example 2, delamination was observed in all tablets of 100 tablets.

[0036]

According to the production method of the present invention, the problem of delamination, which is a problem in the production of multilayer tablets, can be easily overcome. As described above, the delamination of the multilayer tablet was prevented even in the severe tablet friability test. Therefore, the present invention is effective for the coating treatment of the multilayer tablet.

Continued front page    (72) Inventor Takamitsu Uedo             Kanagawa Prefecture Toyama City Totsuka Ward Shinano 12-13 shares             FANCL Central Research Institute F term (reference) 4B048 PE09 PN06 PN16 PQ01 PQ02                       PS01 PS09 PS17                 4C076 AA40 EE30 EE31 EE38 EE43                       FF05

Claims (3)

[Claims] 1. A method for suppressing peeling of a multi-layered tablet, which comprises blending at least one layer of crystalline cellulose having a bulk specific gravity of 0.10 to 0.25 g / ml in the production of the multi-layered tablet. 2. The amount of crystalline cellulose to be blended is 1 to 20 parts by mass in a layer containing crystalline cellulose having a bulk specific gravity of 0.10 to 0.25 g / ml. A method for suppressing peeling of a multilayer tablet. 3. A multi-layer tablet comprising at least one of two or more layers containing crystalline cellulose having a bulk specific gravity of 0.10 to 0.25 g / ml.