KR100386397B1 - Transparent propofol injection formulation - Google Patents

Abstract

The present invention relates to an aqueous injection solution containing propofol, which is used as an anesthetic. , An aqueous solution prepared by adding one or two selected from 12-hydroxysteraic acid polyglycol esters and injecting distilled water or phosphate buffer solution. The solution is transparent and can be easily inspected for the presence of this substance. The particle size is small enough to allow bacterial filtration, so that sterilization process can be omitted in the product manufacturing process. If necessary, polyvinylpyrrolidone is added to increase the viscosity to delay the distribution of propofol in the blood. It relates to an aqueous solution of injection that can be extended.

Description

TRANSPARENT PROPOFOL INJECTION FORMULATION

The present invention relates to an aqueous solution composed of transparent and fine particles containing propofol, and more particularly, to a transparent propofol injection in micelle or microemulsion form prepared by adding a hydrophilic surfactant, a viscosity enhancer and / or vegetable oil to a propofol component. will be.

Propofol has a chemical name of 2,6-diisopropylphenol, which is poorly soluble in water, and has been used as a method of formulating it as an intravenous injection, by dissolving propofol in vegetable oil in a milky milky emulsion state. However, such a preparation is a milky white opaque solution that can not be visually detected whether there is a foreign substance in the injection, and if the foreign substance is injected into the body when administered intravenously, there is a problem such as causing blood circulation disorders. Thus, there has been a desire for a transparent formulation of propofol conventionally.

In addition, the conventional propofol product is inconvenient to adjust the anesthesia time after intravenous injection, such as the need to inject the anesthetic drug by injecting it again when performing long-term surgery, so that the aqueous solution of propofol is transparent and can be maintained for a long time in the blood concentration. A composition that can be desired is desired.

The present inventors have diligently studied to solve the above problems, and when a hydrophilic surfactant, vegetable oil and a viscosity enhancer are added to the propofol component to prepare an injection solution in micelle or microemulsion form, the prepared injection agent is transparent and the particles The present invention has been completed by discovering that the blood concentration can be maintained for a long time while being extremely small.

Furthermore, the composition has a particle size of 100 nm or less and transparent, and it is easy to visually check for the presence of foreign substances, and also because it can filter bacteria, sterilization can be carried out, so that the sterilization process can be omitted. By increasing the viscosity of the present invention, it was possible to maintain blood concentration for a long time, thereby completing the present invention.

1 is a blood concentration graph of the composition 6

2 is a blood concentration graph of the composition 7

3 is a blood concentration graph of the composition 9

4 is a graph of blood concentration of composition 10. FIG. 5 is polyvinyl when formulated with 1 g propofol, 4 g ethyl oleate, 17 g solutol, 2 g polyvinylpyrrolidone, and 76 g pH 7.4 buffer (referred to as E7 composition). Pyrrolidone is a reference diagram that shows the same blood concentration as the control drug dipriban combined.

Hereinafter, the present invention will be described in detail. The present invention is to prepare an aqueous solution for injection in the form of micelles or microemulsions by adding a hydrophilic surfactant or a surfactant, vegetable oil and a viscosity enhancer to the propofol active ingredient used as an anesthetic. Here, as the hydrophilic compounding agent, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil, poloxamers, solutol, and the like can be cited. The vegetable oil may include oleic acid esters, soybean oil, etc. Of these, ethyl oleate is preferable, which is suitable as an oil because it has better microemulsion formation and a smaller particle size than soybean oil.

The light transmittance and particle size of the transparent propofol injection of the present invention are as shown in Examples and Table 1 below, the light transmittance is 85% or more, except for the compositions 16 and 17, the particle size is about 92 ~ 16nm You can check it. As such, the propofol injection of the present invention, which has a light transmittance and a particle size, is easy to formulate by visually inspecting foreign substances that may be present in the injection compared to a conventional product (dipriban) in which emulsion and light transmittance cannot be measured. In addition, as shown in Figs. 1 and 2, the curves of the blood concentrations of the compositions 6 and 7 in which the oil concentration roll is 5% are higher than those of the known product (dipriban). It was high from 5 minutes. This is because the distribution and excretion rate is slower than known products, the anesthesia effect is slow and can be expected to last. In other words, since the bioequivalence is different from each other, the preparation of oil having reduced oil concentration to 4% and the concentration of surfactant to 17%, on the contrary, because the blood concentration curve is sharply lower than that of the known products, the rate of distribution to tissues is faster and more frequent. Risks may arise. Therefore, it is possible to exhibit the same bioavailability as the known product by adding a viscosity enhancer to slow the distribution rate of the blood concentration to show the blood concentration curve as the known product (Diprivan) (eg, propofol 1g, ethyl oleate 4g, 17 g of solutol, 2 g of polyvinylpyrrolidone, 76 g of pH 7.4 buffer (FIG. 5). Particularly, in the propofol injection of the present invention, a viscosity enhancer (e.g., polyvinylpyrrolidone) is formulated in the blood of the diprivan in use. As a formulation design for showing a distribution curve at the same speed as the concentration curve, when the amount of oil, for example, ethyl oleate, is 5%, the blood drug distribution curve is lost more slowly than the conventional product, Dipriban (Fig. 1 and 2) And when the concentration of oil is 5%, the amount of surfactant solutol is 20, 22%, so the formulation of reducing the amount of solutol to 17% and reducing the concentration of oil to 4% is relatively oil. This phenomenon is the blood distribution curve that is faster than when deep Livan being a reduced amount of the toll solution. In order to control this, a thickener, for example, a polyvinylpyrrolidone-containing agent is added at the same rate as the blood concentration curve of a known product (diprivan) (Fig. 5). Kollidon 17PF (BASF) is particularly preferred as a polymer used in intravenous injections. The injections of the present invention can be prepared by conventional methods in the art, and are expensive equipment such as conventional microfluidizers and high-speed homogenizers. Although it may be used, it is possible to manufacture by a simple operation without using expensive equipment in this way. Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.

Composition 1

1.0 g propofol, 0.5 g soybean oil, 7.5 g cremopol RH40 (polyoxy 40 hydrogenated caster oil) and 2.5 g of Tween-20 were stirred at 60 ° C. for 5 minutes, then distilled water was added and stirred again for 5 minutes. Then, the mixture was cooled with gentle stirring to prepare 100 g of a transparent microemulsion solution.

Composition 2

1.0 g of propofol, 7.5 g of Cremopol RH40 and 2.5 g of Tween-20 were stirred at 60 ° C. for 5 minutes, then distilled water was added and stirred for another 5 minutes. Then, the mixture was cooled with gentle stirring to prepare 100 g of a clear micelle solution.

Composition 3

A transparent microemulsion solution 100g was prepared in the same manner as in Composition 1 except that 7.5g of Cremopol EL (polyoxy 35 castor oil) was used instead of 7.5g of Cremopol RH40.

Composition 4

100 g of a clear micelle solution was prepared in the same manner as in Composition 2, except that 7.5 g of Cremopol EL was used instead of 7.5 g of Cremopol RH40.

Composition 5

1 g of propofol was added to 5 g of ethyl oleate, and stirred for about 5 minutes at about 50 ° C to dissolve. 19 g of solutol was added to the solution and stirred for 10 minutes. A pH 7.4 phosphate buffer solution was slowly added to the mixed solution, followed by stirring to prepare 100 g of a transparent microemulsion solution.

Composition 6

100 g of a microemulsion solution was prepared in the same manner as in Composition 5, except that 22 g of solutol was used instead of 19 g of solutol.

Composition 7

1 g of propofol, 5 g of ethyl oleate, 20 g of solutol, pH 7.4 phosphate buffer, and 2 g of polyvinylpyrrolidone were added to the transparent microemulsion solution, which was prepared in the same manner as in composition 5, while heating to 50 ° C., followed by stirring slowly. Cooling to room temperature while preparing a 100g of a micro emulsion solution.

Composition 8

100 g of a microemulsion was prepared in the same manner as in Composition 7 using 1 g propofol, 4 g ethyl oleate, 19 g solutol, 2 g polyvinylpyrrolidone, and pH 7.4 phosphate buffer.

Composition 9

100 g of a microemulsion was prepared in the same manner as in Composition 8, except that 17 g of solutol instead of 19 g of solutol was used.

Composition 10

100 g of a microemulsion was prepared in the same manner as in Composition 9, except that 4 g of polyvinylpyrrolidone was used instead of 2 g of polyvinylpyrrolidone.

Composition 11

1 g of propofol was added to 4 g of soybean oil, and stirred at 50 ° C. for 5 minutes to dissolve. To this solution was added 24 g of solutol and 6 g of PG and stirred for 10 minutes. 100 g of a transparent microemulsion was prepared by slowly adding pH 7.4 phosphate buffer solution to the mixed solution.

Composition 12

1.00 g of propofol was mixed with 2.00 g of Tween-20, and then 30.0 g of 20% poloxamer was added and stirred at room temperature. 2.25 g of glycerin was added to this solution, and distilled water was added while stirring to prepare 100 g of a transparent micelle aqueous solution.

Composition 13

100 g of a clear micelle aqueous solution was prepared in the same manner as in Composition 12, except that pH 7.4 phosphate buffer solution was used instead of distilled water.

Composition 14

100 g of a clear micelle solution was prepared in the same manner as in Composition 12, except that 25.0 g of 20% poloxamer was used instead of 30.0 g of 20% poloxamer.

Composition 15

Except for using a pH 7.4 phosphate buffer solution instead of distilled water was carried out in the same manner as in Composition 14 to prepare a clear micelle aqueous solution 100g.

Composition 16

Except for using 20% poloxamer 20.0g instead of 20% poloxamer 30.0 It was carried out in the same manner as in Composition 12 to prepare a clear micelle aqueous solution 100g.

Composition 17

Except for using a pH 7.4 phosphate buffer instead of distilled water was carried out in the same manner as in Composition 16 to prepare a clear micelle aqueous solution 100g.

Composition 18

1.00 g of propofol is mixed with 1.50 g of Tween-20, and then 30.0 g of 20% poloxamer is added and stirred at room temperature. 2.25 g of glycerin was added to this solution, and distilled water was added while stirring to prepare 100 g of a transparent micelle aqueous solution.

Composition 19

Except for using a pH 7.4 phosphate buffer solution instead of distilled water was carried out in the same manner as in Composition 18 to prepare a clear micelle aqueous solution 100g.

Composition 20

A transparent micelle aqueous solution 100g was prepared in the same manner as in Composition 18, except that 1.00g of Tween-20 was used instead of 1.50g of Tween-20.

Composition 21

100 g of a clear micelle aqueous solution was prepared in the same manner as in Composition 20, except that pH 7.4 phosphate buffer solution was used instead of distilled water.

Composition 22

100 g of a clear micelle solution was prepared in the same manner as in Composition 18, except that 0.50 g of Tween-20 was used instead of 1.50 g of Tween-20.

Composition 23

Except for using a pH 7.4 phosphate buffer solution instead of distilled water was carried out in the same manner as in the composition 22 to prepare a clear micelle aqueous solution 100g.

Composition 24

1.00 g of propofol was mixed with 2.00 g of Tween-20, and then 35.0 g of 20% poloxamer was added and stirred at room temperature. 2.25 g of glycerin was added to this solution, and distilled water was added while stirring to prepare 100 g of a clear micelle solution.

Composition 25

100 g of an aqueous solution of transparent micelles was prepared in the same manner as in Composition 24, except that pH 7.4 phosphate buffer was used instead of distilled water.

Composition 26

1.0 g of propofol, 7.0 g of Tween-80, 3.2 g of PG, and 3.2 g of poloxamer were stirred at 60 ° C. for 5 minutes, and then distilled water was added until the weight was 100 g, followed by further stirring for 5 minutes. Then, the mixture was slowly cooled to room temperature to prepare 100 g of a clear micelle solution.

Particle size measurement The results of particle size measurement under the following conditions are shown in Table 1.

Light source; He-Ne laser

wavelength; 632 nm

Scattering angle of light; 90 °

Temperature; 25 ℃

Measuring cell; 12 mm diameter

TABLE 1

Transmittance Measurement

The sample was diluted 100-fold with 5% glucose solution-physiological saline solution (1: 1) to measure transmittance using UV / VIS Spectrophotometer V550 at a wavelength of 540 nm, and the results are shown in Table 2.

TABLE 2

Blood concentration measurement

Rats were anesthetized with 70% urethane, and then intravenously dosed 20 mg / kg of composition 6, composition 7, composition 10, and placed a cannula in the left femoral vein, and 200 μl each sample was used to quantify blood drug concentration by HPLC. Blood collection times were taken every 1, 2, 4, 6, 8, 10, 15, 20, 30, 45, 60 minutes, and a known product, Dipriban, was used as a control sample. The test results are shown in FIGS. 1, 2, 3, and 4. As shown in the above experimental results, the phosphophore injection of the present invention has a particle size of about 16 to 92 nm, and the light transmittance excludes composition 16. And about 90% is very high, the blood concentration can be seen that high.

The composition is transparent and can be visually inspected for the presence of foreign substances with the naked eye, and the particles are extremely small and can be filtered with bacteria, so that the sterilization process can be omitted, and the propofol component can prevent decomposition by heat. Since vinylpyrrolidone is added, the viscosity is increased to delay the excretion rate, so that blood concentration can be maintained for a long time.

Claims (6)

A propofol injectable, wherein the propofol injectable comprises 0.5-5% by weight of propofol, 0.5-25% by weight of surfactant and 2-7% by weight of viscosity enhancer. 10. A clear propofol injection according to claim 1, further comprising vegetable oil. The transparent propofol injection of claim 1, wherein the viscosity enhancer is polyvinylpyrrolidone. The propofol injection according to claim 1, wherein the surfactant comprises one or two selected from the group consisting of cremopols, twins, solutols, and poloxamers. The propofol injection according to claim 2, wherein the vegetable oil is ethyl oleate. Propofol injections comprising 0.5-1% by weight of propofol, 15-20% by weight of tolutol, 4-5% by weight of ethyl oleate and 2-5% by weight of polyvinylpyrrolidone Intravenous propofol injection.