JP4734910B2 - Solubilizer composition for poorly water-soluble drugs - Google Patents

Description

  The present invention relates to a composition for solubilizing a poorly water-soluble drug and a method for preparing a solubilized solution using the composition.

  When used as an injection, a poorly water-soluble drug requires a large amount of solubilizer and solubilizing agent, resulting in a viscous solution, and a dilute solution causes drug precipitation. Moreover, when it is used as an oral preparation such as a tablet or a capsule, there are problems such as low bioavailability due to low intestinal absorption. Also in new drug development, it is often a very serious problem if it is poorly water-soluble. In particular, most of the new drug candidates such as antineoplastic agents, immunosuppressive agents, antibiotics, antifungal agents, antihyperlipidemic agents, and anti-inflammatory agents are poorly water-soluble and have sufficient pharmacological activity. However, since it cannot be solubilized, various tests such as a toxicity test cannot be performed, and it is often the case that pending or dropout occurs during development.

Conventionally, methods such as solubilization with inclusion compounds such as hydrophilic surfactants and cyclodextrins, and emulsification using vegetable oil and lecithin have been used to apply poorly water-soluble drugs to pharmaceuticals. However, since the former uses a large amount of solubilizer, it cannot be said that the usability as a liquid agent such as an injection is good because the viscosity becomes high and the stability of the solubilized state is low. The latter emulsion has various disadvantages such as thermodynamic instability and often phase separation or the like.
Therefore, recently, solubilization using a thermodynamically stable microemulsion has been studied.
Many of the aforementioned drugs are used in the form of injectable drugs. In addition to solubilizing poorly water-soluble drugs, the stability of the solubilized state, as well as the oxidative stability of the main drug, has been an important issue. .

For example, in Patent Document 1, a microemulsion or a concentrate thereof is prepared using a glycerin monofatty acid ester and / or propylene glycol monofatty acid ester and a surfactant for a poorly water-soluble tricyclic compound. As a specific example, a microemulsion containing a tricyclic compound is prepared using corn oil, glyceryl monooleate, propylene glycol dicaprylate, and polysorbate 80.
However, the solubilizing effect of the compositions described in these patent documents is only for a specific drug, and the solubilizing power for other poorly water-soluble drugs is not sufficient.

In Patent Document 2, a microemulsion or a concentrate thereof is prepared using omega-3 fatty acid oil. As a specific example, a microemulsion pre-concentrate and a microemulsion are prepared using omega-3 fatty acid ethyl ester, polysorbate 80, and PEG-8 caprylic / capric glyceride (trade name Labrasol).
However, when the composition contains a large amount of hydrophilic surfactant, it is relatively easy to form a microemulsion. There is a problem of end up.

Furthermore, in Patent Document 3, various poorly water-soluble drugs are solubilized by using a composition containing a carrier containing a triglyceride and at least two surfactants, at least one of which is hydrophilic. . As a specific example, solubilization is performed using corn oil, polyethylene glycol 400 monooleate, and polysorbate 80.
However, although the composition has a high ratio of the hydrophilic surfactant, when it is used as an aqueous solution, it tends to be in an unstable emulsified state and has a strong tendency to phase-separate in a short time, and the stability is not sufficient.
That is, a composition that can solubilize various poorly water-soluble drugs without decreasing the activity of the main drug and has high stability has not been obtained so far.

WO01 / 077652 JP 2001-525363 A Special table 2003-503440 gazette

  The solubilizer composition of the present invention has a high solubilizing power regardless of the structure of the poorly water-soluble drug, and by using this composition, a highly stable solubilized liquid can be obtained, and further, oxidation degradation Thus, it is possible to obtain a solubilized solution that suppresses the decrease in the activity of the active ingredient due to.

That is, the present invention is as follows.
(1) (a) Triglyceride of fatty acid having 6 to 12 carbon atoms, (b) polyoxyethylene sorbitan fatty acid ester, (c) polyethylene glycol having an average molecular weight of 150 to 650, and (a) to (c) total of three components (A) 2 to 22% by weight, (b) 40 to 85% by weight, (c) 5 to 50% by weight, and (b) / (a) ≧ 7/3 (weight) Ratio) and the organic solvent solution of the poorly water-soluble drug are mixed, and then the organic solvent is removed and water is added .
(2) (b) The preparation method of the said poorly water-soluble chemical | medical agent aqueous solution whose polyoxyethylene sorbitan fatty acid ester is ester which consists of a C16-C18 fatty acid, and the average added mole number of an oxyethylene group is 20.

  The solubilizer composition of the present invention is a composition having a high solubilizing power with respect to various poorly water-soluble drugs, a high stability of the solubilized solution, and further suppressing a decrease in activity due to oxidative deterioration of the active ingredient Obtainable.

  Hereinafter, the present invention will be described in more detail. In the present invention, the poorly water-soluble drug is one having a solubility in ion-exchanged water at 20 ° C. of 10 mg / mL or less. Among them, the use of the present solubilizer composition is particularly preferable for drugs of 1 mg / mL or less, more preferably 0.1 mg / mL or less.

  Examples of poorly water-soluble drugs include anti-inflammatory and / or antipyretic / analgesic drugs (NSAIDs) such as acemetacin, indomethacin, diflunisal, ibuprofen, ketoprofen, mefenamic acid, naproxen, piroxicam, aspirin, fluorometholone, dexamethasone, hydrocortisone, Steroidal anti-inflammatory drugs such as prednisolone and betamethasone, medroxyprogesterone acetate, methotrexate, paclitaxel, mercaptopurine, mitomycin C, tamoxifen citrate, cisplatin, docetaxel hydrate, etc., cyclosporin A, tacrolimus water Immunosuppressants such as Japanese products, antibiotics such as enoxacin and norfloxacin, antifungal agents such as itraconazole and griseofulvin, and anticancer agents such as acyclovir Antihyperlipidemic drugs such as illus, clofibrate, probucol, simvastatin, etc., dipyridamole, nifedipine, pindolol, prazosin hydrochloride, reserpine, verapamil hydrochloride, atenolol, etc., antihypertensive and / or angina treatment, digitoxin, digoxin Antipsychotics such as diazepam, nitrazepam, haloperidol, droperidol, sulpiride, triazolam, etc., antiepileptic drugs such as phenytoin, phenobarbital, etc., clemastine fumarate, terfenadine, cyproheptadine hydrochloride, Antihistamines such as cimetidine, famotidine, omeprazole, lansoprazole, oxesasein, sucralfate, gefarnate, rebamipide, metoclopramide, etc. Antiulcer drugs, retinol palmitate, riboflavin butyrate, pyridoxal phosphate, mecobalamin, folic acid, tocopherol acetate, phytonadione, menatetrenone, vitamins such as furosemide, indapamide, spironolactone, bronchial asthma such as theophylline, tranilast, etc. Antitussives and expectorants such as bromhexine hydrochloride, hormonal agents such as chlormadinone acetate, danazol and methylprednisolone, gout treatments such as benzbromarone and allopurinol, antidiabetic agents such as tolbutamide, Parkinson's disease such as levodopa Therapeutic drugs and the like.

  Component (a) in the present invention is a triglyceride of a fatty acid having 6 to 12 carbon atoms. Specific examples of these compounds include glyceryl tricaproate, glyceryl tricaprylate, glyceryl tricaprate, glyceryl tri (2-ethylhexanoate), glyceryl triundecanoate, glyceryl trilaurate and the like. The acyl group of triglyceride may be one type or a mixture of two or more types. Preferably, the triglyceride of a C8-C10 fatty acid whose peroxide value is 1.0 meq / kg or less is mentioned.

  Component (b) in the present invention is a polyoxyethylene sorbitan fatty acid ester, and specific compounds include polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (4) sorbitan monolaurate ( Polysorbate 21), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), polyoxyethylene (4) sorbitan monostearate (polysorbate 61), poly Oxyethylene (20) sorbitan tristearate (polysorbate 65), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), polyoxyethylene (5) sorbitan monoolee (Polysorbate 81), polyoxyethylene (20) sorbitan trioleate (polysorbate 85), polyoxyethylene (20) sorbitan monoisostearate (polysorbate 120) and the like. And polysorbate 40, polysorbate 60, and polysorbate 80, and more preferably polysorbate 80. More specifically, polysorbate 80 is exemplified.

Component (c) in the present invention is polyethylene glycol having an average molecular weight of 150 to 650.
Specific compounds of component (c) include macrogol 200 (polyethylene glycol having an average molecular weight of 200), macrogol 300 (polyethylene glycol having an average molecular weight of 300), macrogol 400 (polyethylene glycol having an average molecular weight of 400), macrogol. 600 (polyethylene glycol having an average molecular weight of 600), and the like. Preferably, the macrogol 200, 300, 400, 600 in which the combined content of ethylene glycol and diethylene glycol satisfies the following formula is more preferable. Macrogol 200 having a combined content of ethylene glycol and diethylene glycol of 200 ppm or less, Macrogol 30 having a combined content of ethylene glycol and diethylene glycol of 150 ppm or less Content in conjunction with ethylene glycol and diethylene glycol are exemplified the following macrogol 400 100 ppm. Examples of commercially available products include SUNBRIGHT DKH-02HB, SUNBRIGHT DKH-03HB, and SUNBRIGHT DKH-04HB manufactured by NOF Corporation. (C) By using polyethylene glycol having a low content of ethylene glycol and diethylene glycol as a component, in addition to solubilizing power and stability, the safety is higher, and for example, an optimal formulation as an injection such as intravenous injection Become.

In the formula, X is an average molecular weight of polyethylene glycol.
The composition of the present invention comprises (a) triglycerides of fatty acids having 6 to 12 carbon atoms, (b) polyoxyethylene sorbitan fatty acid esters, (c) polyethylene glycol having an average molecular weight of 150 to 650, (a) to (c) 3 (A) 2 to 22 wt%, (b) 40 to 85 wt%, (c) 5 to 50 wt%, preferably (a) 3 to 21 wt%, b) 45 to 80 wt%, (c) 8 to 45 wt%, more preferably (a) 5 to 20 wt%, (b) 50 to 75 wt%, (c) 10 to 40 wt%, It is a poorly water-soluble solubilizer composition for drugs that satisfies (b) / (a) ≧ 7/3 (weight ratio).

  Regarding the composition of the solubilizer composition according to the present invention, even if the component (b) and the component (c) are within the scope of the present invention, if the component (a) is not contained or is lower than 2% by weight, Since the central micelle core (oil phase) holding the drug is small, the amount of solubilization is small, or even if solubilized, the drug often precipitates in a short period of time. On the contrary, when the component (a) is higher than 22% by weight, the ratio of the component (b) to the component (a) decreases, so that the particle size of the micelle formed increases, and the thermodynamically unstable emulsion state Become.

Further, even if the component (a) and the component (c) are within the scope of the present invention, the solubilizer is relatively insufficient when the component (b) is lower than 40% by weight, and the hydrophilic component is higher than 85% by weight. Since it is almost the same as the solubilization of the surfactant alone, the absolute amount of the surfactant necessary for solubilization increases and the viscosity of the solubilized liquid increases, so that it can be used as a liquid agent such as an injection. Deteriorate.
The solubilizer composition of the present invention may contain the components (a), (b), and (c) in the weight ratio as described above, and the range does not hinder the effect of the present invention if this weight ratio is satisfied. Other components may be included. The solubilizer composition of the present invention is preferably composed of only the components (a), (b) and (c).

  Moreover, the peroxide which causes the activity fall of the poorly water-soluble chemical | medical agent of an active ingredient can be reduced by using a triglyceride of a C6-C12 fatty acid as (a) oil-based component. That is, the solubilizer composition containing the poorly water-soluble drug can be stored for a long time.

  Further, by using the solubilizer composition according to the present invention, a highly stable solubilized liquid can be obtained. As the most efficient solubilizing liquid preparation method, (i) the solubilizing agent composition is prepared by adding (ii) an organic solvent solution of a poorly water-soluble drug to (i) :( ii) = 2: 1 to 1:10. (W / w) The mixture was added and mixed thoroughly to make it uniform, and then the organic solvent was removed by a method such as evaporation, and the remaining (iii) drug-solubilizer composition complex (iv ) A method of solubilizing water by adding (iii) :( iv) = 1: 3 to 1:20 (w / w). The organic solvent used for the preparation is preferably a volatile organic solvent such as methanol, ethanol, isopropanol, acetonitrile, acetone, chloroform, or dichloromethane, and the water used for dissolution is preferably water for injection. Moreover, you may further dilute the obtained solubilization liquid with water as needed. Further, the temperature and time of evaporation may be set according to the physical properties of the drug.

  The concentration range of the poorly water-soluble drug suitable for the composition described in the present invention is 5 to 10,000 times, preferably 10 to 5000 times the solubility of each drug in ion-exchanged water at 20 ° C. as the final concentration. More preferably, it is 20 to 2000 times.

Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples.
Table 1 shows the product names and chemical names of the compounds used in the production of the compositions described in the Examples and Comparative Examples.

* 1 Content of both SUNBRIGHT DKH-04HB (manufactured by NOF Corporation) and ethylene glycol and diethylene glycol: 13 [ppm]
* 2 Labrasol is the trade name of caprylocaproyl macrogol-8 glyceride, one of the caprylocaproyl macrogolglycerides listed in the European Pharmacopoeia.
Table 2 shows names and abbreviations of poorly water-soluble drugs described in Examples and Comparative Examples.

The composition of the solubilizer composition is shown in Table 3 for the examples below.
[Examples 1 to 4]

The composition of Example 1 was prepared by accurately measuring the components (a) to (c) and stirring and mixing them while heating to 50 ° C. The compositions of Examples 2 to 4 were prepared in the same manner. For oily components, the peroxide value was measured according to the standard fat test method 2.4.12-86.
The composition of the formulation is shown in Table 4 below for the comparative examples.
[Comparative Examples 1-7]

  The composition of Comparative Example 1 was prepared by accurately weighing each composition component and thoroughly stirring and mixing while heating to about 50 ° C. The compositions of Comparative Examples 2 to 7 were prepared in the same manner. For each oil component, the peroxide value was measured according to the standard fat test method 2.4.12-86.

  Table 6 shows the results of preparing solubilized solutions of poorly water-soluble drugs for the compositions of Examples 1 to 4 and evaluating the solubilizing ability and the stability of the solubilized solutions. The drug concentration of the final lysate was 2.5 mg / mL IND, 7.5 mg / mL CLF, 2.5 mg / mL NFD, 5.0 mg / mL PRB, 1.0 mg / mL PTX. These are concentrations of 5 to 1000 times or more with respect to the solubility of each drug in ion-exchanged water at 20 ° C., and generally sufficiently exceed the clinical use concentration as intravenous injection.

<Preparation method>
10 mg / mL IND, 30 mg / mL CLF, 10 mg / mL NFD, 20 mg / mL PRB, 4 mg / mL PTX solution was prepared using volatile organic solvents such as ethanol and acetonitrile. To 100 mg of the composition of Example 1, 250 μL of each chemical solution was added and mixed well, and dried under reduced pressure at 60 ° C. for 1 hour. A solubilized solution was obtained by gradually adding 900 μL of water for injection to the obtained composition while stirring to make it uniform. The compositions of Examples 2-3 were prepared in the same manner.
<Evaluation method>
The degree of solubilization of each sample was scored by appearance evaluation. For each composition, the solubilization scores immediately after preparation and 7 days after room temperature were averaged, and the change rate of the solubilization degree was calculated.

  Regarding the compositions of Comparative Examples 1 to 7, the solubilization degree was evaluated in the same manner as in the Examples. The results are shown in Table 7.

  For Example 1 and Comparative Example 1, the peroxide value (POV; meq / kg) immediately after preparation and after storage at 40 ° C. for 1 week was measured, and the oxidative stability of the preparations was compared. The results are shown in Table 8.

<Test method>
Using 3 g of the composition of Example 1 after preparation, the peroxide value was measured according to the standard fat test method 2.4.12-86. In addition, 3.5 g of the same composition was weighed into a 4 cc glass container, sealed, stored in a thermostatic bath at 40 ° C., and after 1 week, the peroxide value was similarly measured using 3 g of the sample. The composition of Comparative Example 1 was also tested in the same manner.

  As is clear from these results, the compositions described in the Examples can solubilize all five types of poorly water-soluble drugs having completely different chemical structures, and the solubilized solution is completely preserved after 7 days of preparation at room temperature. I was not able to admit. On the other hand, some of the compositions described in the comparative examples can be temporarily solubilized in some cases, but at least after 7 days at room temperature, precipitation of the drug or phase separation of the emulsified phase with respect to most solutions. Was recognized. In addition, the compositions described in the examples maintained a low POV even under storage conditions at 40 ° C. for one week, but the compositions described in the comparative examples had the initial POV as the compositions described in the examples. The POV was 10 times or more under the storage condition at 40 ° C. for 1 week. This result shows how the compositions described in the Examples have high oxidative stability and prevent oxidative degradation of the drug. That is, the solubilizer composition according to the present invention is characterized by being excellent in all of solubilizing power, solubilized state stability, and oxidation stability.

Claims (2)

(A) Triglycerides of fatty acids having 6 to 12 carbon atoms, (b) polyoxyethylene sorbitan fatty acid ester, (c) polyethylene glycol having an average molecular weight of 150 to 650, and (a) to (c) the total amount of the three components is 100. (B) / (a) ≧ 7/3 (weight ratio) containing (a) 2 to 22% by weight, (b) 40 to 85% by weight, and (c) 5 to 50% by weight, respectively. A method for preparing a poorly water-soluble drug aqueous solution, which comprises mixing a solubilizer composition for a poorly water-soluble drug and an organic solvent solution of the poorly water-soluble drug, and then removing the organic solvent and adding water . (B) The method for preparing a poorly water-soluble drug aqueous solution according to claim 1, wherein the polyoxyethylene sorbitan fatty acid ester is an ester comprising a fatty acid having 16 to 18 carbon atoms, and the average added mole number of oxyethylene groups is 20. .