JP2019034929A - Enteric-coated preparation containing esomeprazole magnesium hydrate, and method for producing the same - Google Patents

Abstract

To improve the stability of the active ingredient in a formulation.SOLUTION: The present invention improves the stability of the active ingredient in a formulation by employing a particular substance as a formulation ingredient. One embodiment of the invention is a formulation (for example, a solid formulation) comprising alkyl cellulose or a derivative thereof as a binder. The binder may be comprised in granule with the active ingredient in a solid formulation. In one embodiment of the invention, provided is a formulation comprising an enteric coated layer having a separated layer comprising alkyl cellulose having an unsubstituted alkyl group, or a derivative thereof.SELECTED DRAWING: None

Description

  The present invention relates to the field of pharmaceutical formulations.

A proton pump inhibitor (PPI) acts on the proton pump of gastric parietal cells and suppresses gastric acid secretion. PPI is used for peptic ulcers (gastric ulcer, duodenal ulcer, anastomosis ulcer, etc.), Zollinger-Ellison syndrome, reflux esophagitis, and Helicobacter pylori eradication assistance. Other drugs that have gastric acid secretion inhibitory action include histamine H2 receptor antagonists (H2 blockers), but proton pump inhibitors have a stronger gastric acid secretion inhibitory action than H2 blockers. And its inhibitory action lasts longer than H2 blockers. Proton pump inhibitors are mainly prodrugs, which are converted into sulfinamide type in wall cells and disulfide bonded to cysteine residues of proton pumps (H ⁺ , K ⁺ -ATPase), thereby making the proton pump irreversible. Inhibits gastric acid secretion.

  The present invention improves the stability of an active ingredient (for example, proton pump inhibitor) in a preparation by adopting a specific substance as a component of the preparation. In particular, the present inventors have found that the chemical stability of the active ingredient is improved by appropriate selection of the binder in the formulation. One embodiment of the present invention is a formulation (eg, a solid formulation) comprising alkyl cellulose or a derivative thereof as a binder. The binder can be included in the granules together with the active ingredient in a solid formulation.

  Proton pump inhibitors include esomeprazole, omeprazole, lansoprazole, rabeprazole, or salts thereof, or hydrates thereof. Preferably, the proton pump inhibitor of the present invention is esomeprazole, a salt or hydrate thereof, more preferably esomeprazole magnesium hydrate.

  In one embodiment, the formulation can include an enteric coating. Enteric coatings enable active ingredients (eg, proton pump inhibitors) that are susceptible to degradation or conversion in an acidic environment to be delivered in the proper state to the portion of the gastrointestinal tract where absorption occurs. Examples of the components of the enteric coating layer include methacrylic acid copolymers. The enteric coating can be applied directly on the uncoated tablet or granule, but it is desirable to have a separating layer between the uncoated tablet or granule and the enteric coating. The inventors have found that proper selection of the material for the separation layer contributes to the stability of the active ingredient.

  In one embodiment of the present invention, a formulation comprising an enteric coating layer having a specific substance as a separation layer is provided. The separation layer preferably contains an alkyl cellulose having an unsubstituted alkyl group or a derivative thereof. More preferably, the separation layer includes alkyl cellulose or hydroxyalkyl alkyl cellulose. An uncoated tablet containing an appropriate binder and an active ingredient in granules may be coated to form a solid preparation containing an enteric coating and a separating layer.

  The formulation can be provided as a tablet. Tablets can be produced, for example, by mixing granules containing active ingredients with additives such as excipients and disintegrants and tableting. In this case, the tablet comprises granules containing the active ingredient. The formulation can also be provided as granules.

  The preparation of the present invention may be a single agent. That is, the formulation of the present invention may contain only a single active ingredient. A preferred active ingredient is esomeprazole magnesium hydrate. In the examples herein, improved stability of esomeprazole magnesium hydrate has been demonstrated.

  The formulation of the present invention may be for the treatment or prevention of gastrointestinal diseases. Also. In another aspect of the invention, there is provided a method for the treatment or prevention of gastrointestinal diseases comprising administering a formulation of the invention.

For example, in the embodiment of the present invention, the following items are provided.
(Item 1)
A solid preparation comprising granules, wherein the granules are
Esomeprazole or a salt thereof, or a hydrate thereof,
A solid preparation comprising alkyl cellulose or a derivative thereof.
(Item 2)
The solid preparation according to the above item, wherein the alkyl cellulose or a derivative thereof is alkyl cellulose, hydroxyalkyl cellulose, hydroxyalkylalkyl cellulose, or carboxyalkyl cellulose ester.
(Item 3)
The solid preparation according to any one of the above items, wherein the alkylcellulose or a derivative thereof is methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose or carboxymethylcellulose ester.
(Item 4)
The solid preparation according to any one of the above items, wherein the alkylcellulose or a derivative thereof is methylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose.
(Item 5)
The solid preparation according to any one of the above items, wherein a disintegrant is included outside the granules, and the disintegrant is sodium starch glycolate, low-substituted hydroxypropylcellulose, or crospovidone.
(Item 6)
The solid preparation according to any one of the above items, comprising the granules.
(Item 7)
The solid preparation according to any one of the above items, which is an uncoated tablet.
(Item 8)
Uncoated tablets or granules containing esomeprazole or a salt thereof, or a hydrate thereof;
An enteric coating layer,
A solid preparation comprising a separation layer containing an alkylcellulose having an unsubstituted alkyl group or a derivative thereof between the uncoated tablet or granule and the enteric coating layer.
(Item 9)
The solid preparation according to the above item, wherein the separation layer contains alkyl cellulose or hydroxyalkyl alkyl cellulose.
(Item 10)
The solid preparation according to any of the preceding items, wherein the separation layer comprises methylcellulose or hydroxypropylmethylcellulose.
(Item 11)
The solid preparation according to any of the preceding items, wherein the enteric coating layer comprises a methacrylic acid copolymer.
(Item 12)
The solid preparation according to any of the above items, comprising the solid preparation according to any of the above items as the uncoated tablet.
(Item 13)
The solid preparation according to any of the preceding items, wherein the uncoated tablet comprises granules containing hydroxypropylcellulose.
(Item 14)
The solid preparation according to any one of the above items, comprising the solid preparation according to any one of the above items as the granule.
(Item 15)
The solid preparation according to any of the preceding items, wherein the granule comprises methylcellulose.
(Item 16)
The solid preparation according to any of the preceding items, wherein the esomeprazole or a salt thereof, or a hydrate thereof is esomeprazole magnesium hydrate.
(Item 17)
The solid preparation according to any one of the above items, for the treatment or prevention of gastrointestinal diseases.

  By selecting suitable ingredients and / or structures in the formulation, the chemical stability of esomeprazole magnesium hydrate can be improved.

  The present invention will be described below with reference to the best mode. Throughout this specification, it should be understood that the singular forms also include the plural concept unless specifically stated otherwise. Thus, it should be understood that singular articles (eg, “a”, “an”, “the”, etc. in the case of English) also include the plural concept unless otherwise stated. In addition, it is to be understood that the terms used in the present specification are used in the meaning normally used in the art unless otherwise specified. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control.

  Hereinafter, definitions of terms particularly used in the present specification and / or basic technical contents will be described as appropriate.

(1. Definition)
In this specification, “or” is used when “at least one or more” of the items listed in the text can be adopted. The same applies to “or”. In this specification, when “within range” of “two values” is specified, the range includes the two values themselves.

  As used herein, “about” refers to a tolerance of up to ± 10% of the indicated value.

  As used herein, “pharmaceutically acceptable” refers to a pharmacopoeia or other generally accepted pharmacopoeia that has been approved by a government regulatory agency for use in animals, and more particularly in humans. It is enumerated in.

(2. Proton pump inhibitor)
In one embodiment of the present invention, a formulation comprising a proton pump inhibitor (PPI) as an active ingredient is provided. Exemplary proton pump inhibitors include esomeprazole, omeprazole, lansoprazole, rabeprazole, or salts thereof, or hydrates thereof.

  Esomeprazole is the S form of omeprazole which is a racemic mixture. Compared to R, omeprazole has lower affinity for CYP2C19 and is less susceptible to the first-pass effect in the liver, so esomeprazole has a lower total metabolic clearance than omeprazole, and the elimination time from plasma slow. As a result, even when the same dose is administered, the AUC is high, and it is said that the clinical effect is excellent. Furthermore, since the contribution rate of CYP2C19 in the metabolism of esomeprazole is lower than that of omeprazole, it is considered that there are few individual fluctuations in pharmacokinetics and pharmacodynamic effects caused by genetic polymorphisms.

  The active ingredient of the formulation of the present invention may be a pharmaceutically acceptable salt of the proton pump inhibitor described herein. Examples of the salt of the proton pump inhibitor include alkali salts such as magnesium salt, sodium salt, potassium salt, or calcium salt. Preferred salts include magnesium salts. The active ingredient of the formulation of the present invention may be a proton pump inhibitor described herein or a hydrate of a salt thereof. Preferably, it may be a hydrate of magnesium salt.

  The tablet of the present invention may be a single agent, and in one embodiment, the formulation of the present invention may contain only a single active ingredient. A single active ingredient is esomeprazole magnesium hydrate, for example.

(3. Binder)
In one embodiment of the invention, a solid formulation comprising a binder is provided. Preferably, a binder is contained in the granule containing the active ingredient. When tableting is performed after granulation, a solid preparation containing the binder in the granule is provided by including the binder during granulation. A binder is an additive for binding powder in the production of tablets or granules. Examples of the binder include, but are not limited to, hypromellose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, povidone, and carmellose sodium. The amount of binder in the formulation is, for example, from about 0.1 to about 10.0%, from about 0.5 to about 8.0%, or from about 3.0 to about 6% by weight relative to the total weight of the formulation. It may be 0.0% by weight. The amount of binder in the formulation is, for example, about 1.0%, about 2.0%, about 3.0%, about 4.0%, about 5.0% by weight relative to the total weight of the formulation. % By weight, about 6.0% by weight, about 7.0% by weight, and about 8.0% by weight, and particularly preferably about 5.0% by weight.

  The binder is preferably alkyl cellulose or a derivative thereof. In the examples of the present specification, it has been demonstrated that the stability of an active ingredient is improved in a preparation containing an alkyl cellulose or a derivative thereof in a granule containing the active ingredient. The alkyl cellulose or derivative thereof can be, for example, an alkyl cellulose, a hydroxyalkyl cellulose, a hydroxyalkylalkyl cellulose, or a carboxyalkyl cellulose ester. More particularly, the alkylcellulose or derivative thereof may be methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose or carboxymethylcellulose ester. Particularly preferred binders are methylcellulose, hydroxypropylcellulose or hydroxypropylmethylcellulose. The most preferred binder is hydroxypropyl cellulose

(4. Additives)
The preparation of the present invention may optionally contain, in addition to the active ingredient, any pharmaceutically acceptable additive known in the art. Representative additives include, but are not limited to, excipients, disintegrants, lubricants, tonicity agents, stabilizers, preservatives, and the like.

  Excipients are additives that increase the bulk of the active ingredient (active ingredient) and make it easier to take and dispense. Examples of the excipient include, but are not limited to, mannitol, lactose, crystalline cellulose, starch, dextrin, sucrose, and precipitated silica. The amount of excipient in the formulation is, for example, from about 35.0 to about 90.0% by weight relative to the total weight of the formulation.

  Disintegrants are additives that are added to disintegrate the formulation after taking it and facilitate the release of the active ingredient. For example, the disintegrant disintegrates the tablet by sucking moisture in the body and expanding.

  Examples of the disintegrant include, but are not limited to, sodium starch glycolate, low-substituted hydroxypropylcellulose, crospovidone, carmellose calcium, carmellose, croscarmellose sodium, and the like. The disintegrant is preferably sodium starch glycolate, low substituted hydroxypropylcellulose or crospovidone. The amount of disintegrant in the formulation is, for example, from about 1.0 to about 20.0% by weight relative to the total weight of the formulation.

  The lubricant is an additive for improving the fluidity of the powder and smoothing the tablet production by preventing the powder from adhering to the apparatus. When a small amount (for example, 1% or less) is added to the powder or granule used as the raw material of the tablet, it adheres to the powder surface and weakens the adhesion between the powders, so that the fluidity of the powder becomes high. Lubricants include, but are not limited to, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, hydrogenated vegetable oils and the like. The amount of lubricant in the formulation is, for example, from about 0.5 to about 5.0% by weight relative to the total weight of the formulation.

  In addition to these, for example, surfactants, coloring agents, flavoring agents, preservatives, buffering agents, fluidity promoters, flavoring agents and the like may be included in the preparation.

(5. Formulation)
The preparation of the present invention can be appropriately produced using techniques known to those skilled in the art. For example, the tablet of the present invention can be produced by compressing granules produced by wet granulation or dry granulation (wet granulation or dry granulation), but preferably by wet granulation It is to compress and manufacture the manufactured granule.

  In the case of the wet granulation method, the active ingredient is mixed with an excipient and, if necessary, a disintegrant, a solution containing the binder is added thereto, and the active ingredient is dried to form granules containing the active ingredient ( Granulation). For granulation, use granulators such as swirling (rotor), kneading, stirring, rolling, fluidized bed, compression (roll press), biaxial extrusion, wet extrusion, etc. Can do. By adding a binder during granulation, it is possible to produce a preparation containing the binder in the granule containing the active ingredient.

  Granules produced by granulation are sized as necessary. The sizing can be performed by wet or dry crushing to a target particle size using a sizing machine.

  The sized product after the sizing step is mixed with a lubricant and, if necessary, a disintegrant and tableted to form an uncoated tablet. A preparation containing the disintegrant only outside the granules containing the active ingredient can be produced by mixing the disintegrant prior to tableting without mixing the disintegrant during granulation. Tableting can be performed using a tableting machine (for example, a single-shot vertical molding machine, a continuous rotary molding machine, etc.).

  After tableting, coating, packaging, etc. can be performed as necessary.

(6. Coating)
Proton pump inhibitors are prone to degradation or conversion in acidic and neutral environments. The decomposition is catalyzed by acidic compounds and is stabilized in a mixture with alkaline compounds. The chemical stability of proton pump inhibitors is also affected by moisture, heat and organic solvents, and to some extent by light. Thus, it may be desirable for solid formulations containing proton pump inhibitors (eg, solid formulations contemplated for oral administration) to include an enteric coating layer. This protects the active ingredient from contact with, for example, acidic gastric juice and can be delivered in a suitable form to the part of the gastrointestinal tract where absorption occurs.

  As the main component (enteric coating agent) of the enteric coating layer, for example, methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, One or more of cellulose acetate trimellitate, carboxymethyl ethyl cellulose and the like can be used alone or in combination. Preferred enteric coating agents include methacrylic acid copolymers. The amount of enteric coating agent in the enteric coating layer can be, for example, about 2.0 wt% or more, or about 3.0 to about 10.0 wt%, based on the total weight of the formulation.

  The enteric coating layer can contain a pharmaceutically acceptable plasticizer to obtain desired mechanical properties such as flexibility and hardness. Examples of the plasticizer include, but are not limited to, triacetin, citrate ester, phthalate ester, dibutyl sebacate, cetyl alcohol, polyethylene glycol, polysorbate, and the like. The enteric coating layer may further contain additives such as a dispersant, a colorant, a pigment, an anti-adhesive agent, and an antifoaming agent as necessary.

  Coating can be suitably performed using techniques known to those skilled in the art. As an example, it can be carried out by uniformly spraying and drying a suspension containing a substance used for coating on uncoated tablets. The enteric coating layer can be applied in a suitable device such as a coating pan, a coating granulator, or in a fluid bed device using water and / or organic solvent for lamination.

  A plurality of layers can be formed by coating by sequentially performing the coating process while changing the components used for each. In one embodiment of the invention, a solid formulation having a plurality of coating layers is provided. In one preferred embodiment, a solid formulation comprising an enteric coating and a separation layer is provided.

(7. Separation layer)
In one embodiment of the present invention, a preparation comprising an uncoated tablet containing an active ingredient (which may be a granule in other embodiments of the present invention) and an enteric coating layer, the uncoated tablet and the enteric coating A solid formulation is provided having a separation layer between the coating layer. The enteric coating layer may have an effect on the active ingredient due to, for example, a free carboxyl group, and the stability of the active ingredient can be improved by including a separation layer.

  Since the separation layer produces a certain effect if physical separation can be realized, it is common to simply use the same components as additives such as excipients used in uncoated tablets. However, the inventors have found that the selection of appropriate separation layer components results in improved stability of the active ingredients.

The main component (coating agent) of the preferred separating layer is an alkyl cellulose having an unsubstituted alkyl group or a derivative thereof. In the examples of the present specification, it has been demonstrated that the stability of an active ingredient is improved in a preparation containing an alkyl cellulose having an unsubstituted alkyl group in a separation layer. Examples of the unsubstituted alkyl group include, but are not limited to, methyl (C ₁ ), ethyl (C ₂ ), propyl (C ₃ ), butyl (C ₄ ), and isobutyl (C ₄ ). Absent.

  The separation layer can include, for example, alkyl cellulose or hydroxyalkyl alkyl cellulose. Particularly preferably, the separating layer can comprise methylcellulose or hydroxypropylmethylcellulose. Most preferably, the separating layer can comprise hydroxypropyl methylcellulose. The amount of coating agent in the separation layer can be, for example, about 1.0 wt% or more, or about 2.0 to about 10.0 wt%, based on the total weight of the formulation.

  The separating layer is coated with different ingredients on a core (eg, granules, uncoated tablets, or tablets with different coatings) described herein or prepared by techniques known to those skilled in the art. Further, it can be formed by coating. Uncoated tablets or granules of any composition described herein can be used as uncoated tablets or granules (core) in a two-layer coating (enteric coating and separation layer) formulation.

(8. Use)
The preparation containing the proton pump inhibitor of the present invention can be used for treatment or prevention of gastrointestinal diseases. More particularly, the formulations of the present invention are useful for the treatment of gastric ulcers, duodenal ulcers, anastomotic ulcers, Zollinger-Ellison syndrome, reflux esophagitis, or non-erosive gastroesophageal reflux disease, during administration of nonsteroidal anti-inflammatory drugs. Suppression of recurrence of gastric or duodenal ulcer, suppression of recurrence of gastric or duodenal ulcer at the time of low-dose aspirin administration, or gastric ulcer, duodenal ulcer, gastric MALT lymphoma, idiopathic thrombocytopenic purpura, stomach after endoscopic treatment for early gastric cancer Alternatively, it can be used to assist in eradication of Helicobacter pylori in gastritis infected with Helicobacter pylori.

  In one aspect of the invention, there is provided a method for the treatment or prevention of gastrointestinal diseases comprising administering a formulation of the invention. For example, the method of the present invention can be used to treat gastric ulcer, duodenal ulcer, anastomotic ulcer, Zollinger-Ellison syndrome, reflux esophagitis, or non-erosive gastroesophageal reflux disease, gastric ulcer or duodenum at the time of nonsteroidal anti-inflammatory drug administration Suppression of recurrence of ulcer, suppression of recurrence of gastric or duodenal ulcer during low-dose aspirin administration, or gastric ulcer, duodenal ulcer, gastric MALT lymphoma, idiopathic thrombocytopenic purpura, stomach after endoscopic treatment for early gastric cancer, or Helicobacter -It may be a method for assisting in eradication of Helicobacter pylori in H. pylori-infected gastritis.

  The amount of active ingredient in the formulations of the invention, or the amount of formulation administered, can vary depending on the nature of the disorder or condition, but can be determined by those skilled in the art according to standard clinical techniques based on the description herein. Further, in some cases, in vitro assays can be used to help identify optimal dosage ranges. The exact dose to be used in the formulation can also vary depending on the route of administration and the severity of the disease or disorder and should be determined according to the judgment of the attending physician and the circumstances of each patient. However, the dose is not particularly limited, and may be, for example, 0.001, 1, 5, 10, 15, 100, or 1000 mg / kg body weight per dose, and within the range of any two of these values There may be. The dosing interval is not particularly limited. For example, it may be administered once or twice per 1, 7, 14, 21, or 28 days, or once or twice per any two of these ranges. Also good. The dose, administration interval, and administration method may be appropriately selected depending on the age, weight, symptoms, target organ, etc. of the patient. The therapeutic agent preferably contains a therapeutically effective amount or an effective amount of an active ingredient that exhibits a desired action. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

  The formulations of the present invention can be administered by any suitable route determined by those skilled in the art and include, but are not limited to, administration selected from oral, intravenous injection, infusion, parenteral, transdermal, etc. It may be formulated to be suitable for administration by route.

  The amount of active ingredient in the formulation can be, for example, from about 10 to about 30%, from about 12 to about 24%, or from about 16 to about 20% by weight relative to the total weight of the formulation. The amount of active ingredient in the formulation is, for example, particularly preferably about 18% by weight. The amount of the active ingredient in the unit dosage form can be, for example, about 10-30 mg, about 15-25 mg, or about 18-22 mg, such as about 11 mg, about It can be 15 mg, about 22 mg, about 25 mg, about 30 mg, or the like.

(9. Preferred embodiment)
In one embodiment, a solid formulation is provided comprising granules comprising esomeprazole or a salt thereof, or a hydrate thereof, and an alkyl cellulose or a derivative thereof. The solid formulations described herein may further comprise an enteric coating and a separation layer. The preparation of the present invention is provided as a preparation (for example, a tablet or a granule) having good storage stability due to the stability of the active ingredient, and can be suitably used for the treatment or prevention of gastrointestinal diseases.

  In one embodiment, a solid formulation is provided that includes alkyl cellulose or a derivative thereof in a granule that contains an active ingredient, and an alkyl cellulose or derivative thereof in a separating layer. The alkyl cellulose or its derivative in the granule (for example, as a binder) and the alkyl cellulose or its derivative in the separation layer may be the same, but different ones can be used.

  In one embodiment, the alkylcellulose or derivative thereof contained in the granules is hypromellose (HPMC), hydroxypropylcellulose (HPC) or methylcellulose (MC), and the alkylcellulose or derivative thereof in the separation layer is hydroxypropylmethylcellulose. Or methylcellulose. Any combination of the indicated ingredients can be used. Particularly preferred preparations contain hydroxypropylcellulose in the granules and hydroxypropylmethylcellulose or methylcellulose in the separating layer. In a preparation containing hydroxypropyl cellulose in the granule, the stability of the active ingredient in the preparation is compared when one containing hydroxypropyl cellulose, which is the same component in the separation layer, is compared with one containing hydroxypropyl methylcellulose or methyl cellulose in the separation layer. Is shown in the examples herein.

  References such as scientific literature, patents and patent applications cited herein are hereby incorporated by reference in their entirety to the same extent as if each was specifically described.

  The present invention has been described with reference to the preferred embodiments for easy understanding. In the following, the present invention will be described based on examples, but the above description and the following examples are provided only for the purpose of illustration, not for the purpose of limiting the present invention. Accordingly, the scope of the present invention is not limited to the embodiments or examples specifically described in the present specification, but is limited only by the scope of the claims.

  The stability of the active ingredient was examined for the solid preparations produced as shown below.

[Example 1]
Esomeprazole magnesium water was added to a solution obtained by adding 665.6 g of D-mannitol to a fluidized bed granulator (manufactured by Paulec Co., Ltd .: MP-01 type) and mixing, and dissolving 52.0 g of hypromellose in 988.0 g of purified water. Fluidized bed granulation was performed by spraying and drying a liquid in which 178.4 g of the Japanese product was suspended. The granules thus obtained were dried and dry-pulverized with a granulator (Powrec: Comil). 18.0 g of low-substituted hydroxypropylcellulose and 6.0 g of magnesium stearate were added to 336.0 g of the sized product thus obtained, and mixed in a polyethylene bag. Subsequently, this mixture was tableted with a punching pressure of 700 kgf using a rotary tableting machine (manufactured by Kikusui Seisakusho: VELA type 5), and an uncoated tablet having a weight of 120.0 mg (round tablet, diameter 7.0 mm, thickness) 3.3 mm).

[Example 2]
Esomeprazole was added to a solution obtained by adding 665.6 g of D-mannitol to a fluidized bed granulator (manufactured by Paulec: MP-01 type) and mixing, and dissolving 52.0 g of hydroxypropylcellulose in 988.0 g of purified water. Fluidized bed granulation was performed by spraying and drying a liquid in which 178.4 g of magnesium hydrate was suspended. The granules thus obtained were dried and dry-pulverized with a granulator (Powrec: Comil). 18.0 g of low-substituted hydroxypropylcellulose and 6.0 g of magnesium stearate were added to 336.0 g of the sized product thus obtained, and mixed in a polyethylene bag. Subsequently, this mixture was tableted with a punching pressure of 700 kgf using a rotary tableting machine (manufactured by Kikusui Seisakusho: VELA type 5), and an uncoated tablet having a weight of 120.0 mg (round tablet, diameter 7.0 mm, thickness) 3.3 mm).

[Example 3]
Esomeprazole magnesium water was added to a solution obtained by adding 696.8 g of D-mannitol to a fluidized bed granulator (manufactured by Paulec Co., Ltd .: MP-01 type) and mixing, and dissolving 20.8 g of methylcellulose in 880.0 g of purified water. Fluidized bed granulation was performed by spraying and drying a liquid in which 178.4 g of the Japanese product was suspended. The granules thus obtained were dried and dry-pulverized with a granulator (Powrec: Comil). 18.0 g of low-substituted hydroxypropylcellulose and 6.0 g of magnesium stearate were added to 336.0 g of the sized product thus obtained, and mixed in a polyethylene bag. Subsequently, this mixture was tableted with a punching pressure of 700 kgf using a rotary tableting machine (manufactured by Kikusui Seisakusho: VELA type 5), and an uncoated tablet having a weight of 120.0 mg (round tablet, diameter 7.0 mm, thickness) 3.3 mm).

[Comparative Example 1]
Esomeprazole magnesium was added to a solution obtained by adding 665.6 g of D-mannitol to a fluidized bed granulator (manufactured by Paulec: MP-01 type) and mixing, and dissolving 52.0 g of polyvinyl alcohol in 988.0 g of purified water. Fluidized bed granulation was performed by spraying and drying a liquid in which 178.4 g of hydrate was suspended. The granules thus obtained were dried and dry-pulverized with a granulator (Powrec: Comil). 18.0 g of low-substituted hydroxypropylcellulose and 6.0 g of magnesium stearate were added to 336.0 g of the sized product thus obtained, and mixed in a polyethylene bag. Subsequently, this mixture was tableted with a punching pressure of 700 kgf using a rotary tableting machine (manufactured by Kikusui Seisakusho: VELA type 5), and an uncoated tablet having a weight of 120.0 mg (round tablet, diameter 7.0 mm, thickness) 3.3 mm).

[Comparative Example 2]
Esomeprazole magnesium water was added to a solution obtained by adding 665.6 g of D-mannitol to a fluidized bed granulator (manufactured by Paulec Co., Ltd .: MP-01 type) and mixing, and dissolving 52.0 g of povidone in 988.0 g of purified water. Fluidized bed granulation was performed by spraying and drying a liquid in which 178.4 g of the Japanese product was suspended. The granules thus obtained were dried and dry-pulverized with a granulator (Powrec: Comil). 18.0 g of low-substituted hydroxypropylcellulose and 6.0 g of magnesium stearate were added to 336.0 g of the sized product thus obtained, and mixed in a polyethylene bag. Subsequently, this mixture was tableted with a punching pressure of 700 kgf using a rotary tableting machine (manufactured by Kikusui Seisakusho: VELA type 5), and an uncoated tablet having a weight of 120.0 mg (round tablet, diameter 7.0 mm, thickness) 3.3 mm).

[Example 4]
The uncoated tablet obtained in Example 2 was put into a coating machine (manufactured by Paulek, Inc .: DRC-200 type). To this, 72.0 g of hypromellose and 8.0 g of talc were added in advance to 648.0 g of purified water. The dispersed liquid was sprayed, coated to a tablet weight of 126.0 mg, and dried to obtain coated tablets.

  The coated tablet was further mixed with 290.0 g of a 30% methacrylic acid copolymer LD suspension (solid content: 87.0 g), 35.0 g of talc, 10.0 g of triethyl citrate, and 8.0 g of titanium oxide, and 590. In addition to 0 g, spray uniformly dispersed liquid, coat until 1 tablet mass is 135.0 mg, and dry to form a two-layer coated tablet (circular 2-stage R tablet, diameter 7.3 mm, thickness 3.7 mm) Got.

[Example 5]
The uncoated tablet obtained in Example 2 was put into a coating machine (manufactured by Paulek, Inc .: DRC-200 type), and 72.0 g of methylcellulose and 8.0 g of talc were added in advance to 1060.0 g of purified water, and uniform. The dispersed liquid was sprayed, coated to a tablet weight of 126.0 mg, and dried to obtain coated tablets.

  The coated tablet was further mixed with 290.0 g of a 30% methacrylic acid copolymer LD suspension (solid content: 87.0 g), 35.0 g of talc, 10.0 g of triethyl citrate, and 8.0 g of titanium oxide, and 590. In addition to 0 g, spray uniformly dispersed liquid, coat until 1 tablet mass is 135.0 mg, and dry to form a two-layer coated tablet (circular 2-stage R tablet, diameter 7.3 mm, thickness 3.7 mm) Got.

[Comparative Example 3]
The uncoated tablet obtained in Example 2 was put into a coating machine (manufactured by Paulek: DRC-200 type), and 72.0 g of hydroxypropylcellulose and 8.0 g of talc were previously added to 648.0 g of purified water. The uniformly dispersed liquid was sprayed, coated to a tablet weight of 126.0 mg, and dried to obtain coated tablets.

  The coated tablet was further mixed with 290.0 g of a 30% methacrylic acid copolymer LD suspension (solid content: 87.0 g), 35.0 g of talc, 10.0 g of triethyl citrate, and 8.0 g of titanium oxide, and 590. In addition to 0 g, spray uniformly dispersed liquid, coat until 1 tablet mass is 135.0 mg, and dry to form a two-layer coated tablet (circular 2-stage R tablet, diameter 7.3 mm, thickness 3.7 mm) Got.

The composition of the uncoated tablets of Examples 1-2 and Comparative Examples 1-2 are shown below.

The composition of the uncoated tablet of Example 3 is shown below.

The composition of the film coating layer in the tablets of Examples 4 to 5 and Comparative Example 3 (the second decimal place is rounded off) is shown below.

<Stability test>
The stability of the active ingredient in the prepared preparation was evaluated. Each preparation was placed in an environment of 60 ° C. and 75% relative humidity for 7 days, and the amount (%) of the related substance of the active ingredient (esomeprazole magnesium hydrate) was evaluated.

  The amount of the related substance was measured by high performance liquid chromatography (quantitative method is area percentage method: by the ratio of the peak area of the related substance to the total peak area of esomeprazole and its related substances).

Changes in the amount of the active substance (esomeprazole magnesium hydrate) related substance (indicating the amount of decomposition of the active ingredient) in the preparations of Examples 1 to 3 and Comparative Examples 1 and 2 using different substances as binders Was as shown in the table below.

  It is understood that when alkyl cellulose or a derivative thereof is used as the binder, the stability of the active ingredient is improved as compared with the case where a different binder is used.

Furthermore, it is effective for the preparations of Examples 4 to 5 and Comparative Example 3 in which enteric coating was applied to the uncoated tablets of Example 2 using hydroxypropylcellulose as a binder, using different components as separation layers. The change in the amount of the related substance of the component (esomeprazole magnesium hydrate) was as shown in the following table.

  When the alkyl cellulose having an unsubstituted alkyl group or a derivative thereof is used as the separation layer, it is shown that the stability of the active ingredient is improved as compared with the case where the components of the other separation layer are used. In Example 2, hydroxypropylcellulose was used as the binder, but unexpectedly, when the same component hydroxypropylcellulose was used in the separation layer, good stability could not be realized. In Comparative Example 3, although the coating was applied, the stability of the active ingredient was lower than that of the uncoated tablet of Example 2, and the selection of the component of the separation layer between the coating layer and the uncoated tablet Is understood to be important.

[Example 6]
(A: Primary core particle / drug layer) Crystalline cellulose (Selfia (registered trademark) CP-203 / manufactured by Asahi Kasei Co., Ltd., particle size: 150 to 300 μm) is a spouted fluidized bed granulator (MP-01-SPC type / Paurec) The solution obtained by dispersing and suspending esomeprazole magnesium hydrate in a solution obtained by dissolving methylcellulose in purified water was sprayed and dried to obtain secondary core particles.
(B: Separation layer) The secondary core particles obtained above are put into a spouted fluidized bed granulator, and a solution obtained by dispersing and suspending talc in a solution obtained by dissolving hydroxypropylmethylcellulose in purified water is sprayed and dried. Then, tertiary core particles were obtained.
(C: Enteric layer) The tertiary core particles obtained above were put into a spouted fluidized bed granulator, and methacrylic acid copolymer LD was dissolved in purified water containing glyceryl monostearate, triethyl citrate and polysorbate 80. (Eudragit (registered trademark) L30D-55 / manufactured by Evonik Japan Co., Ltd.) was added and the mixture gently mixed and stirred was sprayed and dried to obtain coated granules.
In addition, said drug and each additive were used for said manufacture in the quantity which became prescription of the coating granule shown in following Table 6.

  From the results of this example, the active ingredient in the granule is also selected in the same manner as in the tablet example above, the selection of the binder in the granule, the use of the separation layer in the coating, and / or the material of the separation layer. It is understood that stabilization can be achieved by selection.

  The present invention can be used to provide a pharmaceutical preparation that contains an active ingredient stably.

(Note)
As mentioned above, although this invention has been illustrated using preferable embodiment of this invention, it is understood that the scope of this invention should be construed only by the claims. Patents, patent applications, and documents cited herein should be incorporated by reference in their entirety, as if the contents themselves were specifically described herein. Understood.

Claims (17)

A solid preparation comprising granules, wherein the granules are
Esomeprazole or a salt thereof, or a hydrate thereof,
A solid preparation comprising alkyl cellulose or a derivative thereof.   The solid preparation according to claim 1, wherein the alkyl cellulose or a derivative thereof is an alkyl cellulose, a hydroxyalkyl cellulose, a hydroxyalkylalkyl cellulose, or a carboxyalkyl cellulose ester.   The solid preparation according to claim 2, wherein the alkylcellulose or a derivative thereof is methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose or carboxymethylcellulose ester.   The solid preparation according to claim 3, wherein the alkylcellulose or a derivative thereof is methylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose.   The solid preparation according to any one of claims 1 to 4, further comprising a disintegrant outside the granules, wherein the disintegrant is sodium starch glycolate, low-substituted hydroxypropylcellulose, or crospovidone.   The solid preparation according to any one of claims 1 to 4, comprising the granules.   The solid preparation according to any one of claims 1 to 6, which is an uncoated tablet. Uncoated tablets or granules containing esomeprazole or a salt thereof, or a hydrate thereof;
An enteric coating layer,
A solid preparation comprising a separation layer containing an alkyl cellulose having an unsubstituted alkyl group or a derivative thereof between the uncoated tablet or the granule and the enteric coating layer.   The solid preparation according to claim 8, wherein the separation layer contains alkyl cellulose or hydroxyalkyl alkyl cellulose.   The solid preparation according to claim 9, wherein the separation layer contains methylcellulose or hydroxypropylmethylcellulose.   The solid preparation according to any one of claims 8 to 10, wherein the enteric coating layer comprises a methacrylic acid copolymer.   The solid preparation according to any one of claims 8 to 11, comprising the solid preparation according to claim 7 as the uncoated tablet.   The solid formulation of Claim 12 in which the said uncoated tablet contains the granule containing a hydroxypropyl cellulose.   The solid preparation according to any one of claims 8 to 11, comprising the solid preparation according to claim 6 as the granule.   The solid formulation of Claim 14 in which the said granule contains methylcellulose.   The solid preparation according to any one of claims 1 to 15, wherein the esomeprazole or a salt thereof or a hydrate thereof is esomeprazole magnesium hydrate.   The solid preparation according to any one of claims 1 to 16, for the treatment or prevention of gastrointestinal diseases.