TWI605837B - Pharmaceutical composition containing water-insoluble drug and pharmaceutical preparation - Google Patents

Description

Pharmaceutical composition and pharmaceutical preparation containing poorly water-soluble drugs

The present invention relates to a pharmaceutical composition containing a poorly water-soluble drug such as an ion exchange resin.

Previously, ion exchange resins have been used as prophylactic and therapeutic agents for various diseases. For example, a cation exchange resin (calcium polystyrene sulfonate, sodium polystyrene sulfonate, etc.) is used in hyperkalemia, and an anion exchange resin (cholestoleamine) is used in hypercholesterolemia or hyperphosphatemia. (cholestyramine), etc.).

However, since the ion exchange resin represented by calcium polystyrene sulfonate or sodium polystyrene sulfonate is generally insoluble in water, it has a unique mouthfeel (roughness).

On the other hand, as a pharmaceutical composition containing the above-mentioned calcium polystyrene sulfonate, a powdery preparation such as a powder or a dry syrup (Patent Document 1); and a dosage form of a gelling agent (Patent Document 2) are proposed. Further, as the above-mentioned powder and dry syrup, a separate package containing 5 g of calcium polystyrene sulfonate (for example, Kalimate (registered trademark) powder, Kalimate (registered trademark) dry syrup 92.59%) is commercially available as an internal dose. As the gelling agent, 25 g of a gelling agent (containing 5 g of calcium polystyrene sulfonate) (for example, Argamate (registered trademark) 20% gel 25 g) was commercially available.

Further, the above-mentioned powder is administered in an amount of 15 to 30 g (15 to 30 g in terms of calcium polystyrenesulfonate) in two to three times and suspended in 30 to 50 mL of water once a day, and orally administered. The dry syrup system is administered in an amount of 16.2 to 32.4 g (15 to 30 g in terms of calcium polystyrene sulfonate) for 2 to 3 times a day and suspended in 30 to 50 mL of water for oral administration. The gelling agent was administered orally in an amount of 75 to 150 g (15 to 30 g in terms of calcium polystyrenesulfonate) in two to three divided doses per day.

On the other hand, as for the pharmaceutical composition containing sodium polystyrene sulfonate, a dosage form of a powder or a dry syrup is known, and a commercially available powder containing 5 g of sodium polystyrene sulfonate is packaged individually or contains a dry syrup. A separate package of 3.27 g (for example, Kayexalate (registered trademark), Kayexalate (registered trademark) dry syrup 76%).

The above powder system is administered 30 g (30 g in terms of sodium polystyrene sulfonate) in 2 to 3 times a day and suspended in 50-150 mL of water for oral administration, and the dry syrup system is 1 day. 32.94 g (30 g in terms of sodium polystyrene sulfonate) was orally administered in an amount of 2 to 3 times and suspended in 50 to 150 mL of water for oral administration.

Further, a powder containing cholestyramine (for example, Questran (registered trademark) powder 44%) is commercially available. As a usual dose, the powder was taken 2 to 3 times a day, and 9 g (4 g of cholestyramine anhydrate) was suspended in about 100 mL of water once a day.

[Previous Technical Literature]

[Patent Literature]

[Patent Document 1] Japanese Patent Laid-Open Publication No. 2000-103739

[Patent Document 2] International Patent Publication No. WO99/020247

However, any of the above powders or dry syrups needs to be suspended in water at the time of taking it, so it is necessary to prepare water and a container, which is complicated.

On the other hand, since the gelling agent is placed in a plastic cup, it is necessary to use a spoon during the taking, and since the cup itself is bulky, it becomes heavier when carrying a plurality of pieces, which is very inconvenient. carry.

In the context of the above, in recent years, it has been desired to improve a new method of compliance with a pharmaceutical composition containing a poorly water-soluble drug, or to further improve the compliance of the drug.

That is, an object of the present invention is to provide a pharmaceutical composition containing a poorly water-soluble drug which improves compliance with medication.

As a result of intensive studies, the present inventors have found that by containing a cellulose derivative in a pharmaceutical composition containing a poorly water-soluble drug, not only the rough feeling caused by the poorly water-soluble drug is reduced, the taste is softened, and the suspension is also suspended. , dispersion stability is improved.

Accordingly, the present invention provides a pharmaceutical composition comprising a poorly water-soluble drug and a cellulose derivative.

The pharmaceutical composition of the present invention not only has less rough feeling due to poorly water-soluble drugs, but also has a soft mouthfeel and excellent suspension and dispersion stability.

The pharmaceutical composition of the present invention is characterized by containing a poorly water-soluble drug and a cellulose derivative. First, the poorly water-soluble drug used in the present invention will be described.

<Water poorly soluble drugs>

A poorly water-soluble drug is a drug that has a low solubility in water. Specifically, it refers to "almost insoluble" or "very insoluble" in the "solubility" specified in the general rules of the Japanese Pharmacopoeia of the fifteenth edition. drug. That is, the so-called poorly soluble drug used in the present invention means that when the drug is a solid, it is put into water after being formed into a powder, and is violently shaken and mixed for 30 seconds at 20±5° C. every 5 minutes. At the time of the clock, the amount of water required to dissolve 1 g of the drug within 30 minutes is 1000 mL or more.

Examples of the poorly water-soluble drug as described above include, in addition to the ion exchange resin, azithromycin hydrate, acetazolamide, acetaminophen, acesulfame, acemetacin, adipine, and ato Valstatin calcium hydrate, anastrozole, amiodarone hydrochloride, aminoprolone, amphotericin B, amoxapine, allylerythritol, alpha calcitonol, alprazolam, albendazole, Amiprofen, allopurinol, ampoxicam, amprenavir, lenazolone, ibudistat, imidaxin, indapamide, urapidil, exemestane, es Zozolam, etoposide, etretinate, etidazolam, enoxacin, ebastine, efavirenz, eplerenone, everolimus, effluentine hydrochloride, erlotidine hydrochloride Nie, Entacapone, Enprostin, Isoprostone, Anoprofen, Olanzapine, Ornoprost, Olmesartan, Ondansetron, Cabernet, Kabambipine, Malay Cappedipin, carvedilol, carbopol, carmofur, candesartan, quetiapine, clarithromycin, glibenclamide, griseofulvin, grebazole, glibenclamide nice Urea, chlorooxazolyl, ketoprofen, chlorthalidone, gemifloxacin, saquinavir, zafirlukast, sulfasalazine, cyclosporine, dipyridamole, josamycin, c Acid japonicin, cilnidipine, silodosin, simvastatin, sparfloxacin, spiperone, spironolactone, sultamicillin tosylate, succinimide, cephalosporin, cefprozil Peptide, ceftibuten, cefdinir; cefpodoxime, cefuroxime axetil, sertrastat, celecoxib, zalidine, sobutazoxan, zolmitriptan, tacrolimus hydration , Tamibarotene, tamoxifen citrate, dantrolene sodium hydrate, tenoxicam, temocapril hydrochloride, telithromycin, telmisartan, toloxacin mesylate , torasemide, triazolam, amphetamine, tripperamine, triflurane maleate , tromethamine, tolfenamic acid, vitamin A acid, tripiprine, toremifene citrate, nateglinide, nepiprdil, nabumetone, nelfinavir mesylate, Pentaerythritol nicotinate, niprolol, nimetrazepam, nilvadipine, nevirapine, nemiride, pentamidone acetate, valsartan, harazol, pioglitazone, bicalutamide, Vavastatin calcium, pimozide, pimobendan, pyrrolidine, piroxicam, pyrrolic acid, fluorogutriol, fentanyl, fenofibrate, felodipine, phenylalanine, cloth Long, bumetanide, Pronoto, praxipur, piperazine hydrochloride , Prussit hydrate, primidone, flurazepam, flazodazole, fluoxetine, flunitrazepam, fluphenazine citrate, prulifloxacin, proglumide, Malay Proglumin, scallions, diuretic sulfonamide, piperazine Bromozepam, isopropyl benzoate Isopropyl methylene salicylate Benidipine hydrochloride, pimoline, benzyl hydrochlorothiazide , fossavir calcium hydrate, bosentan hydrate, polypuri zinc, voriconazole, formoterol fumarate hydrate, horse scorpion, marlotidate, misoprostol, methazolam, Meixiongnuolong, methylprednisolone, methoxacillin, vitamin K2, mefenamic acid, meloxicam, mosapride citrate, fluconazole, lafutidine, rematriptan , raloxifene hydrochloride, lansoprazole, risperidone, ritonavir, riluzole, letrozole, rebamipide, ribipast, leflunomide, roxithromycin, ro Otamycin, lofeparin hydrochloride, loratadine, chloromethazine and the like. Further, these may be used alone or in combination of two or more.

Among the above water-insoluble drugs, an ion exchange resin is preferred. Examples of the ion exchange resin include an anion exchange resin and a cation exchange resin.

Examples of the anion exchange resin include colestilan, cholestyramine, and sevelamer hydrochloride.

Further, examples of the cation exchange resin include polystyrene sulfonate such as potassium polystyrene sulfonate or sodium polystyrene sulfonate; and polycarbophil calcium.

Among the ion exchange resins as described above, polystyrene sulfonate, cholestyramine, sevelamer hydrochloride, and particularly polystyrene sulfonate are preferred in terms of the amount of administration per one time. Acid salt.

Further, the particle size of the poorly water-soluble drug is not particularly limited, but by making the particle size small, the rough feeling caused by the poorly water-soluble drug can be further reduced. For example, in the case of using a polystyrene sulfonate, the particle size is preferably about 5 to 100 μm.

The content of the poorly water-soluble drug may be appropriately determined according to the amount per one day of administration or the content of the individual packaging (injection unit).

The amount of administration per one time is a free form of a poorly water-soluble drug, and the above content is, for example, about 0.05 to 50 g (preferably 0.1 to 30 g).

Specifically, when kornidine is used as the above-mentioned water-insoluble drug, the amount per dose is about 1.5 g of colestilide.

Further, in the case of using cholestyramine, the amount per dose is about 4 g of the cholesteneamine anhydrate.

Further, in the case of using sevelamer hydrochloride, the amount per administration is about 1 to 3 g of sevelamer hydrochloride.

Further, in the case of using a polystyrene sulfonate, the amount per one time is about 5 g of polystyrene sulfonate.

Further, in the case of using polycarbophil calcium, the amount per dose is about 0.5 to 1 g of polycarbophil calcium.

The content of the poorly water-soluble drug is preferably from 1 to 60% by mass, more preferably from 5 to 40% by mass, particularly preferably from 8 to 30% by mass, based on the total amount of the pharmaceutical composition.

<cellulose derivative>

Next, the cellulose derivative used in the present invention will be described. By containing the cellulose derivative, the texture is reduced, the texture is soft, and the suspension and dispersion stability are improved.

Examples of the cellulose derivative include sodium carboxymethylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose, methylcellulose, and croscarmellose. Sodium or the like may be used alone or in combination of two or more. Among them, hydroxypropylmethylcellulose, hydroxypropylcellulose, and methylcellulose are preferred in terms of lightening, softness, suspension, and dispersion stability in the oral cavity. Hydroxypropyl cellulose, methyl cellulose.

In addition, the content of the cellulose derivative may be appropriately determined depending on the content of the poorly water-soluble drug in the pharmaceutical composition, etc., in terms of reduction in roughness, soft feeling, suspension and dispersion stability, relative to the pharmaceutical composition. The whole is preferably from 0.005 to 15% by mass, more preferably from 0.01 to 5% by mass, even more preferably from 0.05 to 2% by mass.

The pharmaceutical composition of the present invention preferably contains a polysaccharide derived from natural or gelatin in addition to the above-mentioned poorly water-soluble drug and cellulose derivative.

<from natural polysaccharides>

The polysaccharide derived from nature is not particularly limited, and examples thereof include gum arabic, sodium alginate, gelatinized starch, cardramin, carrageenan (kappa-carrageenan, iota-carrageenan). , λ-carrageenan), agar, sanxian gum, guar gum, glucomannan, sram grass, gellan gum, tamarind gum, tara gum, starch, locust bean gum, fruit Glue, etc. Further, these may be used alone or in combination of two or more.

Among these, one or two or more selected from the group consisting of carrageenan, celery gum, locust bean gum, guar gum, and agar are preferred. In addition to carrageenan, the elasticity of the pharmaceutical composition can be improved by using locust bean gum, and the hardness of the pharmaceutical composition can be improved by using agar.

Among them, one or more selected from the group consisting of carrageenan, sanxian gum, and locust bean gum, and a combination of three scent gum and locust bean gum.

The content of the polysaccharide derived from the natural one may be appropriately determined according to the content of the poorly water-soluble drug in the pharmaceutical composition, and is preferably 0.01 in terms of reduction in roughness and softness of the pharmaceutical composition as a whole. It is about 15% by mass, more preferably 0.05 to 5% by mass, and particularly preferably 0.1 to 2% by mass.

The pharmaceutical composition of the present invention may contain a preparation such as a pH adjuster, a sweetener, a fragrance, or a preservative, in addition to the above-mentioned water-insoluble drug, a cellulose derivative, and a polysaccharide derived from nature. These may be used alone or in combination of two or more.

Examples of the pH adjuster include ascorbic acid, L-aspartic magnesium citrate, benzoic acid, sodium benzoate, sodium chloride, dilute hydrochloric acid, calcium citrate, citric acid hydrate, and sodium citrate hydrate. , sodium dihydrogen citrate, disodium citrate, calcium gluconate hydrate, tartaric acid, sodium tartrate, sorbic acid, sodium hydrogencarbonate, lactic acid, calcium lactate hydrate, anhydrous citric acid, anhydrous sodium citrate, anhydrous monohydrogen phosphate Sodium, malic acid, calcium hydrogen phosphate hydrate, sodium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, sodium dihydrogen phosphate, and the like.

Examples of the sweetener include aspartame, liquid sugar, fructose, fructose glucose liquid sugar, reduced maltose water mash, high glucose leeches, saccharin, saccharin sodium hydrate, sucralose, refined white sugar, refined honey, Sorbitol, sorbitol liquid, monosaccharide syrup, white sugar, honey, glucose fructose liquid sugar, powder reduced maltose leeches, maltitol, maltitol liquid, leeches, and the like. Among them, preferred are saccharin, saccharin sodium hydrate, sucralose, maltitol, maltitol liquid, reduced maltose mash, powder-reduced maltose mash, and the like.

Examples of the above-mentioned flavor include orange flavor, kiwi flavor, grapefruit flavor, strawberry flavor, cherry flavor, fruit flavor, Muscat flavor, raspberry flavor, apple flavor, lemon flavor, caramel flavor, Green tea flavors, cocoa flavors, coffee flavors, sugar flavors, honey flavors, vanilla flavors, peppermint flavors, vermut flavors, mint flavors, maple flavors, yogurt flavors, and the like. In the case of administering the pharmaceutical composition of the present invention, it is preferred to convert the reduced rough feeling into a seed of fruit, preferably a kiwi flavor, a strawberry flavor or a raspberry flavor.

Furthermore, the above-mentioned perfume can also be separately filled in the package with the fragrance and the pharmaceutical composition. In this case, a kit in which the pharmaceutical composition of the present invention is placed in a bar-shaped package or the like and a fragrance can be prepared.

Examples of the preservative include benzoic acid, sodium benzoate, polybutylparaben, and propyl p-hydroxybenzoate.

Next, the dosage form of the pharmaceutical composition of the present invention and the like will be described in detail.

As the above dosage form, a suspending agent is preferred. Therefore, even when the amount of the water-insoluble drug (polystyrene sulfonate, cholestylamine, etc.) is contained in a large amount per dose, it can be easily taken.

As the suspending agent as described above, those which are required to be suspended at the time of administration and those which do not need to be suspended when taken are mentioned, and in terms of medication compliance, it is preferred that no suspension is required when administered. The appearance of the suspending agent which does not require suspension at the time of administration may be, for example, a soft candy, a creamy form, a gel form, a milky form, a pudding form, or a paste form. These appearances can be roughly distinguished by their viscosity, viscoelasticity or gel strength.

Among the suspending agents described above, those which are gelatinous are preferred. By preparing the above-mentioned preparation, it can be taken at the time of preparation or resuspension at the time of administration, or even if the sputum is not used at the time of administration, and therefore, when the usual one-time administration is individually packaged (individual packaging) The complexity is reduced. Moreover, since it is suitable for the package of the following tubular or rod shape, it is excellent in portability, and the compliance of the drug is improved.

The pharmaceutical composition of the present invention can be produced and formulated according to a known method described in the general version of the Japanese Pharmacopoeia of the fifteenth edition, or the like.

Next, the packaging form when the pharmaceutical composition of the present invention is packaged and prepared into a pharmaceutical preparation will be described.

When the pharmaceutical composition of the present invention is packaged, it is preferably a package which can prevent liquid or solid impurities from penetrating in a state of usual handling or storage, and more preferably a package which can be hermetically stored. The package may use either a fixed shape or an amorphous shape. The above package is not particularly limited, and is preferably a tubular, SP package (Strip Package) or a stick package. By using these packaging forms to form a pharmaceutical preparation, it can be taken immediately after opening without using a spoon, etc., so that the compliance of the medicine is improved, and it is particularly excellent compared with a package in which the volume of the plastic cup is easy to increase. Portability.

Further, it is preferred that the pharmaceutical composition containing the amount of the poorly water-soluble drug is contained in the packaging unit.

When the pharmaceutical composition of the present invention is used as a pharmaceutical preparation for packaging in a tubular shape, an SP package, a bar package, or the like, one or two or more kinds of known packaging materials such as a metal foil such as aluminum foil or polyethylene may be used. The sheet may be produced by a known method, and the packaging material may be a multi-layered structure which is suitably combined.

As a method of forming a sheet into a multilayer structure using the above two or more kinds of packaging materials, a method of laminating the packaging material to produce a laminated sheet can be mentioned. The laminated sheet can be formed by extrusion lamination, dry lamination, coextrusion lamination, thermal laminate, wet lamination, solventless lamination, heat laminate, and the like. Manufacturing. Further, commercially available products can also be used for sheets for tubular, SP packaging or bar packaging.

The pharmaceutical preparation obtained by packaging the pharmaceutical composition of the present invention in a tubular, SP-pack or rod-shaped package or the like is made into a small number of small packaging units, which can be carried out in a pillow-shaped package or a can, a bottle, a bag, or the like. Secondary packaging, etc.

[Examples]

Hereinafter, the present invention will be specifically described by way of Examples, but the present invention is not limited thereto.

Test Example 1. Preparation of gelled pharmaceutical composition (intracorporeal liquid) ‧ Evaluation (1)

Each component described in Table 1 was mixed, and the mixture was superheated and cooled to prepare a gel-like pharmaceutical composition. Further, the gel-like pharmaceutical compositions of Examples 1 to 4 and Comparative Example 1 were adjusted to have a pH of about 5 by using sorbic acid and sodium citrate hydrate.

Then, with respect to the gel-like pharmaceutical compositions of Examples 1 to 4 and Comparative Examples 1 to 6, 5 g were taken from 3 to 20 adults, respectively, and the rough feeling derived from calcium polystyrene sulfonate in the oral cavity was evaluated. And the hardness of the pharmaceutical composition contained in the mouth.

In addition, 25 g of the above-mentioned pharmaceutical composition was packaged in a bar shape using a laminate film of aluminum-polyethylene, and stored at 40 ° C for 2 months, and the composition in 1 month and 2 months after storage was visually evaluated. Suspension, dispersion stability (suspension and dispersion state of calcium polystyrene sulfonate in the composition). The results are shown in Table 1.

The pharmaceutical compositions of Comparative Examples 1 to 6 were evaluated as follows: Although the degree of chewing was not required to be soft and the feeling of roughness was small, it was not sufficient in terms of suspension and dispersion stability.

On the other hand, the pharmaceutical compositions of Examples 1 to 4 not only do not require a softer degree of chewing, have less roughness, and have excellent suspension and dispersion stability.

From this result, it was confirmed that by blending the cellulose derivative, the rough feeling is small, the soft texture is maintained, and the suspension and dispersion stability can be improved.

Example 5 Gel-like pharmaceutical composition (intracorporeal liquid)

8 g of phenyl phenylamine anhydrate, 0.24 g of Sanxian gum, 0.44 g of locust bean gum, 0.6 g of methylcellulose, 12 g of powder-reduced maltose mash, slightly dissolved in sucralose, dispersed in water, followed by superheating and cooling A total amount of 100 g of a gel-like pharmaceutical composition was prepared. Then, the obtained gel-like pharmaceutical composition was packaged in a rod shape using an aluminum-polyethylene laminate film every 50 g.

Example 6 Gel-like pharmaceutical composition (intracorporeal liquid)

Sevelamer hydrochloride 9 g, Sanxian gum 0.24 g, locust bean gum 0.44 g, methyl cellulose 0.2 g, powder reduced maltose water 饴 7.2 g, sorbic acid 0.45 g, sodium citrate hydrate 0.54 g, sucralose The mixture was dissolved in a small amount, dispersed in water, and then subjected to superheating and cooling to prepare a gel-like pharmaceutical composition having a total amount of 90 g. Then, the gel-like pharmaceutical composition obtained was packed in a rod shape using an aluminum-polyethylene laminate film every 10 g.

(industrial availability)

Even if the pharmaceutical composition of the present invention is stored for a long period of time, the poorly water-soluble drug such as the ion exchange resin in the preparation can be stably maintained in a suspended state and dispersed state. Further, in the case of packaging (subcontracting) in a normal one-time dosage, it is not necessary to adopt a bulky packaging form, and the portability is excellent.

Therefore, when the pharmaceutical composition of the present invention is used for the preparation of a poorly water-soluble drug, it is not necessary to prepare or use a tool such as a spoon, and it is not complicated when taking a packet obtained by subcontracting a usual dose (individual packaging). With the subcontracting, the independence of the individual packaging is also excellent, and it is useful to meet the compliance of medication.

Claims (3)

A pharmaceutical composition comprising a poorly water-soluble drug, a cellulose derivative, and a polysaccharide derived from nature, wherein the poorly water-soluble drug is polystyrene sulfonate, and the cellulose derivative is methyl cellulose. The natural polysaccharides are Sanxian gum and locust bean gum; the dosage form is a suspending agent; the content of the poorly water-soluble drug is 1 to 60% by mass, and the content of the cellulose derivative is 0.005 to 15 with respect to the whole pharmaceutical composition. The mass% is from 0.01 to 15% by mass based on the content of the natural polysaccharide. The pharmaceutical composition of claim 1, wherein the polystyrene sulfonate of the poorly water-soluble drug is calcium polystyrene sulfonate. A pharmaceutical preparation which is obtained by sticking a pharmaceutical composition of the first or second patent application scope.