JP2005132803A - Solid pharmaceutical preparation staying in stomach - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical preparation staying in the stomach by combining a drug with a swelling base material. <P>SOLUTION: This solid pharmaceutical preparation delays the passage of a preparation containing a scarcely water-soluble drug through the pylorus by swelling the pharmaceutical preparation in the stomach. The retention of the pharmaceutical preparation in the stomach improves the systemic absorption rate of the drug. The pharmaceutical preparation especially contains a layer containing the swelling base material and a layer containing the drug in separated state and, accordingly, it is independent of the interaction of the components. The pharmaceutical preparation is swollen, arbitrarily floated and keeps the sustained release function or causes a prolonged mean retention period by the adhesion to the gastric wall to improve the absorption of the drug. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a solid preparation characterized by gastric retention.

  Specifically, it contains a solid substance in the stomach characterized by swelling in the stomach, that is, a swelling base material, and optionally has a property of floating in the stomach or a property of sustained release or a property of adhering to the stomach wall. The present invention relates to a solid preparation characterized by gastric retention.

  More specifically, the present invention relates to a gastric swelling type preparation in which a layer containing a drug having a sustained release function and a layer containing a swelling base material have independent structures.

  The gastrointestinal absorption of drugs occurs mainly in the lower gastrointestinal tract. For example, in the case of a solid preparation, its disintegration rate is the rate-determining rate of drug absorption. Therefore, means for adjusting the absorption of a drug, for example, a method of maintaining the digestive tract absorption by adjusting the disintegration rate of the preparation by changing the hardness of the preparation in various ways, for example, in the sustained absorption preparation. In addition, a method of adjusting absorption by a method of adjusting the rate at which the drug is eluted from the preparation is also used.

  Recently, a gastroretentive formulation has been developed as a new drug delivery system and several proposals have been made.

  For example, the drug-containing preparation part is embedded in the swellable preparation part, and the whole is covered with a film, and the gastric floating drug sustained release solid preparation (see Patent Document 1) contains a uniformly dispersed water-soluble drug. A columnar preparation (see Patent Document 2) comprising an inner layer of a non-disintegrating biocompatible material and an outer layer of a biocompatible material capable of controlling the swelling of the inner layer that is impermeable to water including the periphery of the inner layer is known.

  Further, a gastric swelling preparation that absorbs gastric juice to expand its volume and delays passage through the gastric pylorus is also known (see Patent Document 3). The drug has a property that a large number of small pills (pills) are contained in the layer, and the entire drug is swollen when the pills swell. In such a case, in the case of a poorly water-soluble drug, the interaction between the drug and the swelling base material affects the degree of swelling, and it is difficult to maintain an effective blood concentration for a long time unless it is designed for sustained release. It is done.

  On the other hand, a two-layer preparation having a gastric retention function comprising a first layer mainly having a swelling function and a second layer mainly having a disintegrating function is also known (see Patent Document 4). It relates to sustained release, and is not a measure for poorly water-soluble drug, that is, absorption of the drug and improvement in blood concentration.

  Since a poorly water-soluble drug has a problem caused by mixing with a swelling base material, it has been very difficult to form a swelling drug. So far, there is no known preparation containing a poorly water-soluble drug and having a swelling function and a sustained release function.

JP-A-6-24959 JP-A-7-187994 US Pat. No. 4,434,153 International Publication No. 03/035029 Pamphlet

  An object of the present invention is to provide a gastric retentive solid agent capable of strictly controlling the release of a drug even in a poorly water-soluble drug.

  In view of the above problems, the present inventors have conducted intensive studies.As a result, in order to retain the drug in the stomach, the layer containing the drug and the substrate containing the swelling substrate are each made into independent layers. It was achieved to be a sustained-release preparation of a poorly water-soluble drug. It has been found that by allowing a drug-containing preparation to stay in the stomach for a long time, the drug can be absorbed for a long time in the upper digestive tract, and as a result, the drug can be efficiently absorbed.

The present invention
[1] A solid agent characterized by gastric retention, comprising a drug,
[2] The agent according to [1] above, which swells in the stomach,
[3] The agent according to item [2] above, further having a property of floating in the stomach or a property of sustained release, or a property of adhering to the stomach wall,
[4] The agent according to [2] above, comprising a swelling base material,
[5] The agent according to [4] above, wherein the swelling base material is one or more selected from xanthan gum, guar gum, hydroxypropylmethylcellulose, polyvinyl alcohol and gum arabic.
[6] The agent according to [4] above, further comprising one or more selected from a binder, a lubricant, a poorly water-soluble polymer, and a drug release controlling agent,
[7] The agent according to [4] above, comprising a layer containing a swelling substrate and a layer containing a drug,
[8] The agent according to [7] above, wherein the layer containing the swelling substrate and the layer containing the drug have a multilayer structure,
[9] The agent according to [8] above, comprising 2 to 5 layers,
[10] The agent according to [8], shown in FIG.
[11] The agent according to [8] above, comprising three layers,
[12] The agent according to [11] above, wherein the intermediate layer is a layer containing a drug,
[13] The binder is selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, carboxymethylcellulose, partially pregelatinized starch, pregelatinized starch, sodium alginate, pullulan, gum arabic powder, gelatin and dextrin The agent according to the above item [6], which is one or more types,
[14] The agent according to [6] above, wherein the lubricant is one or more selected from magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc and polyethylene glycol.
[15] One or more selected from water-soluble polymers selected from ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, acrylic acid copolymer, carboxymethyl ethyl cellulose, polyvinyl acetal diethylaminoacetate, shellac, waxes, talc and titanium oxide The agent according to [6] above, which is two or more types,
[16] The drug release controlling agent is hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, carboxymethylcellulose, partially pregelatinized starch, pregelatinized starch, sodium alginate, pullulan, gum arabic powder, gelatin, dextrin The agent according to the preceding item [6], which is one or more selected from xanthan gum, guar gum and polyethylene oxide,
[17] The agent according to [1] above, which is a tablet, capsule, pill, porous agent or nucleated agent,
[18] The agent according to [17], which is a nucleated agent and the inner layer is a layer containing a drug, as shown in FIG.
[19] The agent according to claim 1, wherein the average residence time of the drug is 1.2 to 5 times that of a normal preparation,
[20] The agent described in [1] above, wherein the gastric residence time is 3 to 24 hours,
[21] The agent according to [1] above, wherein the swelling ratio is 1.2 to 10 times,
[22] The agent according to [1] above, wherein the drug is a poorly water-soluble compound,
[23] The agent according to [22] above, wherein the poorly water-soluble compound is pranlukast hydrate.
[24] Consists of a layer containing one or more swelling bases selected from xanthan gum, guar gum, hydroxypropyl methylcellulose, polyethylene oxide, polyvinyl alcohol and gum arabic and a layer containing pranlukast hydrate The agent according to the preceding item [1],
[25] The agent according to [24] above, wherein the drug-containing layer has a sustained release function, and [26] selected from xanthan gum, guar gum, hydroxypropyl methylcellulose, polyethylene oxide, polyvinyl alcohol and gum arabic The agent according to [1] above, wherein one or two or more swelling base materials and pranlukast hydrate are uniformly mixed.

  In the present invention, the stomach-retaining solid agent represents a solid agent that stays in the stomach for a long time.

  In particular, it contains a swollen base material and optionally has (1) a property of floating in the stomach, (2) a property of slow release in the stomach, and / or (3) a property of adhering to the stomach wall. A solid agent that can stay for a long time.

  The property of swelling in the stomach means that the preparation increases its volume by absorbing gastric juice and the like. This makes it difficult for the formulation to pass through the pylorus.

  The property of floating in the stomach means that the preparation is suspended in the gastric juice by making the specific gravity lighter than the gastric juice.

  In order to float the preparation in the stomach, specifically, for example, it is preferable to mix a drug with a low specific gravity substance such as calcium silicate, light anhydrous silicic acid, and foamable cellulose.

  The property of sustained release in the stomach means that a drug is released over a long period of time in order to maintain the blood concentration of the active ingredient at an appropriate level.

  In order to obtain a sustained-release preparation, specifically, for example, it is preferable to mix a drug release controlling agent with a drug or coat the drug with a drug release controlling agent.

  The property of adhering to the stomach wall refers to physical adhesion to the stomach wall by increasing the adhesiveness of the preparation.

  In order to attach the preparation to the stomach wall, specifically, a highly sticky substance such as carboxyvinyl polymer, chitosan, chitin or the like is attached to the surface of the preparation containing the drug and further coated with a gastric soluble polymer. Are preferably used.

  The stomach swelling preparation will be described in detail below.

  In order to swell the preparation in the stomach, a drug release controlling agent is arbitrarily added to the layer containing the drug as appropriate, and the drug release rate is strictly controlled by combining with the layer containing the swelling substrate. it can.

  Moreover, the formulation which does not depend on those interaction can be provided by designing the layer containing a drug and the layer containing a swelling base material each independently.

  More specifically, the present invention relates to a multilayer type gastric swellable solid preparation comprising a combination of a layer containing a swelling substrate and a layer containing a drug.

  In the preparation of the present invention, any drug may be used, for example, pravastatin sodium, amlodipine besylate, famotidine, candesartan cilexetil, atorvastatin, losartan potassium, voglibose, simvastatin, levofloxacin, ofloxacin, tamsulosin, valsartan, Nifedipine, ticlovidin hydrochloride, cefcapene pivoxil hydrochloride, lansoprazole, edaravone, mecobalamin, benidipine hydrochloride, loxoprofen sodium, pranlukast hydrate, rebamipide, clarithromycin, terbinafine hydrochloride, teprenone, ethyl icosapentate, itraconazole, fluconazole, fluconazole Doxazosin acid, enalapril maleate, cefdinir, epalrestat, Ito Conazole, epinastine hydrochloride, diclofenac sodium, paroxetine hydrochloride hydrate, fexofenadine hydrochloride, acyclovir, cilostazol, donepezil hydrochloride, theophylline, limaprost, camostat mesylate, ornoprostil, ozagrel hydrochloride, JP-A 63-17985 Compounds described in JP-A-6-41175, compounds described in JP-A-1-156957, compounds described in JP-A-3-2617562, compounds described in JP-A-6-87811, JP-A-8 -109164, compound described in JP-A-7-316092, compound described in JP-A-2002-97158, compound described in JP-A-62-51672, JP-A-3-90027 Described compounds, JP-A-11- No. 9548, No. 9-278742, No. WO98 / 27053, No. 11-171866, No. 11-193268, No. 97 Compound described in No./47612, Compound described in WO99 / 19296, Compound described in WO98 / 24806, Compound described in WO00 / 03980, Compound described in JP02-138288, WO00 / 00470 Compounds described in the specification, compounds described in the specification of WO01 / 08674, compounds described in the specification of WO00 / 44726, compounds described in the specification of JP-A-07-215943, compounds described in the specification of WO02 / 14280, described in the specification of WO01 / 66520 Compound, WO01 / 40227 Compound described in WO02 / 74770, compound described in WO02 / 51820, compound described in WO02 / 72564, compound described in WO03 / 70707, compound described in WO02 / 53565 Etc.

  In particular, the drug used in the preparation of the present invention is preferably a poorly water-soluble drug, for example, pranlukast hydrate.

  The above drugs include both free forms and salts, and all pharmacologically acceptable ones. The pharmacologically acceptable salt is preferably non-toxic and water-soluble. Suitable salts include, for example, salts of alkali metals (potassium, sodium, lithium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts (tetramethylammonium salt, tetrabutylammonium salt, etc.), organic amines (Triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) methylamine, lysine, arginine, N-methyl-D-glucamine, etc.) salt, acid Adduct salts (inorganic acid salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.), organic acid salts (acetate, trifluoroacetate, lactate, tartaric acid) Salt, oxalate, fumarate, maleate, benzoate Citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate, etc.), etc.). The salt of the compound of the present invention includes a solvate or a solvate of an alkali (earth) metal salt, ammonium salt, organic amine salt or acid adduct salt of the compound of the present invention. The solvate is preferably non-toxic and water-soluble. Examples of suitable solvates include solvates such as water and alcohol solvents (ethanol and the like). The compound of the present invention is converted into a pharmacologically acceptable salt by a known method.

  The preparation in the present invention may contain an additive (formulation base material) in the layer containing the drug.

Additives are optionally included in the layer containing the drug and / or the layer containing the swelling substrate. The form of use of the additive is not particularly limited, but it is particularly preferable that the additive is contained in a layer containing a drug and / or a layer containing a swelling substrate, and particularly preferably contained in a layer containing a drug.
The additive may be any one that is generally used when producing a solid agent, for example, excipients, binders, lubricants, disintegrating agents, flavoring agents, flavoring agents, surfactants, One or two or more of the same or different types selected from a fragrance, a colorant, an antioxidant, a masking agent, an antistatic agent, a fluidizing agent, a wetting agent, and the like can be used as appropriate. Two or more additives for the same purpose can be used in combination. Moreover, the poorly water-soluble polymer used for coating | cover can also be used arbitrarily.

  Examples of the excipient include glucose, fructose, maltose, lactose, isomerized lactose, reduced lactose, sucrose, D-mannitol, erythritol, maltitol, xylitol, palatinose, trehalose, sorbitol, corn starch, potato starch, wheat starch , Rice starch, crystalline cellulose, talc, anhydrous silicic acid, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, and the like, and one or more of these may be appropriately blended and used. Lactose, D-mannitol, corn starch, crystalline cellulose, calcium silicate and anhydrous calcium phosphate are preferred. Particularly preferred are lactose, crystalline cellulose and calcium silicate.

  Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, carboxymethylcellulose, partially pregelatinized starch, pregelatinized starch, sodium alginate, pullulan, gum arabic powder, gelatin, dextrin and the like. These may be used alone or in combination of two or more. The binder is preferably hydroxypropylmethylcellulose or hydroxypropylcellulose. As the hydroxypropyl methylcellulose, those having a viscosity of 2.5 to 17.5 mm2 / s of Tc-5 series are preferable. For example, E (w) grade, R (w) grade, Mw grade, S grade, etc. of Tc-5 are available. Can be mentioned. Hydroxypropyl cellulose (HPC) includes those having a viscosity of 2.0 to 4000 cps, such as HPC-L (6 to 10 cps), HPC-M (150 to 400 cps), HPC-H (1000 to 4000 cps), and the like. It is done. Preferred are hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, partially pregelatinized starch and pregelatinized starch. Particularly preferred are hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and partially pregelatinized starch.

  Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol and the like, and one or more of these may be appropriately blended and used. Also good. Preferred are magnesium stearate, sucrose fatty acid ester, stearic acid, talc and polyethylene glycol. Particularly preferred are magnesium stearate, stearic acid and talc.

  Examples of the disintegrant include low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, hydroxypropyl starch, corn starch and the like, one or two of these. You may mix and use a seed | species suitably.

  Examples of the corrigent include sucrose, D-sorbitol, xylitol, citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, sodium saccharin, dipotassium glycyrrhizin, sodium glutamate, 5′-sodium inosinate, 5 '-Guanylic acid sodium etc. are mentioned, and these 1 type or 2 types or more may be blended suitably and used.

  Examples of the flavoring agent include trehalose, malic acid, maltose, potassium gluconate, anise essential oil, vanilla essential oil, cardamom essential oil and the like, and one or more of these may be used in combination as appropriate.

  Examples of the surfactant include polysorbate (polysorbate 80 and the like), polyoxyethylene / polyoxypropylene copolymer, sodium lauryl sulfate, and the like, and one or more of these may be appropriately blended and used.

  As a fragrance | flavor, lemon oil, orange oil, menthol, brackish oil etc. are mentioned, for example. Examples of the colorant include titanium oxide, food yellow No. 5, food blue No. 2, iron sesquioxide, yellow iron sesquioxide, and the like. Examples of the antioxidant include sodium ascorbate, L-cysteine, sodium sulfite, vitamin E, and the like, and one or more of these may be appropriately blended and used.

  Examples of the colorant include titanium oxide, food yellow No. 5, food blue No. 2, iron sesquioxide, yellow iron sesquioxide, and the like.

  Examples of the antioxidant include sodium ascorbate, L-cysteine, sodium sulfite, vitamin E and the like.

  Examples of the concealing agent include titanium oxide.

  Examples of the antistatic agent include talc, titanium oxide and the like, and one or two of these may be appropriately blended and used.

  Examples of the fluidizing agent include light anhydrous silicic acid, talc, hydrous silicon dioxide, and the like, and one or more of these may be appropriately blended and used.

  Examples of the wetting agent include polysorbate 80, sodium laurate sulfate, sucrose fatty acid ester, macrogol, hydroxypropyl cellulose (HPC), and the like, and one or more of these may be appropriately blended and used. .

  In the preparation of the present invention, in order to provide a sustained release function of the drug, the “layer containing the drug” and / or the “layer containing the swelling substrate” may be further combined with a drug release controlling agent. As the drug release controlling agent, for example, a poorly water-soluble polymer such as an insoluble polymer, an enteric polymer and / or a gastric polymer may be suitably used, and one or more of these may be appropriately blended and used. It may be coated with one or more layers, or may be mixed uniformly. Examples of poorly water-soluble polymers include hydroxypropyl methylcellulose, ethylcellulose (trade name Aquacoat; Asahi Kasei), hydroxymethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, polyethylene glycol, Tween 80, Plunonic F68, castor oil, cellulose acetate. Phthalate, hydroxypropylmethylcellulose acetate succinate, acrylic acid copolymer, carboxymethylethylcellulose, polyvinyl acetal diethylaminoacetate, shellac, waxes, povidone, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, carboxymethylcellulose, partially pregelatinized starch, pregelatinized starch, alginic acid Sodium, pullulan, arabian Powder, gelatin, dextrin, xanthan gum, guar gum, polyethylene oxide, methacrylic acid copolymer (trade name Eudragit L, LD, S), aminoalkyl methacrylate copolymer (E, RS), ethyl acrylate / methyl methacrylate copolymer dispersion (product) Name Eudragit NE30D).

  The drug release controlling agent may be used in any form, but a form that coats the layer containing the drug is particularly preferable.

  These coatings may contain commonly used additives, and examples of the additives include the binder.

  Examples of the swelling base material include xanthan gum, guar gum, polyethylene oxide, hydroxypropyl methylcellulose, polyvinyl alcohol, gum arabic, and the like, and one or more of these may be appropriately blended and used. Particularly preferred are xanthan gum, guar gum and hydroxypropyl methylcellulose.

  As a combination of swelling base materials, for example, the ratio of xanthan gum and guar gum is preferably 0.1 to 3.0, more preferably 0.2 to 2.0, and particularly preferably 0 to xanthan gum 1. .3 to 1.0.

  The ratio of xanthan gum and hydroxypropylmethylcellulose is preferably 0.3 to 3.0, and more preferably 0.4 to 2.0, and particularly preferably 0.5 to 1 with respect to xanthan gum 1. .5.

  The ratio of xanthan gum to guar gum and hydroxypropyl methylcellulose is such that guar gum is 0.1 to 3.0, more preferably 0.2 to 2.0, and particularly preferably 0.3 to 1 with respect to xanthan gum 1. 0.0 and hydroxylpropylmethylcellulose is 0.3 to 3.0, more preferably 0.4 to 2.0, and particularly preferably 0.5 to 1.5.

  The solid preparation of the present invention may be any of tablets, capsules, pills, and porous agents, but tablets and capsules are particularly preferable.

  In designing the solid agent of the present invention, a multilayer structure in which a layer containing a swelling base material and a layer containing a drug are alternately arranged in parallel, a layer containing a swelling base material with the drug containing layer as an inner core, and an outer layer Any of the nucleated agents as parts is preferred, but a multilayer structure is particularly preferred.

  The multilayer structure is preferably 2 to 5 layers, particularly 2 to 3 layers. In the case of a two-layer structure, it is preferable that one is a layer containing a drug and the other is a layer containing a swelling substrate (see FIG. 1). In the case of a three-layer structure, the intermediate layer is preferably a layer containing a drug, and both outer layers are preferably layers containing a swelling substrate (see FIG. 2).

  The multilayer nucleated structure is preferably 2 to 5 layers, particularly 2 to 3 layers. In particular, in a two-layer structure, it is preferable that a layer containing a drug is an inner core portion and a layer containing a swelling substrate is an outer layer portion (see FIG. 3). In the three-layer structure, it is preferable that the drug-containing layer is the core, the drug layer is coated with a poorly water-soluble polymer, and the periphery thereof is coated with a swelling substrate (see FIG. 4).

  1 to 4 schematically illustrate the preparation of the present invention, and the present invention is not necessarily limited to this form, and includes any form that achieves the object of the present invention. .

  The solid preparation of the present invention swells in the stomach, and the swelling degree is preferably about 1.2 times to about 10 times, more preferably about 1.5 times to about 5 times.

  The solid preparation of the present invention is characterized in that it stays in the stomach for a long time by swelling in the stomach. The "long time" that is the residence time in the stomach is preferably about 3 to about 24 hours, more preferably about 4 to about 16 hours, and even more preferably about 5 to about 12 hours.

  The solid preparation of the present invention can improve the bioavailability of a drug. The solid preparation of the present invention is preferably one that improves the bioavailability of the drug by about 1.2 to about 10 times compared to the non-swelling preparation. More preferably, it is about 1.5 times to about 5 times, and more preferably about 2 times to about 4 times.

  The solid agent of the present invention may contain a base material that imparts floatability. Examples of the base material that imparts floatability include calcium silicate, light anhydrous silicic acid, and foamable cellulose.

  The solid preparation of the preparation of the present invention includes, for example, a capsule containing granules. Capsules can be produced by a known method, for example, granules produced by a known method, and if necessary, additives may be hard capsules (for example, gelatin capsules, hydroxypropylmethylcellulose (HPMC) capsules, pullulan capsules, Polyvinyl alcohol (PVA) capsule etc.) can be filled by using a capsule filling machine.

  Further, the solid preparation of the present invention includes a tablet containing granules. Tablets can be produced by a known method, for example, by tableting granules and additives by wet granulation method, dry granule compression method or the like.

  The preparation of the present invention is characterized in that it swells in the stomach, and can optionally increase the gastric retention by having the property of being slowly released or floating in the stomach and / or the property of adhering to the stomach wall.

  When the layer containing the swelling substrate and the layer containing the drug are made independent, it can be formulated regardless of the interaction between the drug and the swelling substrate, and can be applied to a wide variety of drugs, such as poorly water-soluble drugs. Is possible.

  In addition, by incorporating a drug release control agent into the drug-containing layer, it is possible to release the drug strictly even with poorly water-soluble drugs. For the above reasons, the preparation of the present invention is an excellent preparation that can continuously absorb the drug in the body.

  This formulation controls the drug release and swelling independently, thereby extending the residence time in the stomach and maintaining the absorption in the upper gastrointestinal tract, thereby increasing the drug absorption rate and The blood concentration can be maintained at an appropriate level.

In the following, formulation examples and experimental examples are shown as examples, but these are for deepening the understanding of the present invention and do not limit the scope of the present invention.
Formulation Example 1 (Production of bilayer swellable tablet)
A slurry solution prepared by suspending pranlukast hydrate in water with hydroxypropylcellulose (surface modifier) grade SSL (HPC-SSL) and lactose (pranlukast hydrate 200.0 g, HPC-SSL20 .0 g, lactose 25.1 g, and purified water 455.2 g) were sprayed with a spray dryer (L-8 spray dryer: manufactured by Okawahara Kako) to obtain 190 g of pranlukast hydrate spray-dried product. Metrose 90SH-4000 (drug release control agent), lactose / Avicel PH101 (excipient), HPC-SSL (binder), and magnesium stearate (lubricant) are added and mixed to this. A tableting powder was obtained. Next, xanthan gum (swelling base material), Avicel PH101 and Metroz 90SH-30000F (swelling base material) were mixed to obtain a tableting powder of the swelling layer. After first filling the tablet of the elution layer into the mortar (Ф18 × 9mm) of a tableting machine (Okada Seiko, Tab-ALL), after temporary compression, and further filling the tablet of the swelling layer secondly, By carrying out the main compression at a pressure of 1000 kgf, a bilayer caplet tablet having the following formulation was obtained.
Drug-containing layer component Drug-containing spray-dried product ・ Pranlukast hydrate 75mg
・ Lactose 7.5mg
・ HPC-SSL 9.4mg
Adjunct ・ Metroze 90SH-4000 120mg
・ Lactose 49.8mg
・ HPC-SSL 8mg
・ Avicel PH101 122.8mg
・ Magnesium stearate 8mg
Swelling layer component xanthan gum 200mg
・ Avicel PH101 40mg
・ Metroze 90SH-30000F 160mg
Total 800.5mg
Comparative formulation example (Manufacture of tablets)
Slurry liquid prepared by suspending pranlukast hydrate in hydroxypropylcellulose grade SSL (HPC-SSL) and lactose in water (pranlukast hydrate 200.0 g, HPC-SSL 20.0 g, lactose 25.1 g , 455.2 g of purified water) was sprayed with a spray dryer (L-8 spray dryer: manufactured by Okawara Chemical Co., Ltd.) to obtain 190 g of pranlukast hydrate spray-dried product. To this, low substituted hydroxypropylcellulose (disintegrant) type 22 (L-HPC-22) and magnesium stearate (lubricant) were added and mixed to obtain a tableting powder. This tableting powder was tableted using a tableting machine (Tab-ALL, manufactured by Okada Seiko Co., Ltd.) under the conditions of a diameter of 8 mm and a tableting pressure of 700 kgf to obtain a round tablet having the following formulation.
・ Pranlukast hydrate 75.0mg
・ HPC-SSL 7.5mg
・ Lactose 9.4mg
・ L-HPC-22 3.9mg
・ Magnesium stearate 1.0mg
Total 96.8mg
Test Example 1 Absorbability Experiment In the absorption experiment, three beagle dogs weighing approximately 10 kg were used. As for the administration conditions, the preparation of the present invention prepared in Preparation Example 1 and the preparation prepared in Comparative Example 30 were each administered directly into the stomach 30 minutes after meal using a dog gastric sonde. Thereafter, 200 mL of water was injected into the stomach as before. As feeding conditions, 300g of food was given in the morning on the day before the experiment, and 50g of food was given 30 minutes before administration on the day of the experiment. After administration of the preparation, blood was collected over time, and after extraction, the plasma drug concentration was measured by LC / MS / MS. The results are shown in FIG.

  In Table 1, Cmax represents the maximum blood concentration, Tmax represents the maximum blood concentration arrival time, AUC represents the area under the blood concentration-time curve, and MRT represents the average residence time.

  As a result of the dog absorption experiment, when the preparation produced in the comparative preparation example and the present invention preparation produced in the preparation example 1 were compared at the same dose (75 mg / dog), the present preparation produced in the preparation example 1 Cmax (maximum blood concentration) is lower than other control tablets due to slow release of the drug, and it stays in the stomach due to swelling function, Tmax (maximum blood concentration arrival time), MRT (average residence time) ) And an increase in AUC (area under the blood concentration-time curve). As described above, by using the preparation of the present invention, for example, a drug having low absorbability in the lower gastrointestinal tract, such as pranlukast hydrate, can maintain the blood concentration.

  Average residence time is

(C: blood concentration, t: concentration observation time)
It is obtained more and becomes an indicator of the sustainability of the blood concentration, and the longer the average residence time, the higher the function as a sustained-release preparation.
Test Example 2 Evaluation of Drug Release A drug release test was conducted using the preparation of the present invention produced in Formulation Example 1. The test was carried out in accordance with the 14th revised Japanese Pharmacopoeia General Test Method 66 Dissolution Test Method / Second Method (200 rpm). As a test solution, a solution obtained by adding 0.1% polysorbate 80 to the first pharmacopoeia solution was used. The results are shown in FIG.

As a result of evaluating the drug release of the preparation of the present invention produced in Formulation Example 1, the drug release rate was about 80% in 18 hours.
Test Example 3 Evaluation of Swelling Rate of Swelling Layer Tableting the swelling layer component of the preparation of the present invention produced in Formulation Example 1 alone so that the tablet weight becomes 200 mg (Okada Seiko, manufactured by Tab-ALL, with a diameter of 8 mm, The tableting pressure was 1000 kgf), and these tablets were put into a 50 mL plastic container containing Japanese Pharmacopoeia First Solution (15 mL) and shaken at a speed of 180 strokes / minute for 3 hours. The tablets were then removed and the tablet weight and tablet diameter were measured. The swelling rate is the tablet weight after shaking for 3 hours / the tablet weight before starting the test × 100. The results are shown in FIG.

It can be seen from FIG. 7 that the preparation of the present invention produced in Preparation Example 1 has a sufficient swelling function as a swelling layer due to an increase in tablet diameter and swelling rate.
Formulation Example 2 Manufacture of two-layer swelling preparation A slurry liquid prepared by suspending pranlukast hydrate in water with hydroxypropylcellulose grade SSL (HPC-SSL) and lactose (pranlukast hydrate 200.0 g , HPC-SSL20.0g, lactose 25.1g, purified water 455.2g) was sprayed with a spray dryer (L-8 spray dryer: manufactured by Okawara Kako) to obtain 190 g of pranlukast hydrate spray-dried product It was. This spray-dried product, Metroze 90SH-100 (drug release control agent) and lactose / Eudragit L-100 55 (excipient) are put into GPCG-1 (Glatt), and HPC-SSL (bonded) is used in the top spray. Agent) solution was sprayed to obtain a fluidized bed granulated product. To this, magnesium stearate (lubricant) was added and mixed to obtain a tableting powder of the drug-containing layer. Next, xanthan gum, guar gum and Metrows 30000F (swelling base material), Avicel PH101 (excipient), samarium oxide (non-radioactive substance) and magnesium stearate were mixed to obtain a tableting powder of the swelling layer. The tableted powder of the elution layer is first filled into a mortar (Ф17.5 × 7.5mm) of a tableting machine (Okada Seiko, Tab-ALL), then temporarily compressed, and the tableted powder of the swelling layer is filled secondly. After that, it was subjected to main compression at a pressure of 1000 kgf to obtain a two-layer caplet tablet having the following formulation.
Composition drug-containing layer, pranlukast hydrate, dry spray 274.3mg
・ Metroze 90SH-100 112.5mg
・ Eudragit L-100 55 31.5mg
・ Lactose 6.7mg
・ HPC-SSL 16mg
・ Magnesium stearate 9mg
Swelling agent-containing layer xanthan gum 120mg
・ Metroze 30000F 105mg
・ Guar gum 50mg
・ Avicel PH101 23.5mg
・ Samarium oxide 10mg
・ Magnesium stearate 1.5mg
Total 750mg
Formulation Example 3 Manufacture of bilayer swelling formulation A slurry solution prepared by suspending pranlukast hydrate in water with hydroxypropylcellulose grade SSL (HPC-SSL) and lactose (pranlukast hydrate 200.0 g , HPC-SSL20.0g, lactose 25.1g, purified water 455.2g) were sprayed with a spray dryer (L-8 spray dryer: manufactured by Okawara Kako) to obtain 190 g of pranlukast hydrate spray-dried product . This spray-dried product, Metroze 90SH-4000 (drug release control agent), lactose and Eudragit L-100 55 (excipient) are put into GPCG-1 (Glatt), and HPC-SSL (bonded) is used in the top spray. Agent) solution was sprayed to obtain a fluidized bed granulated product. To this, magnesium stearate (lubricant) was added and mixed to obtain a tableting powder of the drug-containing layer. Next, xanthan gum, guar gum, Metrose 30000F (swelling base material), Avicel PH101 (excipient), samarium oxide (non-radioactive substance) and magnesium stearate were mixed to obtain a tableting powder of the swelling layer. The tableted powder of the elution layer is first filled into a mortar (Ф17.5 × 7.5mm) of a tableting machine (Okada Seiko, Tab-ALL), then temporarily compressed, and the tableted powder of the swelling layer is filled secondly. After that, it was subjected to main compression at a pressure of 1000 kgf to obtain a two-layer caplet tablet having the following formulation.
Composition drug-containing layer, pranlukast hydrate, dry spray 274.3mg
・ Metroze 90SH-4000 112.5mg
・ Eudragit L-100 55 31.5mg
・ Lactose 6.7mg
・ HPC-SSL 16mg
・ Magnesium stearate 9mg
Swelling agent-containing layer xanthan gum 120mg
・ Metroze 30000F 105mg
・ Guar gum 50mg
・ Avicel PH101 23.5mg
・ Samarium oxide 10mg
・ Magnesium stearate 1.5mg
Total 750mg
Test Example 5 Drug Release Test of Formulations Produced in Formulation Example 2 and Formulation Example 3 Using the formulations of the present invention produced in Formulation Example 2 and Formulation Example 3, a drug release test was conducted.

  The test was conducted according to the 14th revised Japanese Pharmacopoeia General Test Method 66 Dissolution Test Method / Second Method (200 rpm). As a test solution, a solution obtained by adding 0.1% polysorbate 80 to the first pharmacopoeia solution was used. The results are shown in FIG.

From FIG. 8, the formulation of the present invention prepared in Formulation Example 2 released almost the entire amount of drug in 10-12 hours, while the formulation of the present invention prepared in Formulation Example 3 released almost 90% of the drug after 24 hours. Therefore, it is clear that the preparation of the present invention can easily control the drug release time.
Test Example 6 Retention in the stomach (Gamma scintigraphy analysis)
A gastric retention test of the preparation of the present invention produced in Formulation Example 2 was conducted on 9 boys aged 23-43 years who exchanged clinical trial consent forms. For the gunmachigraphy analysis, the swellable solid preparation to which non-radioactive samarium oxide was added before the administration was subjected to neutron irradiation treatment, and the radioactivity of the whole preparation was adjusted to 0.8 to 1 MBq. After the administration, the gastrointestinal movement of the preparation was followed over time, and the retention of the swellable solid preparation in the stomach was evaluated. The swelling solid agent was administered 30 minutes after breakfast. The results are shown in Table 2.

From Table 2, it was found that the swellable solid agent administered remained in the stomach for an average of 8.53 to 10.12 hours.
Test Example 7 Blood profile in humans Human volunteers (9) using the preparations of the present invention (2 tablets containing 225 mg of pranlukast hydrate per tablet) produced in Formulation Examples 2 and 3 The blood concentration was measured. Two types of administration, morning and evening, were examined. The results are shown in FIGS. 9 and 10, and the parameter comparison is shown in Table 3.

  When the post-breakfast administration and post-dinner administration of the preparations of the present invention produced in Formulation Example 2 and Formulation Example 3 were compared, an increase in Cmax, an increase in Tmax, and an extension of MRT were confirmed in the post-dinner administration.

  The increase in Cmax and prolongation of Tmax and MRT in the post-dinner administration are thought to be due to prolonged gastrointestinal retention and drug release delay due to decreased gastrointestinal motility.

  When the post-breakfast administration and post-dinner administration of the preparations of the present invention produced in Formulation Example 2 and Formulation Example 3 were compared, Cmax was suppressed and Tmax and MRT were prolonged in Formulation Example 3, which releases the drug in 24 hours. It was.

The preparations of the present invention produced in Formulation Example 2 and Formulation Example 3 are found to be useful as a sustained-release preparation, as it is found that the MRT is extended by about 1.3 to 1.7 as compared with immediate-release capsules. It is done.
Test Example 8 Evaluation of Swellability of the Formulation of the Present Invention Produced in Formulation Example 2 The swelling property of the formulation of the present invention prepared in Formulation Example 2 was measured according to the following method. Swellability evaluation of the preparation of the present invention produced in Formulation Example 2 was tested by the 14th revised Japanese Pharmacopoeia General Test Method 66 Dissolution Test Method / Second Method (100 rpm). As the test solution, a solution obtained by adding 0.1% polysorbate 80 to the pharmacopoeia first solution was used. After the test was started, the tablets were taken out over time, and the swellability was evaluated by measuring the long and short diameters of the tablets. The results are shown in FIG.

  FIG. 11 clearly shows that the artificial gastric fluid swells rapidly both in the long diameter and the short diameter, so that a sufficient size is secured to stay in the stomach.

  When the tablet size in the major axis direction and the minor axis direction of the tablet diameter is calculated, it is 1.4 times larger than the first after 1 hour and 1.8 times larger than the first after 4 hours. It turns out that it is a formulation which has a function.

  The preparation of the present invention is an excellent gastric retentive preparation of a drug, and the release of the drug can be strictly controlled by combining with the sustained release of the drug.

It is sectional drawing in one aspect | mode of the 2 layer formulation of this invention. It is sectional drawing in one aspect | mode of the 3 layer formulation of this invention. It is sectional drawing in one aspect | mode of the nucleated bilayer formulation of this invention. It is sectional drawing in one aspect | mode of the nucleated 3 layer formulation of this invention. The blood concentration of pranlukast hydrate in the dog body in the preparation of the present invention prepared in Preparation Example 1 and the preparation prepared in Comparative Preparation Example is shown. The release property of pranlukast hydrate in the preparation of the present invention produced in Preparation Example 1 is shown. The comparison result of the swelling rate of the swelling layer with before the start of the test is shown. The result of the drug release test of the preparation of the present invention produced in Formulation Example 2 and Formulation Example 3 is shown. The comparison result of the blood profile in the human of the administration of this invention manufactured by the formulation example 2 after breakfast and after dinner is shown. The comparison result of the blood profile in the human of the administration of the present invention produced in Formulation Example 3 after breakfast and after dinner is shown. The swelling rate of the formulation of the present invention produced in Formulation Example 2 is shown.

Claims (26)

A solid preparation characterized by retention in the stomach, comprising a drug. The agent according to claim 1, which swells in the stomach. The agent according to claim 2, further having a property of floating in the stomach, a property of sustained release, or a property of adhering to the stomach wall. 3. The agent according to claim 2, comprising a swelling base material. The agent according to claim 4, wherein the swelling base material is one or more selected from xanthan gum, guar gum, hydroxypropyl methylcellulose, polyvinyl alcohol and gum arabic. 5. The agent according to claim 4, further comprising one or more selected from a binder, a lubricant, a poorly water-soluble polymer, and a drug release controlling agent. The agent according to claim 4, comprising a layer containing a swelling substrate and a layer containing a drug. The agent according to claim 7, wherein the layer containing the swelling substrate and the layer containing the drug have a multilayer structure. 9. The agent according to claim 8, comprising 2 to 5 layers. 9. The agent according to claim 8, which is shown in FIG. The agent according to claim 8, comprising three layers. The agent according to claim 11, wherein the intermediate layer is a layer containing a drug. 1 wherein the binder is selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, carboxymethylcellulose, partially pregelatinized starch, pregelatinized starch, sodium alginate, pullulan, gum arabic powder, gelatin and dextrin The agent of Claim 6 which is a seed | species or 2 or more types. The agent according to claim 6, wherein the lubricant is one or more selected from magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc and polyethylene glycol. 1 type or 2 or more types in which a slightly water-soluble polymer is selected from ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, acrylic acid copolymer, carboxymethylethyl cellulose, polyvinyl acetal diethylaminoacetate, shellac, waxes, talc and titanium oxide The agent according to claim 6. The drug release controlling agent is hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, carboxymethylcellulose, partially pregelatinized starch, pregelatinized starch, sodium alginate, pullulan, gum arabic powder, gelatin, dextrin, xanthan gum, The agent according to claim 6, which is one or more selected from guar gum and polyethylene oxide. The agent according to claim 1, which is a tablet, capsule, pill, porous agent or nucleated agent. 18. The agent according to claim 17, which is a nucleated agent and is shown in FIG. 3, wherein the inner layer is a layer containing a drug. The agent according to claim 1, wherein the average residence time of the drug is 1.2 to 5 times that of a normal preparation. The agent according to claim 1, wherein the gastric residence time is 3 to 24 hours. The agent according to claim 1, wherein the swelling ratio is 1.2 to 10 times. The agent according to claim 1, wherein the drug is a poorly water-soluble compound. The agent according to claim 22, wherein the poorly water-soluble compound is pranlukast hydrate. 2. A layer comprising one or more swelling substrates selected from xanthan gum, guar gum, hydroxypropyl methylcellulose, polyethylene oxide, polyvinyl alcohol and gum arabic, and a layer comprising pranlukast hydrate. The agent described. The agent according to claim 24, wherein the drug-containing layer has a sustained release function. The agent according to claim 1, wherein one or more swelling base materials selected from xanthan gum, guar gum, hydroxypropyl methylcellulose, polyethylene oxide, polyvinyl alcohol and gum arabic and pranlukast hydrate are uniformly mixed. .

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