JPH03109332A - Drug composition - Google Patents

Abstract

PURPOSE:To obtain a drug composition having excellent solubility, transmucous and transcutaneous absorbability and high safety by including a scarcely soluble drug in swellable silica. CONSTITUTION:The objective drug composition can be produced by dissolving a scarcely soluble drug (e.g. hydrocortisone, barbital, cyclosporin or griseofulvin) in an organic solvent (e.g. acetone), dispersing swellable silica in the solution, thoroughly stirring the dispersion and removing the organic solvent by vacuum distillation with an evaporator, etc. Since swellable silica has a surface area of as large as 100-380m<2>/g and contains fine pores having a diameter of several tens Angstrom between crystals, it has excellent action to disperse and immobilize a scarcely soluble drug. The solubility and dissolution speed of the scarcely soluble drug can be adjusted by varying the kind, compounding ratio, etc., of the swellable silica.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a pharmaceutical composition comprising a poorly soluble drug and swellable silica. More specifically, the present invention relates to a novel drug composition in which a poorly soluble drug is included in swelling silica by utilizing the excellent inclusion ability of swelling silica.

[Prior Art] When a poorly soluble drug is administered or applied to a living body, it is extremely difficult to absorb the drug effectively due to its low solubility in digestive juices and sebum.

In the first place, about 70% of transmucosal and transdermal membranes are water, and in order for poorly soluble drugs to penetrate, it is desirable that they be in an aqueous solution state. Therefore, there was a close relationship between the transmucosal and transdermal absorption of poorly soluble drugs and their solubility.

Various attempts have been made to improve the absorption of poorly soluble drugs. For example, by forming a complex with a poorly soluble drug using a polymeric substance such as methylcellulose or polyvinylpyrrolidone, by embedding it in a liposome base, or by incorporating a poorly soluble drug into a hydrogenated phospholipid matrix. Attempts have been made to improve the absorption of drugs (Japanese Patent Application Laid-Open No. 172832/1983).

[Problems to be Solved by the Invention] However, the method using a polymeric substance requires the use of a large amount of the polymeric substance when forming a complex with a drug, and has many disadvantages in terms of formulation.

In addition, methods using hydrogenated phospholipid matrices have excellent biocompatibility because phospholipids are biologically derived substances, but they do not have a long-lasting high solubility, and furthermore, they are difficult to prepare for external use on the skin. If the drug is added to the skin, it has the disadvantage that the amount of drug distributed to the sebum is small and the amount absorbed into the skin is also small. Therefore, it has been desired to develop a pharmaceutical composition containing a poorly soluble drug that has good biocompatibility and excellent absorption in the body and skin.

[Means for Solving the Problems] In view of the current situation, the present inventors have developed a method that has excellent solubility and
As a result of intensive research to obtain a drug with excellent transmucosal and transdermal absorbability, we discovered that a drug composition with unprecedented solubility, transmucosal and transdermal absorbability could be obtained, and completed the present invention. did.

That is, the present invention provides a pharmaceutical composition comprising a poorly soluble drug and swellable silica.

Hereinafter, the configuration of the present invention will be explained in detail.

The pharmaceutical composition of the present invention is obtained by dissolving a poorly soluble drug in an organic solvent, dispersing swellable Silica therein, and then removing the solvent by distillation under reduced pressure using an evaporator or the like.

The poorly soluble drug according to the present invention is defined as "slightly soluble" or "slightly soluble" as defined by the Japanese Pharmacopoeia. It refers to drugs that are "hard to swallow", specifically hydrocortisone, hydrocortisone acetate, prednisolone, methylprednisolone, prednisolone acetate, hydrocortisone acetate propionate, prednisolone acetate valerate, dexamethacin, betamethacin, Steroid hormones such as triamcinolone, clobetacin acetate, clobetasol propionate, fluoxynonide, dexamethacin acetate, betamethacin valerate, triamcinolone acetonide, aspirin, salicylic acid, acetaminophen, methyl salicylate, glycol salicylate, mefenamic acid, flufenamic acid, indomethacin, diclofenac , Ketoprofen, Ibuprofen, Flurbiprofen, Fenprofen, Bufexamac, Piroxicam, Oxyphenbutacin, Mepyrizole, Ibuprofen Piconol, Clidanac, Phenylbutacin, Naproxen, Glycyrrhizin, Glycyrrhetinic Acid, Azulene, Camphor, Thymol, Anti-inflammatory analgesics such as l-menthol, dibucaine hydrochloride, ethyl aminobenzoate, procaine hydrochloride, lidocaine, tetracaine hydrochloride, lidocaine hydrochloride, tecaine, benzyl alcohol, bramoxine hydrochloride, tycaine hydrochloride, butanicaine hydrochloride, biperocaine hydrochloride, chloro Local anesthetics such as butanol'IQ, barbiturates, amobarbital, amobarbital sodium, phenobarbital, phanobarbicur sodium, secobarbicur sodium,
bendoparbital calcium, hexobarbicur,
triclofos, promvaleryl urea, glutethimide,
Sleeping sedatives such as methaqualone, verlapine, nitrazebam, estazolam, flurazepam hydrochloride, flunitrazebam, estazolam, cyclophosphamide, busulfan, para-aminosalicylic acid, 5-fluorouracil, mercaptraline, tegaflu, methotrexate, azathioprine, vinblastine sulfate, doxorubicin hydrochloride, hydrochloric acid Anti-cancer agents such as pleomycin, mitomycin C, cyclosporine, L-asparaginase, cisplatin, antibiotics such as chloramphenicol, cefmetazole, bacitracin, penicillin, cephalexin, tetracycline, streptomycin, nyscutin, erythromycin, fradiomycin sulfate, acetic acid Blood circulation promoters such as tocopherol, benzyl nicotinic acid ester, tolazoline, verapamil, caffeine, siflanderate, acetylcholine, tocopherol nicotinate, nifedipine, diviridamol, prenylamine lactate,
Coronary vasodilator drugs such as efloxate, anti-tencan drugs such as phenytoin, zenasemide, ethylzenacemide, ethotoin, primidone, fensaximide, nitrazeban, clonazeban, carbamazepine, antibiotics such as griseofulvin, tolnaftate, crocibacin, phenopropanol, etc. skeletal muscle relaxants such as Mate, antihistamines such as diphenhydramine and metaxine, inotropic drugs such as digoxin, digotoxin, and copidecarenone, arrhythmia drugs such as phenytoin and shisopyramide, and diuretic drugs such as polythiazide, spironolactone, and chlorthalidone. , antihypertensive drugs such as deserpidine, meptame, reserpine, and meptamate; water-insoluble hormones such as prostaglandin F2α tanazole and mevithiostane; It can be used regardless of its shape, solid or liquid.

Further, the swellable silica according to the present invention is not particularly limited, and various silicas having different surface areas can be used. As a commercially available swellable silica, AERO3I
There are L#200, #300, #380 (manufactured by Nippon Aerogel Co., Ltd.), etc. These swellable silicas have a high surface area and are excellent in dispersing and immobilizing poorly soluble drugs.

In carrying out the present invention, one or more types of swellable silicas are arbitrarily selected from among these swellable silicas.

These swellable silicas have a large specific surface area of 100-380 m2/g and also have pores of several tens of angstroms between crystals, so they have excellent inclusion effects. The pharmaceutical composition according to the present invention is obtained by clathrating a poorly soluble drug by utilizing the clathration effect of the swellable silica, and a specific manufacturing method will be described here.

The above-mentioned poorly soluble drug is dissolved in an organic solvent, swellable silica is dispersed therein, the organic solvent is removed after thorough stirring, and the drug composition of the present invention is obtained by thorough drying. Depending on the type of poorly soluble drug used, one or more types can be dissolved at the same time and used, depending on the intended formulation. The best way to remove the solvent is to use an evaporator or vacuum dryer, and the best way to remove the solvent is by using methods such as filtration.
Since the poorly soluble drug that has been dissolved is washed away,
Not the preferred method. As the organic solvent, common solvents such as ethanol, methanol, and acetone may be used.
The amount of solvent and the amount of solvent in which the drug is sufficiently and uniformly dissolved are required. The concentration of the swellable silica to be dispersed in the solvent in which the poorly soluble drug is dissolved is not particularly limited, but is preferably 70% or less. If it exceeds 70%, stirring becomes difficult. Further, the temperature of the solvent in which the swellable silica is dispersed may be any temperature as long as the poorly soluble drug can be dissolved, and room temperature may be sufficient depending on the type of the poorly soluble drug. During production, the ratio of poorly soluble drug to swellable silica varies depending on the type of drug, but is preferably approximately 40% or less by weight. 40
If the ratio exceeds %, it becomes impossible to include the drug in the swellable silica, and excessive drug may precipitate or the swelling ability of the swellable silica may be suppressed, which is not preferable.

The pharmaceutical composition according to the present invention can be produced by the above-mentioned method by utilizing the clathration effect of swellable silica. The water solubility of can be improved to some extent.

The pharmaceutical composition according to the present invention obtained as described above usually contains oily components, polymers, and inorganic powders commonly used in pharmaceuticals, cosmetics, foods, agricultural chemicals, etc. It can coexist with various bases and additives.

[Effects of the Invention] Since the pharmaceutical composition according to the present invention uses swellable silica, there is no problem in adaptability to living organisms and exhibits high safety.

Furthermore, the pharmaceutical composition of the present invention has the function of significantly increasing the solubility of the poorly soluble drug included in water by swelling and uniformly dispersing the swellable silica, which is an inclusion agent, in water. vinegar. When administered into a living body, it is easily dissolved in the gastrointestinal fluid and can enhance the digestive and absorption capacity. Furthermore, when the pharmaceutical composition of the present invention containing an antibacterial drug is added to a base for external use on the skin, distribution of the antibacterial drug to sebum, etc. increases, and it exhibits an excellent antibacterial effect on the skin surface. Furthermore, when an anti-inflammatory drug is added, the skin permeability increases and exhibits an excellent anti-inflammatory effect. Furthermore, by changing the type or blending ratio of the swellable silica, the inclusion ability of the drug changes and the solubility and dissolution rate of the poorly soluble drug can be adjusted.

[Example] The present invention will be specifically explained below with reference to Examples, but the present invention is not limited thereto. In addition, the test methods and evaluation methods employed in each example will also be explained here.

Example I For the above formulation (numbers indicate parts by weight, the same applies hereinafter), griseofulvin was sufficiently dissolved in acetone (in some cases, heated to 40°C) and swellable silica was dispersed therein. Acetone was removed using an evaporator or vacuum dryer to obtain powdered swellable silica containing griseofulvin. That is, powdered samples (1), (2), and (3) containing 5% griseofulvin were obtained.

Solubility test> Samples (1) to (3) were weighed so that the concentration of griseofulvin was 0.005g/100n+1H20, and the solubility of griseofulvin in water at 37°C over time was measured using high performance liquid chromatography. It was measured using HPLC. For comparison with these samples, the solubility was also measured when 0.005 g of griseofulvin alone was weighed. The results are shown in Figure 1. Figure 1 shows the solubility test (unit: 2 μmol) of the pharmaceutical composition of the present invention obtained in Example 1 at 37°C.
e/1) is a graph showing the results. As can be seen from the results in FIG. 1, among the samples shown in this example, samples (2) and (3) with large specific surface areas had higher solubility in water than the griseofulvin alone system shown as a comparison. It can be seen that the solubility is nearly twice that of griseofulvin alone.

<Antibacterial activity test> Example 1 (3) (Griseofulvin/Aerogel
#380 = 0.5 / 9.5 sample) was tested for its antibacterial activity in a system using a liquid medium.

The test method is to use test bacteria (Tlmentagrophyte
The evaluation was performed by determining the MIC (minimum inhibitory concentration; unit: ppm) against s, T, ruburum). Table 1 shows the results.
As shown in Fig. 3, it can be seen that even when griseofulvin is packaged in swellable silica #380, the antibacterial activity of griseofulvin does not decrease and it has the same level of antibacterial activity as the original drug.

Table-1 ☆ Values are MIC (minimum inhibitory concentration, unit: ppm)
) appears.

Example 2 Using sample No. (3) obtained in Example 1, an oily ointment was obtained.

Example 1 - No. (3) Vaseline liquid paraffin The following formulation weight 2 10.0 70.0 20.0 Vaseline and liquid paraffin were mixed and dissolved at 70°C, and No. (3) obtained in Example 1 was mixed and dissolved. sample was added and thoroughly mixed with a lab dispenser to obtain an oily ointment.

Comparative Example 1 Heavy Nz Griseofulvin 0.5 Vaseline
75.0 Liquid paraffin
24.5 Vaseline and liquid paraffin were mixed and dissolved at 70°C, griseofulvin was added thereto, and the mixture was thoroughly stirred and mixed to obtain an oily ointment.

Solubility of griseofulvin in ointment The oily ointments of Example 2 and Comparative Example 1 were dispersed in water, and the solubility of the blended griseofulvin in water was investigated. The results are shown in Table 2.

Table 2 The numerical values are the values determined by adding 1 g of each ointment to 100 ml of 37" warm water and quantifying the ointment using HPLC (high performance liquid chromatography) after 24 hours of stirring.

As can be seen from Table 2, the griseofulvin in the oily ointment obtained in Example 2 showed approximately twice the solubility in water compared to Comparative Example 1, and the pharmaceutical composition of the present invention was found to be more soluble than in Comparative Example 1. , was found to exhibit high solubility.

<Therapeutic Test> Regarding Example 2 and Comparative Example 1, the therapeutic effects were observed over a period of time for 20 people suffering from white feet. The results are shown in Table-3. The therapeutic effect was evaluated as follows.

(Method for determining treatment effectiveness) Excellent response: Significant improvement effect was observed.Effective: Significant improvement was observed.Slightly effective: Improvement was observed.Ineffective: No improvement was observed.Exacerbation: Exacerbation was observed. 3 Unit: name (hereinafter blank) From the results in Table 3, it is shown that the pharmaceutical composition of the present invention obtained in Example 2 has an excellent therapeutic effect on foot whiteness, and is effective in transmucosal and It was revealed that it has excellent transdermal absorption and water solubility.

In particular, the pharmaceutical composition of the present invention exhibited excellent therapeutic effects even without incorporating various percutaneous absorption adjuvants.

Further, from this result and the result of the water solubility test described above, it can be seen that the drug efficacy is improved by the amount corresponding to the increase in solubility.

[Brief explanation of drawings]

Figure 1 shows the pharmaceutical composition of the present invention obtained in Example 1 at 37°C.
1 is a graph showing the results of a water solubility test (unit: μmole/1).

Claims (1)

[Claims] (1) A pharmaceutical composition comprising a poorly soluble drug and swellable silica.