KR20140005930A - Pharmaceutical composition containing drug having poor water solubility - Google Patents

Abstract

Pharmaceutical compositions containing poorly water-soluble drugs and cellulose derivatives with improved drug compliance, in particular, ion-exchange resins in which the poorly water-soluble drugs are polystyrenesulfonates, and the cellulose derivatives selected from hydroxypropylmethylcellulose, hydroxypropylcellulose and methylcellulose It provides the pharmaceutical composition which is 1 type (s) or 2 or more types, which is a jelly type suspension.

Description

Pharmaceutical composition containing poorly water-soluble drug {PHARMACEUTICAL COMPOSITION CONTAINING DRUG HAVING POOR WATER SOLUBILITY}

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

Background Art Conventionally, ion exchange resins have been used as drugs for the prevention and treatment of various diseases. For example, cation exchange resins (calcium polystyrene sulfonate, sodium polystyrene sulfonate, etc.) are used for hyperkalemia, and anion exchange resins (such as cholestyramine) are used for hypercholesterolemia and hyperphosphatemia, respectively.

However, ion exchange resins typified by calcium polystyrene sulfonate or sodium polystyrene sulfonate are generally insoluble in water, and thus have a distinctive taste.

On the other hand, as a pharmaceutical composition containing the said polystyrene sulfonate, powdery formulations, such as a powder and a dry syrup (patent document 1); The thing of the dosage form of the internal use jelly agent (patent document 2) is proposed. Moreover, as said powder and dry syrup, the distribution product containing 5 g as calcium polystyrene sulfonate is marketed (for example, a carmate acid (acid) and a carmate (dry material) 92.59%), and internal use It is commercially available that 25 g (containing 5 g of calcium polystyrene sulfonate) is contained in one potion cup per jelly cup (for example, 25 g of agamate (registered trademark) 20% jelly).

The powder is divided into 15 to 30 g (calcium polystyrene sulfonate 15 to 30 g) twice a day, and suspended once in 30 to 50 ml of water, and the dry syrup is 16.2 per day. -32.4 g (15-30 g as calcium polystyrene sulfonate) are divided into 2 to 3 times, and it is suspended orally and administered once in 30-50 ml of water, and the internal use jelly agent is 75-150 g (polystyrene sulfonic acid per day) 15-30 g) is divided into 2 or 3 times as calcium, and it is orally administered.

On the other hand, about the pharmaceutical composition containing sodium polystyrene sulfonate, the thing of the form of a powder and a dry syrup is known, The distribution product of the powder containing 5 g as sodium polystyrene sulfonate, and the distribution product containing 3.27 g dry syrup are commercially available. (E.g., Kay Exalate® Acid, Kay Exalate® Dry Syrup 76%).

The powder is divided into 30 to 30 g (30 g as sodium polystyrene sulfonate) per day, and is administered orally by suspending one dose in 50 to 150 ml of water, and the dry syrup is 32.94 g (sodium polystyrene sulfonate per day). 30 g) is divided into 2 to 3 times, and an amount is suspended in 50 to 150 ml of water and administered orally.

In addition, cholestyramine-containing powders are commercially available (for example, 44% of Questran® powder). This powder is usually taken as a dosage of 9 g (4 g as cholestyramine anhydride) in about 100 ml of water and taken 2 to 3 times a day.

Japanese Unexamined Patent Publication No. 2000-103739 International publication WO99 / 020247

However, since the powder and dry syrup mentioned above need to be suspended in water at the time of taking all, the water and a container need to prepare water and a container, and there is a complicated point.

On the other hand, since the oral jelly is stored in a potion cup, it is necessary to use a spoon or the like to take it, and since the potion cup itself becomes bulky and heavy when carrying a plurality of pieces, it is quite difficult to carry. have.

Under such a background, recently, a new means for improving the drug compliance of a pharmaceutical composition containing a poorly water-soluble drug, and further improvement in drug compliance is desired.

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

MEANS TO SOLVE THE PROBLEM As a result of earnestly examining, when a cellulose derivative is included in the pharmaceutical composition containing a poorly water-soluble drug, the present invention not only reduces the feeling of dullness resulting from a poorly water-soluble drug, but also feels soft to the mouth, and the suspension and dispersion stability are improved. I found an improvement.

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

The pharmaceutical composition of the present invention has little dullness resulting from poorly water-soluble drugs, has a soft touch to the mouth, and has 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 by this invention is demonstrated.

<Water poorly soluble drug>

A poorly water-soluble drug refers to a drug having low solubility in water, and specifically, a drug which is considered to be "not nearly dissolved" or "very difficult to dissolve" in "solubility" as defined in the general rules of the 15th revised Japanese pharmacy room. Say That is, the poorly soluble drug used in the present invention, when the drug is solid, powdered, and then dissolved in 1 g of the drug within 30 minutes when it is put into water and shaken vigorously for 30 seconds every 5 minutes at 20 ± 5 ℃ It means that the amount of water required to carry out is 1000 ml or more.

Examples of the poorly water-soluble drug include, in addition to the ion exchange resin, azithromycin hydrate, asazolamide, acetylspiramycin, acetohexamide, acemethacin, azelnidipine, atorvastatin calcium hydrate, anastrozole, amiodarone hydrochloride, Amilinone, amphotericin B, amoxapine, allylestrenol, alpha calcidol, alprazolam, albendazole, alfinopropene, allofurinol, ampyroxoxycam, amprenavir, amlexanox, Ibudilast, imidafenacin, indafamid, urapidil, exemstan, estazolam, etoposide, ethretinate, etizolam, enoxacin, ebastin, efavirenz, eplerenone, everoli Mousse, eponidipine hydrochloride, erlotinib hydrochloride, entacapone, enprosteel, oxendolone, oranopine, olanzapine, ornoprosteel, olmesartanmedoxomil, ondansetron, cabergoline, carbamazepine, carr Peep Minmaleates, carvedilols, carbocuone, carmopur, candesartan cilexetil, quazpam, clarithromycin, glyclopyramid, griseofulvin, glybuzol, glymepiride, xaxazolam, clovazam, chlorthaly Money, gefitinib, saquinavir, zafirlucaste, salazulfapyridine, cyclosporin, dipyridamole, probemycin, probemycin propionate, dilnidipine, silodosin, simvastatin, sparfloxacin, spiferon , Spironolactone, sulfamicillin tosylate, sultiam, separanthin, ceftitorenfixil, ceftidibutene, cephnidir,

Cefpodoximeproxetyl, cefuroximexetyl, ceratodast, celecoxib, jotepin, oxalic acid, zolmitriptan, tacrolimus hydrate, tamivarotene, tamoxifencitrate, dantrolene sodium hydrate, tenoxy Kam, Temocapryl Hydrochloride, Telitthromycin, Telmisartan, Tosufloxacin Mesylate, Torracemide, Triazolam, Triamterene, Tripamide, Trifluoroperazine Maleate, Trilostane, Tolfenacic Acid, Tretinoin , Trepibutone, toremifene citrate, nateglinide, naphthopidyl, nabumethone, nalpinavir mesylate, niceritrol, nipradinol, nimetasepam, nilvadipine, nevirapine, nemonaprid, parametha Hand acetate, valsartan, haloxazolam, pioglitazone hydrochloride, bicaltamide, pitavastatin calcium, pimozide, pimobendane, pyretanide, pyroxhamm, pyromide acid, palecalcitriol, finasteride, phenopy Latex, felodipine, phenprobamate, bucolom, bumetanide, flaunotol, prazepam, prazosin hydrochloride, franlukast hydrate, primidone, fludiazepam, flutazolam, flutoprazepam, flunitrazepam , Flufenazine decanoate, prurifloxacin, proglumide, proglumetacin maleate, prosilaridine, furosemide, properiazin, bromazepam, promethazine hibenzate, promethazinemethylene Disalicylate,

Benidipine hydrochloride, femoline, benzylhydrochlorothiazide, phosphamprenavircalcium hydrate, bosentan hydrate, polarpresink, boriconazole, formoterolfumarate hydrate, marginol, malolate, misoprostol, Mexazolam, mestanolone, methylprednisolone, methoxalene, menaterenone, mephenamic acid, meloxycamp, mosapriditrate, mofezolac, laputidine, ramatrobane, raloxifene hydrochloride, lansoprazole, risperidone, ritonavir Le, leulusol, letrozole, rebamipide, repyrilast, reflunoamide, roxythromycin, locitamycin, lofepramine hydrochloride, loratadine, lorametazepam and the like. In addition, these can be used individually or in combination of 2 or more types.

Among the poorly water-soluble drugs, ion exchange resins are preferable. Examples of the ion exchange resins include anion exchange resins and cation exchange resins.

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

Moreover, as cation exchange resin, For example, Polystyrene sulfonate, such as potassium polystyrene sulfonate and sodium polystyrene sulfonate; Polycarbophyll calcium, etc. are mentioned.

Among the ion exchange resins described above, polystyrene sulfonate, cholestyramine, sevelamer hydrochloride are preferable, and polystyrene sulfonate is particularly preferable in terms of dosage per dose.

In addition, the particle size of the poorly water-soluble drug is not particularly limited, and by reducing the particle size, it is possible to further reduce the dark feeling caused by the poorly water-soluble drug. For example, when using polystyrene sulfonate, about 5-100 micrometers of particle sizes are preferable.

What is necessary is just to examine and determine content of a poorly water-soluble drug suitably according to content per dose or distribution product (dosage unit) per day.

Such content is the quantity which a dose per dose is a free body of a poorly water-soluble drug, for example, about 0.05-50 g (preferably 0.1-30 g).

Specifically, when cholestimide is used as the poorly water-soluble drug, the dose per dose is about 1.5 g as cholestimide.

In addition, when cholestyramine is used, the dose per dose is about 4 g as cholestyramine anhydride.

Moreover, when using Sevelamer hydrochloride, the dose per dose is an amount which will be about 1-3 g as Sevelamer hydrochloride.

In addition, when using polystyrene sulfonate, the dose per dose is about 5 g as polystyrene sulfonate.

Moreover, when using polycarbophyl calcium, the dose per dose is an amount which becomes about 0.5-1 g as polycarbo film calcium.

Preferable content of a poorly water-soluble drug is 1-60 mass% with respect to the whole pharmaceutical composition, 5-40 mass% is more preferable, 8-30 mass% is especially preferable.

<Cellulose derivatives>

Next, the cellulose derivative used by this invention is demonstrated. By incorporating such a cellulose derivative, a light feeling is reduced, the touch which touches a mouth is soft, and suspension and dispersion stability improve.

Examples of the cellulose derivatives include sodium carmellose, hydroxypropyl methyl cellulose (hypromellose), hydroxypropyl cellulose, methyl cellulose, croscarmellose sodium, and the like. 2 or more types can be used. Among these, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, and methyl cellulose are preferable, and hydroxypropyl cellulose and methyl cellulose are particularly preferable in terms of softness, softness, suspension, and dispersion stability in the oral cavity. .

The content of the cellulose derivative may be appropriately examined and determined according to the content of poorly water-soluble drug in the pharmaceutical composition, but the content of the cellulose derivative is about 0.005 to 15% by mass relative to the entire pharmaceutical composition in terms of reducing the softness, softness, and suspension / dispersion stability. It is preferable, 0.01-5 mass% is more preferable, 0.05-2 mass% is especially preferable.

As the pharmaceutical composition of the present invention, in addition to the poorly water-soluble drug and the cellulose derivative, it is preferable to contain a naturally occurring polysaccharide or gelatin.

<Naturally derived polysaccharides>

Naturally derived polysaccharides are not particularly limited, for example, gum arabic, sodium alginate, alpha starch, curdlan, carrageenan (κ-carrageenan, ι-carrageenan, λ-carrageenan), agar, xanthan gum, guar gum, glucomannan , Silium seed gum, gellan gum, tamarind seed gum, tara gum, starch, locust bean gum, pectin and the like. In addition, these can be used individually or in combination of 2 or more types.

Among these, 1 type, or 2 or more types chosen from carrageenan, xanthan gum, locust bean gum, guar gum, and agar are preferable. In addition to carrageenan, the elasticity of a pharmaceutical composition can be improved by using locust bean gum, and the hardness of a pharmaceutical composition can be raised by using agar.

Among these, 1 type (s) or 2 or more types chosen from carrageenan, xanthan gum, and locust bean gum are more preferable, and the combination of a xanthan gum and a locust bean gum is especially preferable.

What is necessary is just to examine and determine content of a naturally-derived polysaccharide suitably according to content of the poorly water-soluble drug in a pharmaceutical composition, but about 0.01-15 mass% is preferable with respect to the whole pharmaceutical composition from the point of reducing the softness and softness, and 0.05-5 mass % Is more preferable, and 0.1-2 mass% is especially preferable.

The pharmaceutical composition of this invention may contain formulation additives, such as a pH adjuster, a sweetener, a flavor, and a preservative, in addition to the above-mentioned poorly water-soluble drug, a cellulose derivative, and a naturally derived polysaccharide. These may be used individually or in combination of two or more.

As said pH adjuster, for example, ascorbic acid, L-aspartic acid magnesium, benzoic acid, sodium benzoate, sodium chloride, dilute hydrochloric acid, calcium citrate, citric acid hydrate, sodium citrate hydrate, sodium dihydrogen citrate, sodium citrate, gluconic acid Calcium hydrate, tartaric acid, sodium tartarate, sorbic acid, sodium hydrogencarbonate, lactic acid, calcium lactate hydrate, citric anhydride, sodium citrate anhydrous, monohydrogen phosphate monohydrate, malic acid, calcium hydrogen phosphate hydrate, sodium hydrogen phosphate hydrate, dihydrogen phosphate Calcium hydrate, sodium dihydrogen phosphate, and the like.

As the sweetener, for example, aspartame, liquid sugar, fructose, fructose glucose liquid sugar, reduced maltose syrup, high glucose syrup, saccharin, saccharin sodium hydrate, sucralose, refined white sugar, purified honey, sorbitol, sorbitol liquid, sweet rice Syrup, white sugar, honey, glucose fructose liquid sugar, powdered reduced maltose syrup, maltitol, maltitol liquid, syrup, and the like. Among these, saccharin, saccharin sodium hydrate, sucralose, maltitol, maltitol liquid, reduced maltose syrup, powdered reduced maltose syrup, etc. are preferable.

Examples of the flavor include orange flavor, kiwi fruit flavor, grapefruit flavor, strawberry flavor, cherry flavor, fruit flavor, muscat flavor, raspberry flavor, apple flavor, lemon flavor, caramel flavor, green tea flavor, Cocoa flavor, coffee flavor, sugar flavor, honey flavor, vanilla flavor, peppermint flavor, vermouth flavor, mint flavor, maple flavor, yogurt flavor and the like. When taking the pharmaceutical composition of this invention, kiwi fruit flavor, strawberry flavor, raspberry flavor, etc. are preferable from a viewpoint which can feel the softness to the seed of a fruit.

In addition, the above-mentioned flavor may store a flavor separately from a pharmaceutical composition during packaging. In this case, it is good also as a kit which combined the pharmaceutical formulation and the flavor which contained the pharmaceutical composition of this invention in stick packaging etc.

Examples of the preservative include benzoic acid, sodium benzoate, butyl paraoxybenzoate and propyl paraoxybenzoic acid.

Next, the dosage form of the pharmaceutical composition of this invention, etc. are demonstrated in detail.

As the formulation, a suspending agent is preferable. Thereby, even if it contains a water-soluble drug (polystyrene sulfonate, cholestyramine, etc.) with a large dose per dose, it can be taken easily.

Examples of the suspending agent described above include those in which suspension is necessary at the time of use, and those in which suspension is not necessary at the time of use. However, the suspension is preferably unnecessary at the point of medication compliance. As an external appearance of the suspension agent which does not require suspension in such a case, a Gumi type | mold, cream type, a jelly type, a Barbara type | mold, a pudding type, a paste type etc. are mentioned. These appearances can be roughly divided according to the viscosity, viscoelasticity and gel strength.

Among the suspending agents described above, the jelly type is preferable. By using such a preparation, since it can be taken without using a preparation, resuspension operation, or a spoon, etc. at the time of use, the complexity at the time of taking | distributing the thing with a normal single dose distribution (distribution product) is reduced. . Moreover, since it is suitable for packaging of the tube, stick shape, etc. which are mentioned later, it is excellent in portability and drug compliance is improved.

The pharmaceutical composition of this invention can be manufactured and manufactured according to the well-known method described in 15th revised Japanese pharmacy room formulation general formula, etc., and these descriptions.

Next, the packaging form at the time of packaging the pharmaceutical composition of this invention to make a pharmaceutical formulation is demonstrated.

When packing the pharmaceutical composition of this invention, the package which can prevent a liquid or solid foreign material from invading in the state of normal handling, storage, etc. is preferable, and the package which can be airtightly preserved is more preferable. Packaging can be used in either a fixed form or an indeterminate form. Such packaging is not particularly limited, but tube, SP (Strip Package) packaging, and stick packaging are preferred. By adopting these packaging forms as pharmaceutical preparations, they can be opened without taking a spoon or the like at the time of taking them, resulting in improved drug compliance and significantly superior portability compared to bulky packaging such as potion cups. Is obtained.

Moreover, it is preferable to accommodate the pharmaceutical composition containing the unit dose of a poorly water-soluble drug in packaging units.

When manufacturing the pharmaceutical preparation which packaged the pharmaceutical composition of this invention by the tube, SP packaging, stick packaging, etc., the sheet | seat which used 1 type (s) or 2 or more types of well-known packaging materials, such as metal foils, such as aluminum foil, and polyethylene, was used, What is necessary is just to manufacture by a well-known method, and the said packaging material can also be made into the multilayered structure which combined suitably.

As a method of making a sheet | seat into a multilayered structure using the said 2 or more types of packaging material, the method of laminating the said packaging material and manufacturing a laminated sheet is mentioned. The laminated sheet can be produced by a known method such as extrusion laminate, dry laminate, coextrusion laminate, thermal laminate, wet laminate, non-solvent laminate, heat laminate and the like. Moreover, a commercial item can also be used for the tube, SP packaging, and stick packaging sheet.

The pharmaceutical preparation which packaged the pharmaceutical composition of this invention by the tube, SP packaging, stick packaging, etc. can be secondary-packed in pillow packaging, a can, a bottle, an envelope, etc. as a small packaging unit which combined the predetermined quantity.

Example

Although an Example demonstrates this invention further more concretely below, this invention is not limited to these.

Test Example 1. Preparation and Evaluation of Jelly-type Pharmaceutical Composition (Internal Solution) (1)

Each component of Table 1 was mixed, this was overheated and cooled, and the jelly pharmaceutical composition was prepared. In addition, the jelly-type pharmaceutical compositions of Examples 1-4 and Comparative Example 1 adjusted pH to about 5 using sorbic acid and sodium citrate hydrate.

Next, about the jelly-type pharmaceutical composition of Examples 1-4 and Comparative Examples 1-6, 3-20 adult males are made to take 5g each, and the soft feeling derived from calcium polystyrene sulfonate in an oral cavity, The hardness of the pharmaceutical composition when put in the mouth was evaluated.

Further, 25 g of the pharmaceutical composition was stick-packed using an aluminum / polyethylene laminate film, stored at 40 ° C. for 2 months, and suspension and dispersion stability of the composition in 1 month and 2 months after storage (polystyrenesulfonic acid in the composition). Suspension and dispersed state of calcium) were evaluated by visual observation. The results are shown in Table 1.

The pharmaceutical composition of Comparative Examples 1-6 was soft enough that mastication was unnecessary, and there was little dullness, but it was not enough evaluation in terms of suspension and dispersion stability.

On the other hand, the pharmaceutical compositions of Examples 1-4 were soft enough that mastication was unnecessary, they had little dull feeling, and had the outstanding suspension and dispersion stability.

From these results, it has been found that by blending the cellulose derivative, the suspension and dispersion stability can be improved while maintaining a soft feeling that is less dull or touches the mouth.

Example 5 Jelly Type Pharmaceutical Compositions

8 g of cholestyramine anhydride, 0.24 g of xanthan gum, 0.44 g of locust bean gum, 0.6 g of methyl cellulose, 12 g of powdered maltose starch syrup, and a small amount of sucralose were dissolved in water, dispersed, and then superheated and cooled to make a total amount 100 g jelly-type pharmaceutical composition was prepared. Subsequently, stick packaging of 50 g of the obtained jelly type pharmaceutical compositions was carried out using the aluminum polyethylene laminate film.

Example 6 Jelly Type Pharmaceutical Compositions

9 g of Sevelamer hydrochloride, 0.24 g of xanthan gum, 0.44 g of locust bean gum, 0.2 g of methyl cellulose, 7.2 g of powdered reduced maltose syrup, 0.45 g of sorbic acid, 0.54 g of sodium citrate hydrate, trace amount of sucralose in water, It disperse | distributed, and then superheated and cooled, and prepared 90 g of gummy pharmaceutical compositions in total amount. Subsequently, 10 g of each of the obtained jelly-type pharmaceutical compositions were stick-packed using the aluminum polyethylene laminate film.

Industrial availability

Even if the pharmaceutical composition of the present invention is stored for a long time, a poorly water-soluble drug such as an ion exchange resin in the formulation stably maintains a suspended and dispersed state. Moreover, when it is packaged (distributed) by dividing a conventional single dose, it is not necessary to adopt a bulky packaging form, and it is excellent in portability.

Therefore, since the pharmaceutical composition of the present invention does not require a tool such as preparation or spoon at the time of taking a poorly water-soluble drug, it is not troublesome to take the usual one-dose distribution (distribution product). It is excellent in portability of a distribution product with distribution, and it is useful in satisfying medication compliance.

Claims (8)

A pharmaceutical composition containing a poorly water-soluble drug and a cellulose derivative. The method of claim 1,
Furthermore, the pharmaceutical composition containing a naturally derived polysaccharide. 3. The method according to claim 1 or 2,
A pharmaceutical composition wherein the poorly water-soluble drug is an ion exchange resin. The method of claim 3, wherein
The pharmaceutical composition whose ion exchange resin is polystyrene sulfonate. The method according to any one of claims 1 to 4,
Pharmaceutical composition whose cellulose derivative is 1 type (s) or 2 or more types chosen from hydroxypropylmethylcellulose, hydroxypropylcellulose, and methylcellulose. 6. The method according to any one of claims 1 to 5,
A pharmaceutical composition wherein the formulation is a suspending agent. The method according to claim 6,
A pharmaceutical composition that is a jelly type suspension. The pharmaceutical formulation which stick-packed the pharmaceutical composition in any one of Claims 1-7.