KR19980031601A - Method of solubilizing poorly soluble drugs - Google Patents

Abstract

The present invention relates to a solubilizing method of poorly soluble drugs, and more particularly, solubilizing poorly soluble drugs in oil-in-water type microemulsion containing a range of oil components and polyoxyethylene-based surfactants more than conventional micelle solution. A method of solubilizing poorly soluble drugs that can be used for the targeting of drugs with a composition that exhibits an improved solubilization rate and contains an oil component in formulation.

Description

Method of solubilizing poorly soluble drugs

The present invention relates to a solubilizing method of poorly soluble drugs, and more particularly, solubilizing poorly soluble drugs in oil-in-water type microemulsion containing a range of oil components and polyoxyethylene-based surfactants more than conventional micelle solution. A method of solubilizing poorly soluble drugs that can be used for the targeting of drugs with a composition that exhibits an improved solubilization rate and contains an oil component in formulation.

Conventionally, solubilization methods of poorly soluble drugs include solubilization using cosolvents, formation of complex compounds, prodrugs of drugs, formation of water-soluble salts, or mechanical grinding and grinding of poorly soluble drugs, and dispersion of solids. There has been a solubilization method through size reduction, and in addition, a solubilization method has been used through the use of crystal polymorphs, the use of solvates, and the reduction of interfacial tension using surfactants. In the solubilization method using a co-solvent, ethanol, propylene glycol, glycerin, etc. are often used as co-solvents. In this case, not only a large amount of co-solvent is required to reach the necessary concentration solubilization, but also the temperature is reduced or diluted with body fluids. If precipitated there is a problem of stimulating tissue at the administration site. The solubilization method by the formation of a complex compound is pointed out that the problem of small solubility increase is pointed out because of the problem of precipitation formation due to dilution and the selection of ligand used at that time. The prodrugation method, which chemically modifies the drug to return to the original drug enzymatically or non-enzymatically in the body, has a problem that the activity of the drug itself decreases, and before the drug reaches the site of action after administration. There was a difficulty in meeting the limitations of changing to an active drug. In addition, the method of solubilizing poorly soluble drugs with a water soluble salt to become a strong electrolyte affects the bioavailability due to the lattice energy of the salt, and the potassium or sodium salt reacts with carbon dioxide in the air or returns to its original properties that are poorly soluble in water. Precipitation may occur, and there is a problem causing pain in the upper abdomen after oral administration due to the alkaline nature of the salt. In addition, the solubilization method by reducing the particle size increases the free energy of the undifferentiated particles and due to the strong van der Waals forces between the non-polar molecules due to the aggregation between the particles, the effective effective surface area does not increase so that the dissolution rate is slowed And wettability and fluidity are often lowered. In addition, when using a surfactant, there is a problem that a surfactant having a low critical micelle concentration needs to be developed because the drug may precipitate when the concentration of the surfactant in the preparation is diluted below the critical micelle concentration (CMC). .

In order to solve the problems of the conventional method of solubilizing poorly soluble drugs, a method for solubilizing poorly soluble drugs using liposomes has recently been reported. Liposomes can structurally encapsulate both fat-soluble drugs and water-soluble drugs. It is excellent in that it is degradable in the body and is not toxic or antigenic. However, in order for the liposome to be formulated, physical and chemical instability due to coagulation, sedimentation, fusion, hydrolysis of phospholipids, oxidation, and metathesis of encapsulated drugs have to be solved. Production of scale is difficult and there is a problem such as low reproducibility, so it has not reached the practical use stage. In addition, as an attempt to improve the problems of liposomes, methods of using antioxidants, addition of charged phospholipids to form complexes, and methods of polymerizing liposomes by adding chemical modifications have been proposed. Only a certain degree of stability was improved, but practical formulation was limited.

On the other hand, in order to solve the problems of the existing solubilization method, there is increasing interest in microemulsion system having a very small particle size, thermodynamically stable and easy to manufacture. Since the microemulsion system was first discovered in 1943 by British chemist JH Schulman, its potential was evaluated in the 1970s, and then the potential for application of microemulsion as a drug delivery system began to be evaluated. Since the 1980s. In this example, Halbert et al. (International Jounal of Pharmaceutics, 21, 219-232, 1984) studied the solubilization of fat-soluble fragrances into microemulsions as a drug delivery system to increase the efficiency of drugs by applying microemulsions. Jayakrisnan et al. (J. Soc. Cosmec. Chem., 34, 335, 1983) studied the solubilization of hydrocortisone, a corticosteroid, using commercially available surfactants Ariacel 186 and Brij 35. Studies using microemulsions as sieves are known (J. Pharmacy and Pharmacology, 43, 451, 1991).

Microemulsion can be used as a drug carrier because of its very small droplet size and excellent thermodynamic stability, and it is possible to improve the utilization rate by the solubilizing property of the surfactant, so that the microemulsion in the case of poorly soluble drugs in which the drug is hydrophobic and has low solubility When used in oral formulations, it is expected that bioavailability can be enhanced by the solubilizing properties of the surfactants, and the advantages of the fat-soluble drug can be easily administered by the hydrophilic drug as the continuous phase, and can be sterilized by filtration. It is also expected to be used as an injection. As an external preparation using a microemulsion, there is much interest in cosmetics and the like, and this has been expected to be applicable as a transdermal delivery system. On the other hand, the use of micelles as a system for solubilizing poorly soluble drugs has been studied for a long time. The present invention prepares an oil-in-water microemulsion containing a range of oil components and a polyoxyethylene-based surfactant in the process of studying solubilization of poorly soluble drugs using a polyoxyethylene-based surfactant to form micelles. This is to solve the problem of poor solubility of the drug.

In the present invention, efforts to solve the problems appearing in the conventional method of solubilizing poorly soluble drugs, as a result of the oil-in-water type microemulsion containing a range of oil components and polyoxyethylene-based surfactant significantly compared to micelle solution The present invention has been completed by knowing the ability to solubilize large, poorly soluble drugs.

1 is a view showing the results of measuring the droplet size distribution of the oil-in-water type microemulsion according to the present invention by the dynamic light scattering method,

2 is a view showing the results of measuring the droplet size distribution state of the conventional micelle solution by the dynamic light scattering method,

3 and 4 are diagrams showing the degree of solubilization of indomethacin in micelle solution and the oil-in-water microemulsion of the present invention.

The present invention is characterized by solubilizing the poorly soluble drug in an oil-in-water type microemulsion system consisting of an oil component and a polyoxyethylene-based nonionic surfactant.

Referring to the present invention in more detail as follows.

The present invention relates to a method for solubilizing poorly soluble drugs in oil-in-water microemulsions in which oil-based oil phases and polyoxyethylene-based nonionic surfactants are mixed in purified water or buffers at various ratios, and the oil-in-water microemulsion is stored. It is excellent in stability and can be used as a drug carrier to increase the efficiency of drugs.

When preparing an oil-in-water microemulsion according to the present invention, one or two or more selected from soybean oil, olive oil, castor oil, mineral oil, corn oil, peanut oil and isopropyl myristate are used. At this time, the oil component is preferably contained 1.0 to 10.0% by weight in the total oil-in-water microemulsion composition, if the content of the oil component is less than 1.0% by weight only solubilizing the poorly soluble drug in the form of oil-filled micelles If it is weak and exceeds 10% by weight, the microemulsion cannot be formed and is thermally and thermally unstable, thereby causing stability problems. In the present invention, one or two or more lipids, fatty acids and alcohols may be added to the oil component. As lipids, triglycerides, trilaurin, tricapryloin, and the like can be used. As fatty acids, decanoic acid, lauric acid, and miri may be used. Mystic acid, palmitic acid, stearic acid, etc. may be used. Alcohols include lauryl alcohol, myristyl alcohol, and cetyl alcohol. alcohol), stearyl alcohol (stearyl alcohol) and the like can be used. As a result, the poorly soluble drug is encapsulated in the oil nucleus of the microemulsion so that the poorly soluble drug can be effectively applied to the body, and the drug encapsulated in the microemulsion system is continuously discharged to exhibit an excellent therapeutic effect.

In preparing an oil-in-water microemulsion according to the present invention, a polyoxyethylene-based nonionic surfactant is added as another component. For example, at least one selected from polyoxyethylene higher fatty acid esters and polyoxyethylene higher fatty alcohol ethers may be used as a microemulsion. In the system, at least one selected from polyoxyethylene (10) oleyl ether and polyoxyethylene (10) cetyl ether is preferably used. At this time, the polyoxyethylene-based surfactant is preferably contained in the total oil-in-water microemulsion composition 2.0 to 30.0% by weight, if the content is less than 2.0% by weight does not form a microemulsion, if it exceeds 30.0% by weight fluidity This gels off.

As described above, the oil-in-water microemulsion according to the present invention comprises 1.0 to 10.0% by weight of an oil component, 2.0 to 30.0% by weight of a polyoxyethylene-based nonionic surfactant, and 40.0 to 93.0% by weight of purified water or a buffer solution. In oil-in-water microemulsions having this composition, the resulting microemulsions have an average droplet size of 5 to 100 nm and are thermodynamically stable and appear transparent, milky or slightly turbid when diluted with water. The oil-in-water microemulsion according to the present invention not only increases the apparent solubility by solubilizing poorly soluble drugs but also does not precipitate when diluted with water or body fluids, thereby significantly improving the bioavailability of poorly soluble or insoluble drugs. In addition, various formulation designs can be applied as an effective drug transport system through external preparations such as aerosols, oral or medicinal preparations such as liquids or parenteral medicaments such as injections.

In addition, the poorly water-soluble drug that is physically enclosed in the hydrophobic inner core of the oil-in-water type microemulsion having the above composition is not particularly limited, for example, hepatic disease treatment agents such as biphenyl dimethyl carboxylate; Immunosuppressive agents such as cyclosporin; Anti-inflammatory analgesic agents such as ibuprofen, indomethacin and pyroxycam; Anticancer agents such as paclitaxel, docetaxel, camptothecin, etoposide, 6-mercaptopril, fluorouracil, adriamycin, teniposide, etoposide, amphotericin B, daunomycin, methotrexate, mitomycin C; Hormones such as testosterone and prednisolone; Antidepressants such as haloperidol and diazepam; Antibacterial chemotherapeutic agents such as ciprofloxacin; And other anesthetics.

In order to physically encapsulate such poorly soluble drugs in oil-in-water microemulsions, methods such as stirring, heating, and ultrasonic irradiation may be used alone or in combination. In addition, if an excess of drug is used, the method includes filtration to remove the undissolved excess of poorly soluble drug.

As described above, in the solubilization method of the poorly soluble drug of the present invention, since the poorly soluble or insoluble drug is enclosed in an oil-in-water type microemulsion containing a certain composition of oil components and a polyoxyethylene-based nonionic surfactant, conventional micelles It shows a higher degree of solubilization than a solution, has excellent properties of being able to directly flow out of blood vessels in the size of a microemulsion, and can be used to target drugs in a composition containing an oil component during formulation.

Hereinafter, the present invention will be described in detail with reference to Examples, as follows. However, the present invention is not limited to Examples.

Examples 1-18

The oil and water surfactants and water phases were mixed and stirred at 70 ° C. for 5 minutes with the compositions and contents shown in Table 1 below to prepare oil-in-water microemulsions.

Examples 19-20

The oil and water surfactants and the water phase were mixed with the compositions and contents shown in Table 1 and ultrasonically dispersed for 5 minutes to prepare an oil-in-water microemulsion.

Comparative Examples 1 to 3

The micelle solution was prepared in the same manner as in Example 1 using polyoxyethylene (10) oleyl ether to have a concentration having the content shown in Table 1.

( weight% ) division Yu Sang Surfactants Awards Soybean oil olive oil Isopropyl myristate POE ^a PCE ^b Purified water Example One 2.0 10 88 2 2.0 15 83 3 2.0 20 78 4 4.0 10 86 5 4.0 15 81 6 4.0 20 76 7 2.0 10 88 8 2.0 15 83 9 2.0 20 78 10 4.0 10 86 11 4.0 15 81 12 4.0 20 76 13 2.0 10 88 14 2.0 15 83 15 2.0 20 78 16 4.0 10 86 17 4.0 15 81 18 4.0 20 76 19 2.0 15 83 20 2.0 20 78 Comparative example One 10 90 2 15 85 3 20 80

A: Polyoxyethylene (10) oleyl ether

b: polyoxyethylene (10) cetyl ether

Experimental Example 1 Droplet Size Measurement

The droplet size distribution of the oil-in-water microemulsion of the present invention and the conventional micelle solution was measured by a dynamic light scattering method using a light scattering apparatus. He-Ne laser was used as the light source, and the wavelength was selected as 632.8 nm of red, which is the main wavelength of the light source, and the scattering angle is the least affected by the shaking of light or dust in the sample. The temperature was set to 90 ° and the measurement temperature was kept constant at 25 ° C. The results are shown in the following Table 2, FIG. 1 and FIG.

Figure 1 (a) to (e) shows the droplet size distribution of the oil-in-water microemulsion of the present invention obtained in each of Examples 1, 2, 3, 5 and 6 in the conventional micelle solution through a comparative example Compared to the measured value of FIG. 2 showing the droplet size distribution, the droplet size is smaller.

division Droplet size distribution (nm) ^* Droplet Average Size (nm) ^* Example One 10 to 15 13.1 ± 0.24 2 8 to 15 11.3 ± 0.29 3 9 to 13 11.2 ± 0.52 5 12 to 20 14.1 ± 0.16 6 10 to 16 13.1 ± 0.13 Comparative example One 14 to 26 18.6 ± 0.26 2 14-25 18.7 ± 0.55 3 14-25 19.1 ± 0.29

Note: Results are expressed as mean ± standard deviation.

Experimental Example 2: Solubility Degree Measurement

In order to measure the solubility of the oil-in-water microemulsion of the present invention and the conventional micelle solution, it was measured by using an excess amount of indomethacin. That is, 10 ml of each sample was placed in a 30 ml vial, and then a constant amount (20 mg) of indomethacin was added to the reciprocating shaker at 25 ° C. and 150 rpm for 8 days to reach equilibrium. To remove unsolubilized indomethacin, centrifuged at 5,000 rpm for 1 hour at 25 ° C. and filtered with a 0.22 μm Millipore filter. The filtrate was appropriately diluted with secondary distilled water, and the concentration of indomethacin was determined by high pressure liquid chromatography (HPLC) to calculate the degree of solubilization. As a result, it is shown in Figures 3 and 4.

3 and 4 show that the solubility of insoluble methasin, a poorly soluble drug, is increased by using the microemulsion system in the present invention as compared with the solubility of the micelle solution in the comparative example.

Experimental Example 3

The droplet size distribution of the oil-in-water type microemulsion in which indomethacin was solubilized was measured by dynamic light scattering. The amount, solubilization degree and droplet size distribution of indomethacin added to the oil-in-water microemulsion made from soybean oil are shown in Table 3 below.

Oil-in-water microemulsion Average droplet size (nm) ^a Indomethacin added concentration (mg / ml) Encapsulation amount (mg / ml) Droplet size distribution ^b (nm) Average droplet size ^b (nm) ^a Rate Mean Square (× 10 ⁴ ) Example 2 11.3 ± 0.29 1.0 0.781 8 to 15 11.2 ± 0.22 10.7 5.0 2.371 9-14 11.5 ± 0.15 9.02 20.0 2.976 9-16 12.1 ± 0.24 18.6 Example 5 14.1 ± 0.16 1.0 0.772 11-19 15.0 ± 0.09 5.78 5.0 2.348 11-18 14.8 ± 0.21 9.62 20.0 3.466 9-24 16.0 ± 0.11 7.54

Note: The results are expressed as mean ± standard deviation.

b: Measurement result after solubilizing indomethacin in microemulsion.

Experimental Example 4

In order to measure the stability of the oil-in-water microemulsion according to the present invention, after being sealed and stored for 3 months at room temperature, both were transparent and fluid when visually observed. The particle size measurement results of the microemulsion using olive and polyoxyethylene (10) oleyl ether are shown in Table 4 below.

Oil-in-water microemulsion Droplet size distribution (nm) Average droplet size (nm) ^* Rate Mean Square (× 10 ⁴ ) Example 7 8 to 20 13.5 ± 0.27 16.6 Example 8 8-19 12.5 ± 0.33 1.43 Example 9 7-13 10.1 ± 0.25 14.7 Example 11 11-19 14.4 ± 0.24 9.95 Example 12 10-18 13.0 ± 0.20 7.91

Note: Results are expressed as mean ± standard deviation.

As can be seen from the results of the above experimental example, the droplet size distribution of the microemulsion system used to solubilize the poorly soluble drug used in the present invention has a small value and shows a good safety state. The application of the system to solubilization of certain drugs has shown improved solubility when using conventional micelle solutions.

Claims (7)

A method for solubilizing a poorly soluble drug, wherein the poorly soluble drug is solubilized in an oil-in-water type microemulsion comprising an oil component and a polyoxyethylene-based nonionic surfactant. The oil-in-water microemulsion of claim 1, wherein the oil-in-water microemulsion contains 1.0 to 10.0 wt% of an oil component, 2.0 to 30.0 wt% of a polyoxyethylene-based surfactant, and 40.0 to 93.0 wt% of purified water or a buffer solution. Method of solubilization of the drug. The method of claim 1, wherein the oil is vegetable oil is soybean oil, olive oil, castor oil, mineral oil, corn oil, peanut oil, isopropyl myristate solubilizing method of poorly soluble drugs, characterized in that used in the form of one . The method of claim 1 or 2, wherein the polyoxyethylene-based nonionic surfactant is poorly soluble, characterized in that at least one selected from polyoxyethylene higher fatty acid ester and polyoxyethylene higher fatty alcohol ether is used. Method of solubilization of the drug. The method of claim 4, wherein the polyoxyethylene-based nonionic surfactant is poorly soluble, characterized in that at least one selected from polyoxyethylene (10) oleyl ether and polyoxyethylene (10) cetyl ether is used. Method of solubilization of the drug. The method of claim 1, wherein the poorly water-soluble drug is biphenyldimethylcarboxylate, cyclosporine, ibuprofen, indomethacin, pyricampam, paclitaxel, docetaxel, campotesin, etoposide, 6-mercaptopril, Poorly soluble, characterized by the use of fluorouracil, adriamycin, teniposide, etoposide, amphotericin B, daunomycin, methotrexate, mitomycin C, testosterone, prednisolone, haloperidol, diazepam, ciprofloxacin and anesthetics Method of solubilization of the drug. The method for solubilizing poorly soluble drugs according to claim 1, wherein a method such as stirring, heating, or ultrasonic irradiation is used alone or in combination to physically enclose the poorly soluble drug in the oil-in-water microemulsion solution.