JPH1025255A - Poorly soluble drug with improved solubility - Google Patents

Abstract

(57) [Summary] [Object] To provide a solid preparation which can be industrialized and has improved solubility of a poorly soluble drug by a usual production method. (A) one or more selected from the group consisting of (a) glycyrrhizic acid, a salt of glycyrrhizic acid, glycyrrhetinic acid and salts and esters of glycyrrhetinic acid, and (b) a sparingly soluble drug is dissolved in a solvent, A solid preparation obtained by distilling off the solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a solid preparation having improved solubility of a poorly soluble drug.

[0002]

BACKGROUND OF THE INVENTION Drugs are often administered orally in the form of solid preparations. In order for an orally administered drug to effectively act on a living body, it must first be disintegrated and eluted to absorb the drug. If the drug used at this time has extremely poor solubility in water, the blood concentration of the drug may be low and the expected drug effect may not be obtained. In designing a solid preparation of a poorly soluble drug, improving its solubility is extremely important from the viewpoint of treating various disease states.

Regarding the dissolution rate of a drug, according to Neues and Whitney, a diffusion layer theory as shown below is reported (J. Am. Chem. Soc., 19, 930-934, 1987). dc / dt = DS · (C−Cs) / h (where dc / dt is the dissolution rate of the drug, D is the diffusion constant of the drug in the solution, and S is the effective surface area of the drug particle. And C is the drug concentration at time t, Cs is the solubility of the drug, and h is the thickness of the diffusion layer around the drug particles. That is, the dissolution rate of the drug depends on the solubility and effective surface area of the drug. It can be seen that the ratio is proportional to (particle diameter), and increasing these values leads to an improvement in the dissolution rate. From such a viewpoint, as a method for increasing the solubility Cs, cyclodextrin (Uekama, K., et al, J. Pharm. Dyn., 6, 124-127,
1983) and polymorphs (Aguir, AJ & Zelmer, JE, J. Phar
m. Sci., 58, 983-987, 1969). In addition, as a method of increasing the effective surface area S, crystal particles are made into fine particles using mechanical energy of a pulverizer or the like and mixed and pulverized with microcrystalline cellulose (Naka
i, Y, Fukuoka, E., et al., Chem. Pharm. Bull., 25, 334
0-3346, 1977).

[0004]

As a means for improving the solubility of a poorly soluble drug, the above-mentioned techniques can be considered. However, in order to produce a cyclodextrin into a solid preparation, a manufacturing method such as a freeze-drying method is used. Therefore, from the viewpoint of production, the production time and the number of steps are increased, and it cannot be said that this is a method having much merit from the viewpoint of industrializing an internal solid preparation.

The pulverization method is the most widely used method without any problem in the production time, but it is impossible to increase the concentration to a level higher than the solubility from a physicochemical point of view, Can often cause trouble. For example, during the pulverization due to the adhesion and cohesiveness of the raw material, there is a problem that the pulverization adheres to a wall or a screen of the pulverization machine and cannot be pulverized. In such a case,
It will have a great capacity in the pulverization process. Further, the mixing and pulverization has a drawback that the amount of the compounded medicine is limited.

[0006] Therefore, from the standpoint of manufacturing pharmaceuticals, there is a demand for a method that can be industrialized by ordinary manufacturing methods.

[0007]

Means for Solving the Problems In view of such circumstances, the present inventors have enthusiastically searched for various additives and manufacturing methods for improving the solubility of poorly soluble drugs. As a result, glycyrrhizic acids were dissolved in an organic solvent or the like together with a poorly soluble drug, and then the solid preparation obtained by distilling off the solvent was dissolved in water. It was found that the apparent solubility and dissolution rate were extremely high, and the present invention was completed.

That is, the present invention relates to (a) glycyrrhizic acid, a salt of glycyrrhizic acid, glycyrrhetinic acid and one or more of glycyrrhetinic acid salts and esters (hereinafter referred to as component (a)). And (b) a poorly soluble drug (hereinafter sometimes referred to as component (b)) in a solvent, and then the solvent is distilled off to obtain a solid preparation. The solid preparation of the present invention can be obtained by dissolving the component (a) together with the component (b) in a solvent or the like, and then distilling off the solvent.
It is preferable to dissolve the component (b) in a solvent, then add and dissolve the component (a), and then distill off the solvent. When the poorly soluble drug does not dissolve in the solvent, it is preferable to dissolve the component (b) by performing a heat treatment.

In the present invention, the component (a) is added in an amount of 0.5 to 20 parts by weight, based on 1 part by weight of the component (b), in terms of the weight of glycyrrhizic acid. When the glycyrrhizic acid-equivalent content of the component (a) is less than 0.5 part by weight based on 1 part by weight of the component (b), the solubility of the poorly soluble drug becomes insufficient. When the component (b) is used in a large amount, the formulation may not be established. As the component (a), it is preferable to use one or more selected from the group consisting of glycyrrhizic acid and salts of glycyrrhizic acid (eg, sodium salt, potassium salt, ammonium salt, etc.).

In the present invention, examples of poorly soluble drugs include protective factor anti-ulcer agents, poorly soluble anti-inflammatory agents, poorly soluble anti-allergic agents, and poorly soluble local anesthetics. Examples of protective factor anti-ulcer agents include aldioxa, gefarnate, sulpiride, proglumide, cetraxate hydrochloride, sofacolcon, teprenone, troxipide, pranotol, ornoprostil, irsogladine maleate, rebamipide and the like.

Examples of anti-inflammatory agents include anthranilic acid drugs such as mefenamic acid, flufenamic acid and aluminum flufenamic acid; salicylic acid drugs such as etenzamide, sazapyrine and diflunisal; pyrazolone drugs such as phenylbutazone; Fenbufen, methiathidic acid, etc., phenylpropionic acid drugs, ibuprofen, ketoprofen, naproxen, flurbiprofen, loxoprofen, etc.
Oxicams such as tenoxicam, chlortenoxicam, piroxicam and other drugs include indomethacin, acemethacin, oxaprozin and the like. Examples of the antiallergic drug include tranilast, repirinast, ibudilast, tazanolast, ketotifen fumarate, oxatomide, terfenadine, azelastine hydrochloride, amlexanox, mequitazine and the like. Examples of the local anesthetic include ethyl aminobenzoate, oxesazein, ethyl piperidinoacetylaminobenzoate and the like. Among these poorly soluble drugs, the effects of the present invention are great when ibuprofen, lornoxicam, oxaprozin, ketotifen fumarate, and sofacolcon are used.

The compounding amount of the poorly soluble drug in the whole preparation varies depending on the drug, but the lower limit is the amount that exerts the medicinal effect as the active ingredient, and the upper limit is the amount of the side effect and the maximum effect. And the upper limit of the amount in which the preparation can be produced. Therefore, although the amount of the component (b) cannot be determined, it is generally 0.1 to 70% by weight.

Examples of the solid preparation include tablets, granules, fine granules, powders, capsules, chewables, and foaming agents. These preparations can be produced by a conventional method using a mixture of the component (a) and the component (b) prepared by the above method. In this case, excipients (lactose, corn starch, sucrose, mannitol, crystalline cellulose, light anhydrous silicic acid, calcium hydrogen phosphate, etc.), binders (hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpolypyrrolidone, Alpha starch, methylcellulose, pullulan, dextrin, gum arabic, etc.), disintegrants (carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, starches, crosslinked sodium carboxymethylcellulose, crosslinked polyvinylpolypyrrolidone, etc.), lubrication Agents (magnesium stearate, calcium stearate, hydrogenated castor oil, talc, sucrose fatty acid ester, sodium lauryl sulfate, etc.) can be added Of two or more may be added. In addition, a surfactant, a solubilizing agent, a buffer, a preservative, a fragrance, a coloring matter, a flavoring agent, a flavoring agent, and the like can be blended as needed within a range that does not impair the effects of the present invention.

As the solvent used in the present invention, for example, ethanol, acetone, isopropyl alcohol,
Water or a mixture of these solvents can be used. A binder may be appropriately added to the solvent in order to facilitate the unit operation of the solid preparation.

[0015]

According to the present invention, it has become possible to provide a solid preparation having good solubility of a poorly soluble drug without using complicated techniques. Therefore, it is expected that the absorbability in the body is improved and the therapeutic effect is improved. Furthermore, when combined with anti-ulcer drugs, anti-inflammatory drugs, and anti-allergic drugs, synergistic effects can be expected as well as promotion of dissolution. Can be reduced, and an effective and safe pharmaceutical composition can be provided.

[0016]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to test examples as examples, but the present invention is not limited thereto.

Example 1 1 g of indomethacin was dissolved in 50 g of alcohol, and 9 g of glycyrrhizic acid was added and dissolved. The solvent was distilled off from this solution at 50 ° C. and around 10 torr, and the mixture was sieved through 24 mesh to obtain granules.

(Experimental Example 1) The granules obtained in Example 1 were used as a sample A, and a disk A having a diameter of 10 mm was obtained under the conditions of a tableting pressure of 700 kg / cm ² while sucking using a tableting machine for IR.
It was created. Separately, as a control, a disc was prepared using indomethacin alone under the same conditions. Figure 1 shows the created disc
The test solution was fixed with an epoxy resin so that only a certain surface was in contact with the test solution using an apparatus as shown in (1) and used for a dissolution rate test. The dissolution rate test was performed as follows. That is, the test solution was 500 m of pH 6.0 phosphate buffer at 37 ° C.
Using l, the amount of indomethacin eluted over time was determined by liquid chromatography (HPCL method). The rotation speed was 50 rpm. As a result, as shown in FIG. 2, it was found that the slope of the straight line of sample A was clearly higher than that of the control, and the dissolution rate was accelerated.

(Experimental example 2) Sample A1 used in Experimental example 1
g, and the dissolved concentration over time was measured for 100 mg of indomethacin as a control. That is, pH 6 at 37 ° C.
0 Each sample was put into 500 ml of phosphate buffer and the number of rotations was 2
The test was performed under the condition of 00 rpm, and the test solution was collected over time, filtered through a membrane filter (pore size 0.45 μm), and diluted with a pH 6.0 phosphate buffer as needed.
Next, the concentration of the dissolved indomethacin in the filtrate was determined by the HPLC method. As a result, as shown in FIG. 3, the dissolution pattern showing a supersaturation phenomenon was exhibited for sample A, and it was found that dissolution of indomethacin was promoted as compared with the control.

Example 2 After dissolving 1 g of oxaprozin in 50 g of alcohol, 2 g of glycyrrhizic acid was added and dissolved. The solvent was distilled off from this solution at 50 ° C. and around 10 torr, and the mixture was sieved through 24 mesh to obtain granules.

(Experimental Example 3) The granules obtained in Example 2 were mixed with Sample B
Was subjected to the same dissolution test as in Experimental Example 2. As a control, a mixture of 1 g of oxaprozin and 2 g of glycyrrhizin was used in the experiment. However, a phosphate buffer of pH 6 was used for the test, and the amount of eluted oxaprozin was determined by HPLC. As a result, as shown in FIG. 4, it was revealed that oxaprozin in sample B exhibited higher solubility than the control. By the way, the pharmacokinetics of oxaprozin in humans has a biological half-life of about 47 hours, which is extremely long disappearing from the body, and the time to reach the maximum blood concentration is about 2.3 hours. Hopefully, it's a bit slow. It is thought that the slower time to reach the maximum blood concentration is due to the solubility of oxaprozin itself. It can be used as an agent.

Example 3 After dissolving 10 g of indomethacin in 500 g of alcohol, 50 g of glycyrrhizic acid was dissolved.
g was added and dissolved. Next, a mixed powder of 400 g of lactose and 290 g of Avicel was placed in a fluidized bed granulator (FLO-1, manufactured by Freund), and the supply air temperature: 40 ° C. and the liquid velocity: 20
The above solution was sprayed under the condition of g / min. After the predetermined liquid was sprayed, the liquid was dried under the condition of the supply air temperature: 60 ° C., and sieved with a 24-mesh sieve. Weigh 375 g of sieved product, and use L-HP
120 g of C-LH21 and 5 g of magnesium stearate
Was added and mixed, and the mixture was tableted using Collect 19 (manufactured by Kikusui Co., Ltd.) under the conditions of a tableting pressure of 1 ton and a rotation speed of 25 rpm to obtain a tablet of 250 mg per tablet.

Example 4 A mixed powder of 100 g of Avicel and 100 g of Ezilol was placed in a kneader, and 100 g of oxaprozin and 100 g of glycyrrhizic acid were gradually dissolved in 500 g of a mixed solvent of alcohol and acetone (mixing ratio 1: 1). And kneaded together. Next, the kneaded material was sized using a speed mill (screen: 24 mesh), and dried at 70 ° C. for 1 hour using a box drier. Dry matter 20
After mixing 0 and 1 g of magnesium stearate, the mixture was tableted using Collect 19 (manufactured by Kikusui Co., Ltd.) under the conditions of a tableting pressure of 1 ton and a rotation speed of 25 rpm to obtain a tablet of 400 mg per tablet.

[Brief description of the drawings]

FIG. 1 shows an apparatus used in a dissolution test by a rotating disk method in Experimental Example 1, wherein 1 denotes a container, 2 denotes a test solution, 3 denotes an epoxy resin, and 4 denotes a surface of the epoxy resin in contact with the test solution.

FIG. 2 is a graph showing test results according to Experimental Example 1, in which the vertical axis represents indomethacin concentration and the horizontal axis represents time.

FIG. 3 is a graph showing test results according to Experimental Example 2, in which the vertical axis represents indomethacin concentration and the horizontal axis represents time.

FIG. 4 is a graph showing test results according to Experimental Example 3, in which the vertical axis represents oxaprozin concentration and the horizontal axis represents time.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical display location // A61K 31/405 AAH A61K 31/405 AAH

Claims (7)

[Claims] 1. A method comprising dissolving (a) glycyrrhizic acid, one or more selected from the group consisting of glycyrrhetic acid salts, glycyrrhetinic acid and salts and esters of glycyrrhetinic acid, and (b) a sparingly soluble drug in a solvent. And a solid preparation obtained by distilling off the solvent. 2. A compound obtained by dissolving (a) one or more kinds selected from the group consisting of glycyrrhizic acid and a salt of glycyrrhizic acid and (b) a poorly soluble drug in a solvent, and then distilling off the solvent. Solid preparations. (B) dissolving a poorly soluble drug in a solvent, and then (a) glycyrrhizic acid, a salt of glycyrrhizic acid,
A solid preparation obtained by adding and dissolving one or more selected from the group consisting of glycyrrhetinic acid and salts and esters of glycyrrhetinic acid, and distilling off the solvent. (B) dissolving a poorly soluble drug in a solvent, and then adding and dissolving one or more kinds selected from the group consisting of (a) glycyrrhizic acid and a salt of glycyrrhizic acid, followed by distilling off the solvent; A solid preparation obtained by the above. 5. A solvent comprising: (a) one or more selected from the group consisting of glycyrrhizic acid, a salt of glycyrrhizic acid, glycyrrhetinic acid and salts and esters of glycyrrhetic acid, and (b) a poorly soluble drug, When a poorly soluble drug is dispersed in a solvent, a solid preparation obtained by heating until the poorly soluble drug is dissolved, and then distilling off the solvent. 6. A method comprising adding (a) one or more selected from the group consisting of glycyrrhizic acid and a salt of glycyrrhizic acid and (b) a sparingly soluble drug to a solvent, wherein the sparingly soluble drug is dispersed in the solvent. In this case, a solid preparation obtained by heating until the poorly soluble drug is dissolved, and then distilling off the solvent. 7. The sparingly soluble drug is one or more selected from the group consisting of a sparingly soluble protective factor anti-ulcer agent, a sparingly soluble anti-inflammatory agent, a sparingly soluble antiallergic agent and a sparingly soluble local anesthetic. The solid preparation according to any one of claims 1 to 6.