JP7064683B2 - Composition for preventing damage to the enteric layer - Google Patents

Description

The present invention relates to a novel coating composition, enteric granules in which damage to the enteric layer is prevented by coating with the present composition, and an enteric preparation containing the same.

The enteric-soluble preparation is a preparation devised so that it does not elute in the stomach but elutes only after it is transferred to the intestine when a drug that decomposes in the stomach, a drug that causes gastric disorders, or a drug that wants to be transferred to the intestine. .. Technically, it is a solid internal preparation that does not dissolve in acidic gastric juice but dissolves in alkaline intestinal juice, or the capsule itself is enteric-soluble. It is a fine granule, granule, pill, tablet, capsule. Agents and microencapsulated ones have been reported.

Enteric-coated preparations used for such purposes have been applied to various drugs due to their usefulness, but on the other hand, they have some problems. For example, in the production of enteric granules coated with an enteric coating, the enteric layer is damaged at the time of tableting, and as a result, the content component exudes from the granule or the formulation containing the granule, and the content component Problems such as reduction and tableting disorder in formulation can be mentioned. Therefore, since a high tableting pressure cannot be applied at the time of tableting, the hardness of the obtained tablet is not sufficient, and there is a concern that the tablet may be damaged during tablet transportation. Further, in the case of a drug that decomposes in the stomach, if the enteric coating is damaged, there is a concern that the main drug is decomposed by gastric juice at the time of administration and does not exhibit sufficient medicinal effect.
Therefore, it is desired to develop enteric granules and stable enteric-coated preparations in which damage to the enteric-coated layer is suppressed during the production of such enteric-coated preparations.

As prior art related to these, for example, in Patent Document 1, each of the benzimidazole compositions containing a plurality of compression units and capable of rapidly disintegrating in or out of the intestine (i). A composition comprising a substrate comprising benzimidazole, (ii) an enteric coating layered on the substrate; (iii) an outer coating substantially layered over the entire enteric coating and comprising a pressure absorber. Is disclosed. Further, microcrystalline cellulose, polysaccharides, starch and the like are disclosed as pressure absorbers.

Special Table 2009-538901

The present invention provides a coating composition for preventing damage to the enteric layer during tableting in an enteric-coated preparation, enteric-coated granules coated with the present-coating composition, and an enteric-coated preparation containing the present granules. With the goal.

As a result of various studies on techniques for suppressing damage to the enteric layer in enteric granules, the present inventors have applied a coating composition containing D-mannitol and polyethylene glycol to the outside of the enteric layer and / or the enteric layer. It has been found that the damage of the enteric layer can be prevented by coating any one of the layers, and the present invention has been completed.

That is, the present invention provides a coating composition containing D-mannitol and polyethylene glycol.
The present invention also provides an enteric granule coating composition containing D-mannitol and polyethylene glycol.
The present invention also provides enteric-coated granules coated with a coating composition containing D-mannitol and polyethylene glycol.
The present invention also provides an enteric-coated formulation containing enteric-coated granules coated with a coating composition containing D-mannitol and polyethylene glycol.

The enteric-coated granules coated with the coating composition of the present invention are useful for producing an enteric-coated preparation because the content of the main ingredient due to the breakage of the enteric-coated layer is reduced and the tableting disorder is improved.

Hereinafter, the present invention will be described in more detail.
As the D-mannitol used in the present invention, a generally known commercially available D-mannitol can be used.

The polyethylene glycol used in the present invention includes polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 11000 or Examples thereof include polyethylene glycol 20000, preferably polyethylene glycol 400, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000, and more preferably polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol. 6000 is mentioned.

The blending ratio of D-mannitol and polyethylene glycol used in the present invention can be in the range of 10: 1 to 1: 1 by mass ratio, but is preferably 9: 1 to 6: 4, more preferably 8: The range is 2 to 6: 4, more preferably 8: 2 to 7: 3.

The enteric granules and solid preparations of the present invention may be appropriately combined with a binder, a disintegrant, an excipient, a coating base, an auxiliary agent for formulation of a surfactant and the like, a flavoring agent, a coloring agent, a fragrance and the like, if necessary. Can be blended in the required amount.

Binders that can be used in the present invention include methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, gelatin, agar, alginic acid, sodium alginate, partially saponified polyvinyl alcohol, pullulan, partially pregelatinized starch, dextrin, and kitansan gum. , Arabic rubber powder, etc. Preferred are hydroxypropyl cellulose, hypromellose and polyvinylpyrrolidone. These may be alone or a mixture of two or more.

Examples of the disintegrant that can be used in the present invention include crystalline cellulose, carboxymethyl cellulose (carmellose), croscarmellose sodium, carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose, crospovidone, hydroxypropyl starch, starch, and partial α. Examples thereof include calciumized starch, sodium starch glycolate, calcium carbonate, precipitated calcium carbonate, calcium citrate, light anhydrous silicic acid, synthetic aluminum silicate, and the like, preferably croscarmellose sodium, sodium starch glycolate, and crospovidone. More preferably, it is crosspovidone. Further, as the crosspovidone used in the present invention, polyplusdon (registered trademark) XL, polyplusdon (registered trademark) XL-10, polyplusdon (registered trademark) INF-10 (all manufactured by Ashland), corridon. Examples thereof include CL (registered trademark) CL, corridon (registered trademark) CL-F, corridon (registered trademark) CL-SF, corridon (registered trademark) CL-M, and the like, preferably corridon CL, corridon CL-F, corridon CL-. SF, Corridon CL-M (all manufactured by BASF Japan, Inc.), and particularly preferably Corridon CL-F. The blending amount of the disintegrant used is preferably 5 to 30% by mass, more preferably 5 to 15% by mass in the nuclear particles. Further, when blended in an orally disintegrating tablet, it is preferably 1 to 10% by mass, more preferably 2 to 6% by mass in the posterior powder.

Excipients that can be used in the present invention include celluloses such as crystalline cellulose, ethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose (hypromerose, etc.), corn starch, potato starch, wheat starch, and the like. Starches such as rice starch, partially pregelatinized starch, hydroxypropyl starch, sugars such as glucose, lactose, sucrose, refined sucrose, powdered sugar, trehalose, dextran, dextrin, sugars such as (D-mannitol, xylitol, sorbitol, erythritol) Examples thereof include inorganic salts such as alcohols, glycerin fatty acid ester, magnesium aluminometasilicate, synthetic hydrotalcite, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, calcium hydrogenphosphate hydrate, and sodium hydrogencarbonate. The shaping material can be blended in an amount of 10 to 70% by mass in the solid preparation.

Examples of the coating base that can be used in the present invention include methacrylic acid copolymers L, S (for example, Eudragit® L100, Eudragit® S100, manufactured by Evonik), aminoalkyl methacrylate copolymer E (eg, Eudragit). (Registered Trademarks) E100, Eudragit® EPO, manufactured by Evonik), Methacrylic Acid Copolymer LD (eg, Eudragit® L100-55, Eudragit® L30D-55, manufactured by Evonik), acrylic acid. Ethyl-Methacrylic Acid Copolymer (eg, Eudragit® NE30D, manufactured by Evonik), Aminoalkyl Methacrylic Acid Copolymer RS (eg, Eudragit® RL100 / RLPO / RL30D, Eudragit® RS100 / RSPO / RS30D) , Evonik) and the like, and examples thereof include methacrylic acid copolymers L and S, and methacrylic acid copolymer LD. These coating bases can be used alone or in combination of two or more. The content of the acrylic polymer is about 1 to about 50% by weight, preferably about 5 to about 40% by weight, and more preferably about 10 to about 30% by weight, based on the weight of the polymer solid content in the coating layer.

Surfactants that can be used in the present invention include cations such as bis- (2-ethylhexyl) sodium sulfosuccinate (sodium doxate), alkyltrimethylammonium bromide (eg, cetyltrimethylammonium bromide (cetrimid)). Agents, especially nonionic agents such as polyoxyethylene sorbitan (eg Tween ^TM 20, 40, 60, 80 or 85), and other sorbitans (eg Span Span ^TM 20, 40, 60, 80 or 85). ).

Examples of the flavoring agent that can be used in the present invention include sugar alcohol, aspartame, stevia, saccharin sodium, glycyrrhizin dipotassium, thaumatin, acesulfame potassium, sucralose and the like. These may be alone or a mixture of two or more.

The colorants that can be used in the present invention include edible blue No. 1, edible blue No. 2, edible yellow No. 4, edible yellow No. 5, edible red No. 2, edible red No. 3, edible red No. 102, and edible blue No. 1. No. Aluminum Lake, Edible Blue No. 2 Aluminum Lake, Edible Yellow No. 4 Aluminum Lake, Edible Yellow No. 5 Aluminum Lake, Edible Red No. 2 Aluminum Lake, Edible Red No. 3 Aluminum Lake, Edible Red No. 102 Aluminum Lake, Iron Tricarbonate ( Red), titanium oxide, yellow iron sesquioxide, orange essence, caramel, talc, green tea powder and the like. These may be alone or a mixture of two or more.

Examples of the fragrance that can be used in the present invention include mint, lemon fragrance, orange corton, pineapple flavor, l-menthol, black tea micron and the like. These may be alone or a mixture of two or more.

In the present invention, the components to be blended in the drug layer are not particularly limited, but preferably, the components are preferably decomposed and released in the intestine, such as decomposition in the stomach or damage / burden on the stomach. Examples thereof include proton pump inhibitors (omeprazole, lansoprazole, etc.), analgesics (aspirin, etc.), pharmaceuticals such as salazosulfapyridine, and components used in health foods such as fish oil, garlic, lactic acid bacteria, and bifidus bacteria.

The coating composition of the present invention can be produced, for example, by adding D-mannitol and polyethylene glycol to a solvent and, if necessary, removing the solvent. Examples of the solvent used in the production include water, alcoholic media such as methyl alcohol and ethyl alcohol, and a mixed solution thereof.

The enteric granules having a multi-layered structure in the present invention are composed of, for example, a nucleus containing crystalline cellulose or lactose, (1) a drug layer containing a main ingredient, (2) an enteric layer, and (3) a coating composition of the present invention. It can be manufactured by coating with a coated layer (enteric layer damage prevention layer). Further, the multi-layer structure referred to in the present invention means enteric-soluble granules composed of at least three or more layers (1) to (3), but if necessary, a drug layer containing a different drug and elution control. It can be covered with a layer or a barrier layer that blocks between the layers. At this time, it is preferable that the enteric layer damage prevention layer of the present invention is located outside the drug layer. The production can be carried out by a generally known method, for example, a fluidized bed granulation method such as a rolling fluidized bed granulation, a fluidized granulation method, a rolling granulation method such as a centrifugal rolling granulation method, a stirring granulation method and the like. Can be manufactured by The film thickness of the enteric layer damage prevention layer is not particularly limited, but if it is too thin, the effect of the present invention cannot be sufficiently exerted, and if it is thicker than necessary, the particle size of the granules becomes large. A suitable film thickness is 10 to 100 μm, preferably 20 to 80 μm, and more preferably 30 to 50 μm, because the tablet hardness may be lowered and discomfort may occur as roughness when disintegrated in the oral cavity. ..

The enteric-soluble granules of the present invention can be used by being contained in an enteric-coated preparation, and a solid preparation is particularly preferable. Can be mentioned. Tablets are preferable from the viewpoint of ease of handling and the like. In addition, these solid formulations can be coated as needed.

The orally disintegrating tablet of the present invention is formed by mixing generally known methods, for example, enteric granules and additives (excipients, disintegrants, etc.) of the present invention in the presence or absence of a solvent, and molding the mixture, if necessary. It can be manufactured by drying. Mixing can be performed using an apparatus such as a V-type mixer, a universal kneader, a fluidized bed granulator, and a tumbler mixer.
The solid preparation of the present invention can be molded into tablets and orally disintegrating tablets by, for example, using a rotary tableting machine or the like.
The drying may be performed by any method used for general drying of the pharmaceutical product, such as vacuum drying and fluidized bed drying.

The enteric granules and enteric-coated preparations of the present invention can be produced, for example, by the following steps.
(Process 1: Layering / classification process)
Crystalline cellulose is placed in a rolling fluidized bed granulator and sprayed with a suspension of the drug (purified water, drug, hypromellose and polysorbate 80) for layering. Then, after drying, it is passed through a sieve for classification.
(Step 2: Intermediate layer coating / classification process)
The graded product produced in the first step is placed in a rolling fluidized bed granulator and sprayed with an intermediate layer coating liquid (purified water, hydroxypropyl cellulose, talc, magnesium stearate) to coat the intermediate layer. Then, after drying, it is passed through a sieve for classification (step 3: elution control layer / classification step).
The graded product produced in the second step is placed in a rolling fluidized bed granulator and sprayed with a coating liquid (purified water, ammonioalkyl methacrylate copolymer, triethyl citrate, polysorbate 80 and glycerin monostearate) for coating. .. Then, after drying, it is passed through a sieve for classification.
(Step 4: Enteric coating / classification step)
The graded product produced in the third step is placed in a rolling fluidized bed granulator and sprayed with an enteric coating solution (purified water, methacrylic acid copolymer LD, polyethylene glycol, polysorbate 80 and glycerin monostearate) to enteric coating. I do. Then, after drying, it is passed through a sieve for classification.
(Process 5: Damage prevention layer coating / classification process)
The graded product produced in the fourth step is placed in a rolling fluidized bed granulator and sprayed with a damage prevention layer coating liquid (purified water, polyethylene glycol and D-mannitol) to perform damage prevention layer coating. Then, after drying, it is passed through a sieve for classification.
(Step 6 :)
The graded product produced in the fifth step is placed in a V-type mixer, and D-mannitol, crystalline cellulose, crospovidone, magnesium silicate aluminate and aspartame are placed therein and mixed. Then, magnesium stearate is added and mixed.
(Step 7: Locking step)
The mixed granules produced in the sixth step are locked using a rotary locking machine.

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

(Example)
Spherical crystalline cellulose is placed in a rolling fluid layer granulator (SFC-MINI, manufactured by Freund Sangyo Co., Ltd.), and esomeprazole magnesium hydrate, hypromellose, low-substituted hydroxypropyl cellulose and polysorbate 80 are dissolved and dispersed in water. It was coated while spraying the liquid. The obtained drug layer-coated particles were dried and then coated by spraying a solution prepared by dissolving and dispersing hypromellose, talc and D-mannitol in water. After drying the obtained intermediate layer coating particles, a solution of ammonioalkyl methacrylate copolymer dispersion (solid content 30%), triethyl citrate, glycerin monostearate and polysorbate 80 dissolved and dispersed in water is sprayed and coated. bottom. After drying the obtained elution control layer coating particles, a solution prepared by dissolving and dispersing methacrylic acid copolymer LD dispersion (solid content 30%), macrogol 6000, glycerin monostearate, polysorbate 80 and iron sesquioxide in water was added. Coated while spraying. The obtained enteric layer-coated particles were dried and classified, and then coated with a solution prepared by dissolving Macrogol 6000 and D-mannitol in water while spraying. The obtained breakage-preventing layer-coated particles were dried and classified to obtain coated fine particles having an average particle diameter of 300 μm and an enteric layer damage-preventing layer having a thickness of 30 μm.

D-mannitol / corn starch granulated product, crospovidone, aspartame, magnesium aluminometasilicate and magnesium stearate were added to and mixed with the obtained granules to obtain a powder for tableting. Tableting was performed with a rotary type tableting machine (VELA5) at a tableting pressure of 9 kN to obtain a tablet having a diameter of 10.0 mm.

(Comparative example)
Instead of coating the damage-preventing layers Macrogol 6000 and D-mannitol, tablets were obtained by the same operation as in Examples except that the amount of D-mannitol / corn starch granulated product was increased.

(Test example)
For the tablets obtained in Examples and Comparative Examples, the tablet hardness and the elution property with the first liquid were confirmed.
The results are shown in Table 3.

以上の結果より、実施例の錠剤は、錠剤硬度が上昇することが判明した。さらに、打錠による腸溶性皮膜の破損を軽減できることが判明した。

From the above results, it was found that the tablet of the example had an increased tablet hardness. Furthermore, it was found that the damage to the enteric film due to tableting can be reduced.

Claims (7)

In enteric granules having a multi-layered structure including a drug layer, an elution control layer and an enteric layer, the layer outside the enteric layer and / or the enteric layer is used to prevent damage to the enteric layer containing D-mannitol and polyethylene glycol. Enteric-coated granules characterized by being coated with a composition for use. The enteric granule according to claim 1, wherein the ratio of D-mannitol to polyethylene glycol is 10: 1 to 1: 1. The enteric granule according to claim 1 or 2, wherein the polyethylene glycol is one or more selected from polyethylene glycol 400, polyethylene glycol 4000, and polyethylene glycol 6000. The enteric granule according to any one of claims 1 to 3, wherein the main ingredient contained in the enteric granule is a proton pump inhibitor. A solid preparation containing the enteric-soluble granules according to any one of claims 1 to 4. The solid preparation according to claim 5, which is a tablet. The solid preparation according to claim 5, which is an orally disintegrating tablet.