KR101947198B1 - Pharmaceutical composition containing drug having poor water solubility - Google Patents

Abstract

A medicinal composition containing a water-insoluble drug and a cellulose derivative improved in drug compliance, particularly an ion-exchange resin in which the water-soluble drug is a polystyrene sulfonate, and the cellulose derivative is selected from hydroxypropylmethylcellulose, hydroxypropylcellulose and methylcellulose Or a pharmaceutically acceptable salt thereof, which is a jellied suspension agent.

Description

[0001] PHARMACEUTICAL COMPOSITION CONTAINING DRUG HAVING POOR WATER SOLUBILITY [0002]

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

BACKGROUND ART Conventionally, ion exchange resins have been used as preventive and remedies for various diseases. For example, cation exchange resins (calcium polystyrenesulfonate, sodium polystyrenesulfonate, etc.) are used for hyperkalemia, and anion exchange resins (cholestyramine, etc.) are used for hypercholesterolemia and hyperinflammation, respectively.

However, an ion exchange resin typified by calcium polystyrene sulfonate or sodium polystyrene sulfonate is generally insoluble in water, and thus has a unique taste (unevenness).

On the other hand, as the pharmaceutical composition containing calcium polystyrene sulfonate, a powdery preparation such as a powder or dry syrup (Patent Document 1); There has been proposed a formulation of a jelly preparation for internal use (Patent Document 2). A distribution product containing 5 g of calcium polystyrene sulfonate is commercially available (for example, Calimate (registered trademark) acid, Calimate (registered trademark) dry syrup 92.59%) as the acid and dry syrup, As jelly, 25 g of jelly (containing 5 g of calcium polystyrene sulfonate) is put on the market per one potion cup (for example, 25 g of Agamate (registered trademark) 20% jelly).

The powder is divided into two to three divided doses of 15 to 30 g (15 to 30 g as calcium polystyrene sulfonate) per day, suspended in 30 to 50 ml of water per a day, and the dry syrup is administered 16.2 To 32.4 g (15 to 30 g as calcium polystyrenesulfonate) is divided into two or three divided doses, and one dose is suspended in 30 to 50 ml of water to be administered orally. The intravenous jellies are 75 to 150 g per day (polystyrene sulfonic acid 15-30 g as calcium) is orally administered in two or three divided doses.

On the other hand, a pharmaceutical composition containing sodium polystyrenesulfonate is known to be in the form of powder or dry syrup, and a distribution product containing 5 g of sodium polystyrene sulfonate or a distribution product containing 3.27 g of dry syrup is commercially available (For example, Kay Acatalate (registered trademark) acid, Kay Acetate (registered trademark) dry syrup 76%).

30 g of the powder (30 g as sodium polystyrene sulfonate) is divided into two or three divided doses per day, suspended in 50 to 150 ml of water and administered orally, and the dry syrup is 32.94 g per day (sodium polystyrene sulfonate 30 g) is divided into two or three times, and one dose is suspended in 50 to 150 ml of water to be administered orally.

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

Japanese Patent Application Laid-Open No. 2000-103739 International Publication No. WO99 / 020247

However, since the above-mentioned acid or dry syrup agent needs to be suspended in water when taking it all, it is necessary to prepare water and container, which is troublesome.

On the other hand, since the filling jelly preparation is stored in the potion cup, it is necessary to use a spoon or the like when taking it. In addition, since the potion cup itself becomes bulky and becomes heavy when carrying a plurality of pieces, have.

Under these circumstances, it is recently desired to improve the medicinal compliance of medicinal compositions containing water-insoluble medicines, and to further improve the medicinal-medicinal compliance.

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

As a result of intensive studies, the inventors of the present invention have found that the inclusion of a cellulose derivative in a pharmaceutical composition containing a water-insoluble drug can alleviate the uncomfortable feeling caused by the water-insoluble drug, smooth touch to the mouth, I found that it improved.

Accordingly, the present invention provides a medicinal composition containing a water-insoluble drug and a cellulose derivative.

The medicinal composition of the present invention has a low feeling of tingling caused by a water-miscible drug, 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 water-soluble drug and a cellulose derivative. First, the water-insoluble drug used in the present invention will be described.

<Drug tolerance drugs>

Refers to a drug having a low solubility in water and specifically refers to a drug which is considered to be &quot; hardly soluble &quot; or &quot; hardly soluble &quot; in &quot; solubility &quot; defined by the general rule of the Japanese Pharmacopoeia . That is, the poorly soluble drug used in the present invention means that when the drug is a solid, it is converted into a powder, and when it is shaken for 30 seconds at 20 ± 5 ° C for 5 minutes, it dissolves 1 g of the drug within 30 minutes Means that the amount of water required for the treatment is 1000 ml or more.

Examples of the water-insoluble drug include ion-exchange resins such as azithromycin hydrate, acetazolamide, acetyl spiramycin, acetohexamide, acetethyceine, azelidipine, atorvastatin calcium hydrate, anastrozole, amiodarone hydrochloride, But are not limited to, aminophenol, aminophenol, aminophenol, aminophenic acid, aminophenol, amphotericin B, amoxapine, allyltestrenol, alphalcystol, alprazolam, albendazole, alminoprofen, allopurinol, amphoxicam, amphrenavir, But are not limited to, ibuprofen, ibuplilast, imidaphenacin, indapamide, urafidil, xamestan, esthazolam, etoposide, etretinate, ethiazolam, enoxacin, evastin, epavirenx, But are not limited to, mousse, ephonodipine hydrochloride, erlotinib hydrochloride, entacapone, norfostil, oxendolone, auranofin, olanzapine, ornoprostil, olmesartan medoxomil, ondansetron, carbergoline, carbamazepine, Pipla But are not limited to, maleic acid, maleic acid, maleic acid, maleic acid, maleic acid, maleic acid, maleic acid, maleic acid, maleic acid, maleic acid, maleic acid, maleic acid, maleic acid, maleic acid, maleic acid, maleic acid, maleic acid, , Gempytinib, saquinavir, jaffe lucast, salazosulfapyridine, cyclosporin, dipyridamole, irradiamycin, irradiated mycin propionate, cynidipine, silodocin, simvastatin, sparfloxacin, Spironolactone, sulphonolactone, sulphonolactone, sulphonolactone, sulphonolactone, sulphonolactone, sulphonolactone, sulphonolactone,

Cefuroxime axetil, ceratologist, celecoxib, jotepine, oxtribic acid, zolmitriptan, tacrolimus hydrate, tamibarotene, tamoxifen citrate, monotrolene sodium hydrate, tenoxy But are not limited to, camphor, camphor, camphoryl chloride, telithromycin, telmisartan, tocloxacin mesylate, toracamide, triazolam, triamterene, tripamid, trifluoperazine maleate, trilostane, tolphenic acid, , Norepinephrine, norepinephrine, norepinephrine, norepinephrine, norepinephrine, norepinephrine, norepinephrine, norepinephrine, norepinephrine, norepinephrine, norepinephrine, Fenoglucan hydrochloride, bicalutamide, pitavastatin calcium, fimozide, fomobenzene, piretanide, piroxycam, pyromide acid, palacecitriol, pinasteride, phenonthiophene The present invention also relates to a pharmaceutical composition comprising at least one compound selected from the group consisting of pramiprofen, felodipine, fenprodimine, bacolol, bumetanide, flanoidol, plazenil, , Progesterone dehydrogenase, progesterone dehydrogenase, progesterone dehydrogenase, progesterone dehydrogenase, progesterone dehydrogenase, progesterone dehydrogenase, Dissalicylic acid salts,

Benzofuran hydrochloride, benzoprofen hydrochloride, benzophenol hydrochloride, benzindipine hydrochloride, pemoline, benzylhydrochlorothiazide, phosphamprenavir calcium hydrate, bosentan hydrate, polar prezink, voriconazole, formoterol fumarate salt hydrate, marzone, malotilate, But are not limited to, meczazolam, mestazolol, mestanolol, methylprednisolone, methoxalen, menatetrenone, mefenamic acid, meloxicam, mosafride citrate, mofezolac, rafutidine, ramatroban, raloxifene hydrochloride, lansoprazole, risperidone, Levulinate, levorphinast, re flunomide, roxithromycin, rocitamycin, ropepramine hydrochloride, loratadine, and roll metazepam, and the like. These may be used alone or in combination of two or more.

Of the above water-insoluble drugs, ion-exchange resins are preferred. Examples of the ion exchange resin include anion exchange resin and cation exchange resin.

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

Examples of the cation exchange resin include polystyrene sulfonic acid salts such as potassium polystyrene sulfonate and sodium polystyrene sulfonate; Polycarbophil calcium, and the like.

Of the ion exchange resins as described above, polystyrenesulfonate, cholestyramine and cevamer hydrochloride are preferable in terms of the dose per one time, and polystyrenesulfonate is particularly preferable.

In addition, the particle size of the water-soluble drug is not particularly limited, but it is possible to further alleviate the rough feeling caused by the water-soluble drug by reducing the particle size. For example, when polystyrene sulfonate is used, the particle size is preferably about 5 to 100 mu m.

The content of the water-soluble drug may be determined by appropriately considering the dose per day or the content in the distribution product (dosage unit).

Such a content is such that the dosage per unit dose becomes, for example, 0.05 to 50 g (preferably 0.1 to 30 g) as the free form of the water-insoluble drug.

Concretely, when cholestimide is used as the poorly water-soluble drug, the amount of cholestyme is about 1.5 g per dose.

In the case of using cholestyramine, the amount of cholestyramine anhydrous is about 4 g per dose.

In the case of using cevamer hydrochloride, the amount of cevamer hydrochloride per dose is 1 to 3 g or so.

When a polystyrenesulfonate salt is used, the amount of the polystyrenesulfonate salt is about 5 g per one dose.

When polycarbophil calcium is used, the amount of polycarbophil calcium is 0.5 to 1 g per dose.

The preferable content of the water-soluble drug is from 1 to 60 mass%, more preferably from 5 to 40 mass%, and particularly preferably from 8 to 30 mass% with respect to the whole pharmaceutical composition.

<Cellulose derivatives>

Next, the cellulose derivative used in the present invention will be described. The inclusion of such a cellulose derivative alleviates the rough feeling and softens the touch to the mouth, resulting in improved suspension and dispersion stability.

Examples of the cellulose derivative include carmellose sodium, hydroxypropylmethylcellulose (hypromellose), hydroxypropylcellulose, methylcellulose, croscarmellose sodium and the like, which may be used singly or in combination of two or more thereof. Two or more species can be used. Of these, hydroxypropylmethylcellulose, hydroxypropylcellulose and methylcellulose are preferable, and hydroxypropylcellulose and methylcellulose are particularly preferable in view of alleviation of rubbing in the mouth, softness, suspension and dispersion stability, .

The content of the cellulose derivative may be determined by suitably examining the content of the water-insoluble drug in the pharmaceutical composition, and is preferably about 0.005 to 15% by mass relative to the total amount of the medicinal composition from the viewpoints of reduction in thickness, softness, , More preferably from 0.01 to 5 mass%, and particularly preferably from 0.05 to 2 mass%.

The pharmaceutical composition of the present invention preferably contains a naturally occurring polysaccharide or gelatin in addition to the water-insoluble drug and the cellulose derivative.

<Natural-derived polysaccharide>

The natural-derived polysaccharide is not particularly limited, and examples thereof include, but are not limited to, gum arabic, sodium alginate, alpha starch, curdlan, carrageenan (κ-carrageenan, ι-carrageenan, λ-carrageenan), agar, xanthan gum, guar gum, , Silicate seed gum, gellan gum, tamarind seed gum, tara gum, starch, locust bean gum, pectin and the like. These may be used alone or in combination of two or more.

Among them, one or two or more selected from carrageenan, xanthan gum, locust bean gum, guar gum and agar are preferable. By using locust bean gum in addition to carrageenan, the elasticity of the medicinal composition can be enhanced, and the hardness of the medicinal composition can be increased by using agar.

Among them, one or more selected from carrageenan, xanthan gum and locust bean gum are more preferable, and a combination of xanthan gum and locust bean gum is particularly preferable.

The content of the polysaccharide derived from natural origin is preferably 0.01 to 15% by mass or more, more preferably 0.05 to 5% by mass with respect to the total amount of the medicinal composition in view of alleviation of the spreading and softness of the medicinal composition. %, And particularly preferably from 0.1 to 2% by mass.

The medicinal composition of the present invention may contain a pharmaceutical additive such as a pH adjusting agent, a sweetener, a flavor, and an antiseptic in addition to the water-miscible drug, the cellulose derivative and the natural polysaccharide described above. These may be used individually or in combination of two or more.

Examples of the pH regulator include ascorbic acid, magnesium L-aspartate, benzoic acid, sodium benzoate, sodium chloride, dilute hydrochloric acid, calcium citrate, citric acid hydrate, sodium citrate hydrate, sodium dihydrogen citrate, sodium citrate, gluconic acid Sodium hydrogenphosphate, sodium hydrogenphosphate anhydrous, calcium hydrogenphosphate hydrate, sodium hydrogenphosphate hydrate, calcium dihydrogenphosphate, calcium hydrogenphosphate, calcium hydrogenphosphate, sodium hydrogenphosphate, sodium hydrogenphosphate, sodium hydrogenphosphate, calcium hydrogenphosphate, sodium hydrogenphosphate, sodium hydrogenphosphate, sodium hydrogenphosphate Hydrate, sodium dihydrogenphosphate, and the like.

Examples of the sweetener include sweeteners such as aspartame, liquid sugar, fructose, fructose glucose syrup, reduced maltose syrup, high glucose syrup, saccharin, saccharin sodium hydrate, sucralose, refined sugar, purified honey, sorbitol, sorbitol, Syrup, white sugar, honey, glucose fructose liquid sugar, powdered maltose starch syrup, maltitol, maltitol solution, and starch syrup. Among these, saccharin, sodium saccharin hydrate, sucralose, maltitol, maltitol solution, reduced maltose syrup, powdered maltose syrup and the like are preferable.

The flavor includes, for example, orange flavor, kiwifruit flavor, grapefruit flavor, strawberry flavor, cherry flavor, fruit flavor, muscat flavor, raspberry flavor, apple flavor, lemon flavor, caramel flavor, Cocoa flavor, coffee flavor, sugar flavor, honey flavor, vanilla flavor, peppermint flavor, vermouth flavor, mint flavor, mapple flavor and yogurt flavor. From the viewpoint of reducing seeds of fruit when the medicinal composition of the present invention is administered, kiwifruit flavor, strawberry flavor or raspberry flavor and the like are preferable.

In addition, the flavor described above may contain the flavor separately from the pharmaceutical composition during packaging. In this case, the kit may be a combination of a pharmaceutical preparation containing a medicinal composition of the present invention in a stick packaging or the like and a flavor.

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

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

As the above-mentioned formulations, a suspending agent is preferable. This makes it possible to take it easily even when the dose per one dose contains a lot of water-soluble drugs (polystyrene sulfonate, cholestyramine, etc.).

Suspensions such as those described above may be ones requiring suspension when used, and those not requiring suspension when used. From the viewpoint of compliance with medicines, it is preferable that suspension is not required. Examples of the appearance of the suspension which does not require such suspension include a western type, a cream type, a jelly type, a barber type, a pudding type, a paste type and the like. These appearances are largely divided into viscosities and gel strengths.

Of the above-described suspensions, jellies are preferred. By using such a preparation, it is possible to take the composition without using a spoon or the like at the time of preparation, resuscitation, or administration, so that it is possible to alleviate the complication upon administration of a normally distributed single dose (distributed product) . In addition, since it is suitable for packaging such as tubes and sticks, which will be described later, it is excellent in portability and the compliance with medicines is improved.

The pharmaceutical composition of the present invention can be manufactured and formulated in accordance with the known methods described in the General Regulations of the Japanese Pharmacopoeia of 15th Ed.

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

When the medicinal composition of the present invention is packaged, it is preferable that the packaging is such that liquid or solid foreign matter does not enter in a normal handling or preservation state, and more preferable is a package that can be kept airtight. Packaging can be either orthopedic or amorphous. Such a package is not particularly limited, but is preferably a tube, a SP (Strip Package) package, or a stick package. By adopting these packaging forms and employing a pharmaceutical preparation, it is possible to open the capsule without using a spoon or the like at the time of taking it, and to take it immediately, thereby improving the compliance with medicines, and significantly improving portability .

In addition, it is preferable that the medicinal composition containing the unit dose of the water-soluble drug is contained in a package unit.

When the medicinal composition of the present invention is packaged in a tube, an SP package, a stick package, or the like, it is preferable to use a sheet made of at least one of metal foil such as aluminum foil and publicly known packaging material such as polyethylene It may be produced by a known method, and the packaging material may be a multilayer structure suitably combined.

As a method of making the sheet into a multilayer structure using the above two or more kinds of packaging materials, there is a method of producing a laminated sheet by laminating the packaging material. The laminated sheet can be produced by a known method such as an extrusion laminate, a dry laminate, a coextrusion laminate, a thermal laminate, a wet laminate, a non-solvent laminate, and a heat laminate. In addition, commercially available products such as tubes, SP packages, and stick packing sheets may be used.

The pharmaceutical preparation of the present invention packed with a tube, SP package, stick pack or the like can be packaged in a pillow package, a can, a bottle, a bag or the like as a small package unit of a certain quantity.

Example

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

Test Example 1. Preparation and evaluation of jelly-type medical composition (underwear liquid preparation) (1)

Each component described in Table 1 was mixed and overheated and cooled to prepare a jellied medical composition. The jellied medical compositions of Examples 1 to 4 and Comparative Example 1 were adjusted to a pH of about 5 using sorbic acid and sodium citrate hydrate.

Next, the jellied medical compositions of Examples 1 to 4 and Comparative Examples 1 to 6 were administered with 5 g to 3 to 20 adult men, respectively, and the feeling of being born from calcium polystyrene sulfonate in the oral cavity, The hardness of the pharmaceutical composition when it was put into the mouth was evaluated.

Further, 25 g of the above-mentioned medicinal composition was stick-packed using an aluminum-polyethylene laminate film and stored at 40 占 폚 for 2 months, and the suspension and dispersion stability of the composition at one month and two months after storage (the polystyrene sulfonic acid Suspended and dispersed state of calcium) were visually evaluated. The results are shown in Table 1.

The medicinal compositions of Comparative Examples 1 to 6 were soft enough that chewing was unnecessary, and the feeling of rancidity was small, but the evaluation was not sufficient in terms of suspension and dispersion stability.

On the other hand, the pharmaceutical compositions of Examples 1 to 4 were not only so soft that they did not require chewing, they had a small feeling of roughness, and had excellent suspension and dispersion stability.

From these results, it was proved that the suspension and dispersion stability can be improved while keeping the feeling of being tainted by blending the cellulose derivative or maintaining a soft texture touching the mouth.

Example 5 Jelly-type pharmaceutical composition (anti-inflammatory agent)

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 sucralose were dissolved and dispersed in water, g of a jellied medical composition was prepared. Then, 50 g of each of the obtained jellied pharmaceutical compositions was stick-packed using an aluminum-polyethylene laminate film.

Example 6 Jelly-type medical composition (underwear solution)

9 g of Sorbamer 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, Followed by overheating and cooling to prepare a jelly-type medical composition having a total amount of 90 g. Then, 10 g of each of the obtained jellied medical compositions was stick-packed using an aluminum-polyethylene laminate film.

Industrial availability

Even when the pharmaceutical composition of the present invention is stored for a long period of time, the water-insoluble drug in the preparation, for example, the ion exchange resin, stably remains in a suspended and dispersed state. In addition, when the capsule is packaged (divided) in a single dose, there is no need to adopt a packaging form in which the volume becomes large, which is excellent in portability.

Therefore, since the medicinal composition of the present invention does not require a preparation such as a preparation or a spoon when taking a water-soluble drug, it is not troublesome for taking a medicine with a single dose (distributed product) It is excellent in portability of distribution products along with the distribution, and it is useful because it satisfies the medication compliance.

Claims (8)

Wherein the formulation is a suspension, wherein the natural polysaccharide is a combination of xanthan gum and locust bean gum. delete delete The method according to claim 1,
Wherein the polystyrene sulfonate is calcium polystyrene sulfonate or sodium polystyrene sulfonate. The method according to claim 1,
Wherein the content of polystyrene sulfonate is 8 to 30 mass%. A pharmaceutical preparation stick-packed with the pharmaceutical composition according to claim 1. delete delete