KR100993291B1 - Injectable compositions comprising propofol and methods for preparing the same - Google Patents

Abstract

A novel injectable composition containing propofol (2,6-diisopropylphenol) and a process for its preparation are provided. Novel injectable compositions containing propofol include propofol at a concentration of 1 to 2% weight / volume (% w / v), poloxamer 188 at a concentration of 6 to 15% weight / volume, and a macro of 0.2 to 1% weight / volume concentration. Bone 15 hydroxystearate and edetate from 0.0001% to 0.001% weight / volume concentration.

Propofol, Phloxamer 188, Macrogol 15 Hydroxystearate, Sterile Injection

Description

Composition for injection comprising propofol and method for preparing the same {Composition for injection including propofol and method of preparing the same}

The present invention relates to a novel injectable composition containing propofol and a process for the preparation thereof.

The present invention relates to a novel injectable composition containing propofol and a process for the preparation thereof.

Propofol (2,6-diisopropylphenol) is a drug that has a very rapid distribution and metabolism after administration as a general anesthetic. Due to the fast metabolism rate, it hardly accumulates in the body, so it is suitable for cases in which short anesthesia is required as well as long anesthesia. In addition, it is easy to control the depth of anesthesia when the anesthesia is maintained, the recovery from anesthesia is fast and the consciousness is clear at the time of recovery, and side effects such as nausea and vomiting are hardly seen.

Injectable compositions containing propofol show anaphylactoid reactions when Cremophor EL is used as a surfactant. In addition, in the case of using lipid components such as soybean oil and egg lecithin as solubilizing agents of the microemulsion, such lipid components may cause side effects such as hyperlipidemia and thrombosis when used in large amounts in long-term surgery. In addition, since lipid components cause the growth of microorganisms, careful handling of the formulation is required.

To overcome this drawback of oil-in-water emulsions, efforts have been made to develop formulations of solubilizing propofol in water using hydrophilic surfactants. In particular, there is a need for a composition for injection that is not only pharmaceutically stable to maintain safety and transparency even in large doses, but also to be sterilized under high pressure for sterilization of microorganisms.

The technical problem to be achieved by the present invention is to provide a composition for injection containing propofol which is safe even in large doses, is maintained regardless of temperature change during the storage period, and capable of autoclaving.

Another technical problem to be achieved by the present invention is to provide a method for producing such an injectable composition.

The technical objects of the present invention are not limited to the above-mentioned technical problems, and other technical subjects not mentioned can be clearly understood by those skilled in the art from the following description.

The present invention relates to a novel injectable composition containing propofol and a process for the preparation thereof.

Composition for injection according to an embodiment of the present invention for achieving the above technical problem is propofol of 1 to 2% weight / volume (% w / v) concentration, poloxamer 188, 0.2 of 6 to 15% weight / volume concentration Macrogol 15 hydroxystearate at a concentration of 1% by weight / volume and edetate at a concentration of 0.0001% to 0.001% weight / volume.

Method for preparing a composition for injection according to an embodiment of the present invention for achieving the above another technical problem is to dissolve poloxamer 188 of 6 to 15% by weight / volume concentration in purified water, 1 to 2% by weight / volume (% w / v) After adding propofol at a concentration, it is stirred and macrogol 15 hydrate to contain 0.2-1% weight / volume of macrogol 15 hydroxystearate and 0.0001% to 0.001% weight / volume of edetate at room temperature. Adding roxtearate and edetate, and adding a pH adjuster to adjust the pH to about 6.0-8.5.

Specific details of other embodiments are included in the detailed description.

The composition for injection containing propofol according to an embodiment of the present invention is safe even in large doses, maintains transparency during the storage period, and thermodynamically stable to enable high pressure steam sterilization. In addition, there is no change in transparency and particle size even when mixed with the sap or stored at high and low temperatures. Other, more specific effects of the present invention are included in the detailed description of the invention.

Advantages and features of the present invention and methods for achieving them will be apparent with reference to the embodiments described below in detail. However, the present invention is not limited to the embodiments disclosed below, but will be implemented in various forms, and only the present embodiments are intended to complete the disclosure of the present invention, and the general knowledge in the art to which the present invention pertains. It is provided to fully convey the scope of the invention to those skilled in the art, and the present invention is defined only by the scope of the claims.

Accordingly, well known techniques in some embodiments are not described in detail in order to avoid obscuring the present invention.

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. In this specification, the singular also includes the plural unless specifically stated otherwise in the phrase. As used in this specification, inclusions and / or comprisings are used in the sense that they do not exclude the presence or addition of one or more other elements, steps, other than the components mentioned.

Injectable compositions according to one embodiment of the invention are propofol at a concentration of 1 to 2% by weight / volume (% w / v), poloxamer 188 at a concentration of 6 to 15% by weight / volume, 0.2 to 1% by weight / volume Macrogol 15 hydroxystearate, 0.0001% to 0.001% weight / volume concentration of edetate, glycerin, sodium ascorbate and sodium hydroxide.

Microemulsions are a kind of emulsions, unlike emulsions, and may be a thermodynamically stable formulation consisting of fine particles having a size of 100 nm or less. Injectable composition according to an embodiment of the present invention is a transparent microemulsion having a particle size of less than 100nm, as will be described later, as well as sterile filtration as well as high pressure steam sterilization is possible. Since it is a transparent microemulsion, it is possible to check the presence of foreign matters with the naked eye, and it is easy to formulate and can prevent risks such as contamination of foreign matters.

Injectable compositions according to one embodiment of the present invention comprise propofol at a concentration of 1-2% weight / volume (% w / v).

Propofol (2,6-diisopropylphenol) is used for induction of general anesthesia, maintenance of general anesthesia, and sedation of critically ill patients in ventilation. Propofol is 1.5 to 2.5 mg / kg at the induction of general anesthesia, maintenance of clinical anesthesia blood concentration is 2-10 μg / ml and the actual dose may be 4-12 mg / hr / kg. The composition for injection according to an embodiment of the present invention is safe even when administered in large amounts such as 1 L per day.

Injectable compositions containing propofol may be pharmaceutically unstable due to reversible oxidation. Propofol exists in the form of a colorless monomer but is transformed into a dimer form by oxidation to form a yellow propofol dimer quinone (Free radical and drug oxidation prodructs in an intensive care unit sedative: Propofol with sulfite.Max T. Baker, Marc S. Gregerson, Sean M. Martin, Garry R. Buettner.Crit Care Med 2003, Vol. 31, No. 3, 787-792). This discoloration is reversible and occurs depending on the state of energy. Specifically, when the energy is high, that is, when light is applied, it is colorless and transparent, but the energy is low, that is, yellow in the dark, which is a reversible reaction.

Injectable compositions according to one embodiment of the present invention may include an edtate of 0.0001% to 0.001% weight / volume concentration to overcome pharmaceutical instability due to the reversible oxidation of propofol. Edetate means ethylenediaminetetraacetic acid (EDTA) and its derivatives, for example the disodium derivative is known as disodium edetate. Edetate may show the effect of inhibiting the growth of microorganisms depending on the concentration used, but the effect of inhibiting the growth of microorganisms does not appear in the concentration range of the edetate used in the composition for injection according to an embodiment of the present invention. In the case of the composition for injection according to an embodiment of the present invention within the range that does not exhibit the effect of inhibiting the growth of microorganisms, it may be used to overcome the instability of the formulation due to the reversible oxidation of propofol. In general, edetate as a chelating agent (chelating agent) can not only suppress the reaction caused by trace metals through chelating on the solution, but also remove the free ions of the solution to inhibit the oxidation reaction by the ions. As a result, edetate at 0.0001% to 0.001% weight / volume concentration, more specifically 0.0001 to 0.0008% weight / volume concentration, prevents yellowing of the composition comprising propofol and helps to maintain a colorless transparent formulation.

Injectable compositions according to one embodiment of the present invention include a Ploxamer 188 at a concentration of 6-15% by weight / volume as a surfactant. Fluxamers are generally nontoxic polymeric surfactants and are poly (a-oxyethylene-b-oxypropylene-a-oxyethylene) triblock copolymers. Their water-solubility is generally good, but the properties of individual poloxamers vary substantially. The pharmaceutical compatibility of the various phloxamers is well established, in particular P407 and P188 approved for parenteral administration. Among them, Ploxamer 188 is used for intravenous injection, and clinical trials have shown no side effects even at doses up to 2960 mg / kg per day (Safety of purified poloxamer 188 in sickle cell disease: Phase I study of a non- ionic surfactant in the management of acute chest syndrome. Samir K. Ballas, Beatrice Files, Lori Luchtman-Jones, Lennette Benjamin, Paul Swerdlow. Hemoglobin 2004, Vol. 28, No. 3, 85-102), an injection containing propofol It may be safe even when a large amount of the composition is used. Assuming a dose of up to 2960 mg / kg per day, the clinically acceptable concentration of floxamer 188 may be 15% weight / volume concentration. Fluxamer is a block copolymer composed of hydrophilic polyoxyethylene and hydrophobic polyoxypropylene, and the hydrophobic portion is enclosed inside and the water-soluble portion is hydrated with external water to form micelles.

Injectable compositions according to one embodiment of the present invention may preferably comprise Ploxamer 188 of at least 10 and up to 15% weight / volume concentration. Propofol can be dissolved even at the 6% weight / volume concentration of Ploxamer 188, but concentrations intended to maintain phase stability even when used in combination with fluids or other injections for clinical use are greater than 10% weight / volume concentrations, eg 10.1. % Weight / volume concentration. Fluxamer 188 below 15% weight / volume concentration is safe for clinical use.

Injectable compositions according to one embodiment of the present invention is a macrogol 15 hydroxystearate (solutol HS 15 ^T , BASF, Germany) of 0.2 to 1% weight / volume concentration, specifically 0.7 to 1% weight / volume concentration ). Macrogol 15 hydroxystearate also causes side effects such as cytotoxicity at high doses, but no side effects have been reported at low doses (LD50 rat, iv = 1.2 g / kg) and can be used as an adjuvant solubilizer. Macrogol 15 hydroxystearate at a concentration of 0.2 to 1% weight / volume can be used to ensure phase stability of the composition for injection according to an embodiment of the present invention. Injectable compositions containing 0.1% of macrogol 15 hydroxystearate may cause turbidity when the fluid is diluted. If only floxamer 188 is used as a solubilizer, the particle size may increase and re-turbidity may occur at low temperatures, but by using macrogol 15 hydroxystearate as a co-solubilizer with floxamer 188, temperature change Formulation stability for can be secured. When macrogol 15 hydroxystearate is used at a high dose in excess of 1% weight / volume concentration, stability is a problem, and turbidity may occur during autoclaving.

Injectable composition according to an embodiment of the present invention comprises a macrogol 15 hydroxystearate of 0.2 to 1% by weight / volume concentration and poloxamer 188 of 6 to 15% by weight / volume concentration, capable of high pressure steam sterilization Do. Sterile filtration through sterile operations or filters is not only a high probability of contamination during the manufacturing process, it is difficult to manufacture and costly. Therefore, it may be preferable to aseptically prepare the composition for injection by high pressure steam sterilization, but thermodynamically stable, there is no fear that the phase will not be broken and reclouded even through high pressure steam sterilization. The composition for injection according to an embodiment of the present invention may not be affected by the size or transparency of particles even under high pressure steam sterilization.

Injectable compositions according to an embodiment of the present invention may include an antioxidant. Antioxidants can be, for example, sodium ascorbate, ascorbic acid, sulfite compounds, cysteine, propyl gallate, thiodipropionic acid, monothioglycerol, and the like. Specifically, when sodium ascorbate is used as an antioxidant, the oxidation reaction of propofol may be inhibited to maintain the same properties as before autoclaving even after autoclaving. Sodium ascorbate may be used at 0.005% to 4.8%, more specifically at a weight / volume concentration of 0.005% to 0.1%.

Injectable compositions according to one embodiment of the present invention may be suitably formulated using a pH adjuster such as sodium hydroxide, if necessary, to a physiologically neutral pH, usually 6.0 to 8.5. The pH adjusting agent may be used, for example, but not limited to sodium hydroxide, citric acid, acetic acid, phosphoric acid, gluconic acid, ascorbic acid, succinic acid and the like.

Injectable compositions according to one embodiment of the present invention can be prepared to be isotonic with blood using an appropriate osmotic modifier. Osmotic modifiers may be, for example, but not limited to, glycerin, trehalose, glucose, fructose, sorbitol, mannitol, and the like.

The composition for injection according to an embodiment of the present invention does not have a physical change such as particle size and shape when mixed with other drugs, and thus may be mixed with other fluids or drugs during clinical use. In addition, stability can be maintained even at temperature changes, so that there is no change in particle size, properties, etc. in the temperature change range that may occur during distribution.

Hereinafter, the manufacturing method of the said composition for injection is demonstrated. Processes that can be formed according to processes well known to those of ordinary skill in the art upon description will be briefly described in order to avoid being ambiguously interpreted. In addition, description of each component will be omitted or briefly described in order to avoid duplication of description.

In the preparation method of the injectable composition according to an embodiment of the present invention, 6 to 15% weight / volume concentration of poloxamer 188 is dissolved in purified water, and propofol of 1 to 2% weight / volume (% w / v) concentration. After the addition, the mixture is stirred and macrogol 15 hydroxystearate and edetate are included at a room temperature to contain 0.2-1% weight / volume concentration of macrogol 15 hydroxystearate and 0.0001% to 0.001% weight / volume concentration of edetate. And adding a pH adjuster to adjust the pH to about 6.0-8.5.

The composition for injection according to the preparation method according to the embodiment of the present invention is in the form of a transparent microemulsion.

Specifically, poloxamer 188 at a concentration of 6 to 15% by weight / volume was dissolved in purified water, propofol at a concentration of 1 to 2% by weight / volume (% w / v) at about 60 to 70 ° C. was added, followed by stirring and room temperature. Macrogol 15 hydroxystearate and edetate may be added to include macrogol 15 hydroxystearate at a concentration of 0.2 to 1% weight / volume and edetate at a concentration of 0.0001% to 0.001% weight / volume. The reason why macrogol 15 hydroxystearate is added at room temperature is that cloudiness occurs when the macrogol 15 hydroxystearate is added at high temperature. After adjusting the pH to about 8 by adding a pH adjuster, the solution can be filtered and autoclaved. This is because, after autoclaving, the pH may drop by approximately one degree. As a result, the final pH after autoclaving can be adjusted to about 7. Even after high pressure steam sterilization, the composition for injection containing propofol can maintain its transparent properties.

The method for preparing an injectable composition according to an embodiment of the present invention may further include adding an antioxidant before adjusting the pH to about 6.0 to 8.5 by adding a pH adjusting agent.

The method for preparing a composition for injection according to an embodiment of the present invention may further include adding an osmotic modifier before adjusting the pH to about 6.0 to 8.5 by adding a pH adjuster.

In the preparation method of the injectable composition according to an embodiment of the present invention, the floxamer 188 may have a weight / volume concentration of 10 to 15% or less.

In the method of preparing the composition for injection according to an embodiment of the present invention, the macrogol 15 hydroxystearate may be 0.5 to 0.7% weight / volume concentration.

More detailed information about the present invention will be described through the following specific experimental examples, and details not described herein will be omitted because it can be inferred technically by those skilled in the art.

Example

≪ Example 1 >

Injectable compositions containing 10 mg of propofol per ml of microemulsion for propofol injection have the composition shown in Table 1 below. (100 ml production)

TABLE 1

ingredient mg / mL % w / v Propofol 10 One Poloxamer188 101 10.1 Macrogol 15 hydroxystearate 7 0.7 glycerin 10 One Sodium ascorbate 0.1 0.01 Disodium edetate 0.008 0.0008 Sodium hydroxide Quantity Quantity Distilled water Quantity Quantity

Using the above components, preparation of the microemulsion for propofol injection is carried out as follows. All process steps are performed under nitrogen purging and the weight is the weight at the final volume. After dissolving 10 g of poloxamer 188 in 80 ml of distilled water, 1 g of propofol is added at 60 to 70 ° C. and stirred for about 2 hours. After dissolving propofol, it is left at room temperature and then 0.7 g of macrogol 15 hydroxystearate is added. Thereafter, 1 g of glycerin, 0.01 g of sodium ascorbate, and 0.0008 g of disodium edetate are added to dissolve it. After adjusting to pH 8 with sodium hydroxide, nitrogen-filled and filtered, and autoclave sterilization (SH-29A, manufacturer Human Science) at 121 ° C. for 20 minutes to adjust the final pH to 7.

<Example 2>

A propofol injection having the same composition as in Example 1 (see Table 2) except that it contained 15% w / v of poloxamer 188 was prepared in the same manner as in Example 1.

TABLE 2

ingredient mg / mL % w / v Propofol 10 One Poloxamer188 150 15 Macrogol 15 hydroxystearate 7 0.7 glycerin 10 One Sodium ascorbate 0.1 0.01 Disodium edetate 0.008 0.0008 Sodium hydroxide Quantity Quantity Distilled water Quantity Quantity

Example 3

A propofol injection having the same composition as in Example 1 (see Table 3) was prepared by the same process as in Example 1, except that it contained 0.5% w / v of macrogol 15 hydroxystearate.

[Table 3]

ingredient mg / mL % w / v Propofol 10 One Poloxamer188 101 10.1 Macrogol 15 hydroxystearate 5 0.5 glycerin 10 One Sodium ascorbate 0.1 0.01 Disodium edetate 0.008 0.0008 Sodium hydroxide Quantity Quantity Distilled water Quantity Quantity

Example 4

A propofol injection having the same composition as in Example 1 (see Table 4) was prepared by the same process as in Example 1 except that it contained 0.2% w / v of macrogol 15 hydroxystearate.

[Table 4]

ingredient mg / mL % w / v Propofol 10 One Poloxamer188 101 10.1 Macrogol 15 hydroxystearate 2 0.2 glycerin 10 One Sodium ascorbate 0.1 0.01 Disodium edetate 0.008 0.0008 Sodium hydroxide Quantity Quantity Distilled water Quantity Quantity

&Lt; Example 5 >

A propofol injection having the same composition as in Example 1 (see Table 5) except that it contained 1% w / v of macrogol 15 hydroxystearate was prepared in the same process as in Example 1.

TABLE 5

ingredient mg / mL % w / v Propofol 10 One Poloxamer188 101 10.1 Macrogol 15 hydroxystearate 10 One glycerin 10 One Sodium ascorbate 0.1 0.01 Disodium edetate 0.008 0.0008 Sodium hydroxide Quantity Quantity Distilled water Quantity Quantity

<Example 6>

A propofol injection having the same composition as in Example 1 (see Table 6) except that it contained 0.0001% w / v of disodium edetate was prepared in the same process as in Example 1.

TABLE 6

ingredient mg / mL % w / v Propofol 10 One Poloxamer188 101 10.1 Macrogol 15 hydroxystearate 7 0.7 glycerin 10 One Sodium ascorbate 0.1 0.01 Disodium edetate 0.001 0.0001 Sodium hydroxide Quantity Quantity Distilled water Quantity Quantity

Example 7

A propofol injection having the same composition as in Example 1 (see Table 7) except that it contained 0.001% w / v of disodium edetate was prepared in the same process as in Example 1.

TABLE 7

ingredient mg / mL % w / v Propofol 10 One Poloxamer188 101 10.1 Macrogol 15 hydroxystearate 7 0.7 glycerin 10 One Sodium ascorbate 0.1 0.01 Disodium edetate 0.01 0.001 Sodium hydroxide Quantity Quantity Distilled water Quantity Quantity

<Example 8>

A propofol injection having the same composition as in Example 1 (see Table 8) except that it contained 0.005% w / v of disodium edetate was prepared in the same process as in Example 1.

[Table 8]

ingredient mg / mL % w / v Propofol 10 One Poloxamer188 101 10.1 Macrogol 15 hydroxystearate 7 0.7 glycerin 10 One Sodium ascorbate 0.1 0.01 Disodium edetate 0.05 0.005 Sodium hydroxide Quantity Quantity Distilled water Quantity Quantity

Comparative Example 1

Ploxamer 407 and Ploxamer 188 are prepared in a ratio of 7: 3 to prepare a microemulsion for propofol injection in Table 9 (Example 7 of WO 2001/64187).

TABLE 9

ingredient mg / mL % w / v Propofol 10 One Poloxamer 407 70 7 Poloxamer188 30 3 glycerin 22.5 2.25 Sodium hydroxide Quantity Quantity Distilled water Quantity Quantity

Comparative Example 2

A microemulsion for propofol injection comprising the composition as shown in Table 10 was prepared (Example 1 of KR20010039671).

TABLE 10

ingredient mg / mL % w / v Propofol 10 One Poloxamer 407 5 0.5 Poloxamer188 40 4 Macrogol 15 hydroxystearate 10 One glycerin 20.8 2.08 Sodium hydroxide Quantity Quantity Distilled water Quantity Quantity

Comparative Example 3

A microemulsion for propofol injection comprising the composition as shown in Table 11 was prepared.

TABLE 11

ingredient mg / mL % w / v Propofol 10 One Poloxamer188 45 4.5 Macrogol 15 hydroxystearate 20 2 glycerin 22.5 2.25 Sodium hydroxide Quantity Quantity Distilled water Quantity Quantity

<Comparative Example 4>

A microemulsion for propofol injection comprising the composition as shown in Table 12 was prepared.

TABLE 12

 ingredient mg / mL % w / v Propofol 10 One Poloxamer188 60 6 glycerin 10 One Sodium hydroxide Quantity Quantity Distilled water Quantity Quantity

The preparation of propofol injections using the above components is carried out as follows. Dissolve 6 g of poloxamer 188 in 80 ml of purified water, add 1 g of propofol and dissolve until clear. After dissolving, glycerin is added, followed by marking to adjust pH to 8 with sodium hydroxide, nitrogen filling and filtering, and autoclaving at 121 ° C. for 20 minutes using autoclave (SH-29A, manufacturer Human Science) to adjust final pH to 7. .

Comparative Example 5

Poloxamer 188 propofol injections containing 10% w / v were prepared in the same composition and process as in Comparative Example 4.

TABLE 13

ingredient mg / mL % w / v Propofol 10 One Poloxamer188 100 10 glycerin 10 One Sodium hydroxide Quantity Quantity Distilled water Quantity Quantity

Comparative Example 6

Except for disodium edetate in Example 1 was prepared in the same composition and process.

[Table 14]

ingredient mg / mL % w / v Propofol 10 One Poloxamer188 101 10.1 Macrogol 15 hydroxystearate 7 0.7 glycerin 10 One Sodium ascorbate 0.1 0.01 Sodium hydroxide Quantity Quantity Distilled water Quantity Quantity

&Lt; Comparative Example 7 &

Propofol injections containing 0.1% w / v of macrogol 15 hydroxystearate are prepared in the same composition and process as in Example 1.

TABLE 15

ingredient mg / mL % w / v Propofol 10 One Poloxamer188 101 10.1 Macrogol 15 hydroxystearate One 0.1 glycerin 10 One Sodium ascorbate 0.1 0.01 Disodium edetate 0.008 0.0008 Sodium hydroxide Quantity Quantity Distilled water Quantity Quantity

The following experimental examples are for illustrating the present invention, but the present invention is not limited to these experimental examples.

Experimental Example 1 Change in appearance after autoclaving in Examples and Comparative Examples

The Examples and Comparative Examples were autoclaved at 121 ° C. for 20 minutes to observe changes in light transmittance and properties. Light transmittance was measured at a wavelength of 600 nm with a UV / VIS spectrophotometer V 550 (manufactured by Jasco). The results are shown in Table 16.

TABLE 16

Light transmittance (%) Change of appearance Example 1 99.3 Colorless Example 2 98.7 Colorless Example 3 98.9 Colorless Example 4 98.4 Colorless Example 5 97.9 Colorless Example 6 99.5 Colorless Example 7 97.8 Colorless Example 8 98.4 Colorless Comparative Example 1 96.8 Yellowing Comparative Example 2 97.4 Yellowing Comparative Example 3 0.0 Yellowing Comparative Example 4 97.8 Yellowing Comparative Example 5 98.2 Yellowing Comparative Example 6 99.1 Colorless Comparative Example 7 98.4 Colorless

Looking at Table 16, in Examples, there was no change in properties or transparency after autoclaving, but in Comparative Examples, properties were changed after autoclaving. Comparative Examples 1 to 5 were colorless and transparent at the time of manufacture but yellowed due to the oxidation reaction after autoclaving, but the examples including sodium ascorbate remained colorless even after autoclaving. In addition, in Comparative Example 3 it was confirmed that the content of the macrogol 15 hydroxystearate is high and turbid after the high-pressure steam sterilization and the phase becomes unstable. Macrogol 15 hydroxystearate content Example 5, which is 1%, maintains transparency, but when it contains 1% or more, cloudy appearance occurs after autoclaving.

Experimental Example 2 Stability Tests of Examples and Comparative Examples

After the autoclave sterilization of the Examples and Comparative Examples at 121 ° C. for 20 minutes, the light transmittance at the time of one month elapsed at 75% humidity at room temperature and 40 ° C. It measured by the same method as Experimental example 1.

TABLE 17

Storage condition Room temperature
(After 1 month) 40 ℃ Humidity 75%
(After 1 month) cow
(After 1 day) Example 1 Colorless Colorless Colorless Example 2 Colorless Colorless Colorless Example 3 Colorless Colorless Colorless Example 4 Colorless Colorless Colorless Example 5 Colorless Colorless Colorless Example 6 Colorless Colorless Colorless Example 7 Colorless Colorless Colorless Example 8 Colorless Colorless Colorless Comparative Example 1 Colorless Yellowing Yellowing Comparative Example 2 Colorless Yellowing Yellowing Comparative Example 3 Colorless Yellowing Yellowing Comparative Example 4 Colorless Yellowing Yellowing Comparative Example 5 Colorless Yellowing Yellowing Comparative Example 6 Colorless Yellowing Yellowing Comparative Example 7 Colorless Colorless Colorless

 Table 17 shows that both the Examples and Comparative Examples were colorless and stable after 1 month at room temperature, but after 1 day of storage in the dark, all Comparative Examples containing no edetate turned yellow and turned colorless when light was applied again. In addition, all other comparative examples except Comparative Example 7 yellowed after one month at 40 ° C 75% relative humidity. When the edetate contained more than 0.0001% concentration it was confirmed that the formulation is stable by preventing discoloration due to the reversible oxidation reaction. This is because edetate as a chelating agent inhibits the reaction caused by trace metals through chelating in the solution, as well as removing the free ions from the solution to inhibit the oxidation reaction by ions.

Experimental Example 3 Dilution Test with the Sap of Examples and Comparative Examples

 Propofol anesthetics should be mixed with other fluids for clinical use, so there should be no phase change when mixed with fluids. Therefore, after diluting the Examples and Comparative Examples by concentration in 0.9% saline solution, 5% glucose solution, Hartmann solution by the concentration in the same manner as in Experimental Example 1 and measured the light transmittance in each sap at a concentration of 1/10 One result is shown.

TABLE 18

Light transmittance (%) 0.9% saline 5% glucose solution Hartman solution Example 1 98.5 98.1 98.6 Example 2 99.2 98.7 99.3 Example 3 99.1 99.4 99.3 Example 4 97.4 97.8 97.2 Example 5 98.5 99.2 99.1 Example 6 98.9 98.5 98.7 Example 7 99.5 99.0 98.9 Example 8 99.1 99.0 98.0 Comparative Example 1 97.5 98.4 98.0 Comparative Example 2 97.9 98.2 98.1 Comparative Example 3 98.4 98.7 99.5 Comparative Example 4 27.8 30.5 30.8 Comparative Example 5 35.2 34.1 35.9 Comparative Example 6 98.7 99.0 99.5 Comparative Example 7 56.7 51.8 52.7

Looking at Table 18 it can be seen that Examples and Comparative Examples 1, 2, 3, 6 maintain the stability and transparency of all phases when diluting the sap. Referring to the light transmittances of Comparative Examples 4 and 5, the poloxamer 188 alone became turbid over time when diluted with sap. In Example and Comparative Example 6, macrogol 15 hydroxy was used as an auxiliary surfactant. By containing stearate, it was confirmed that there was no physical change such as particle size and property of the formulation even when mixed administration with the sap. In Example 4 containing 0.2% of macrogol 15 hydroxystearate, transparency was maintained at the time of dilution of the sap, but in Comparative Example 7 containing 0.1%, turbidity was observed.

<Experimental Example 4 > Test of the change in appearance according to the storage conditions of Examples and Comparative Examples

Propofol injections may be exposed to high or low temperatures during distribution or storage. Therefore, in order to observe the change of the properties in such harsh storage conditions, the phase change was observed at a high temperature of 60 ℃ and a low temperature of 4 ℃, the light transmittance was measured in the same manner as in Experimental Example 1 and the results are shown in Table 19.

TABLE 19

High temperature (60 ℃)
(After one week) Low temperature (4 ℃)
(After 1 day) Light transmittance (%) Change of appearance Light transmittance (%) Example 1 98.5 Colorless 97.6 Example 2 98.1 Colorless 98.5 Example 3 99.3 Colorless 97.6 Example 4 98.4 Colorless 97.8 Example 5 97.8 Colorless 97.4 Example 6 98.7 Colorless 98.8 Example 7 98.6 Colorless 98.9 Example 8 97.4 Colorless 98.7 Comparative Example 1 98.2 Yellowing 97.4 Comparative Example 2 99.6 Yellowing 90.4 Comparative Example 3 86.4 Yellowing 90.7 Comparative Example 4 99.3 Yellowing 28.6 Comparative Example 5 98.4 Yellowing 96.4 Comparative Example 6 98.3 Yellowing 97.5 Comparative Example 7 99.1 Colorless 98.3

Looking at Table 19, the comparative example 7 containing an Example and an edetate showed that there was no change in transparency or property change at the time of high temperature or low temperature storage. All of the comparative examples containing no edetate were yellowed, and Comparative Example 3 was unturbid at high or low temperatures, resulting in a decrease in light transmittance. In Comparative Example 4, the phase became unstable and turbid when stored at low temperature, and as shown in Comparative Example 5, it was found that transparency was maintained at low temperature storage above 10% w / v of poloxamer188.

Experimental Example 5 The effect of the concentration of edetate on the composition for injection containing propofol.

The concentration of edetate contained in the composition for injection according to an embodiment of the present invention was tested whether the effect of inhibiting microbial growth. Escherichia coli, Pseudomonas aeruginosa and Candida albicans were used as test microorganisms. In one preferred embodiment, the present invention provides a microemulsion prepared by emulsifying propofol dissolved in a water-immiscible solvent with water and stabilized with a surfactant, and in addition to each microorganism Escherichia coli, Pseudomonas aeruginosa and Candida albicans. The washed suspension of was incubated at 20-25 ° C. per ml and the viable water was examined after 24 hours, 48 hours, and 7 days, respectively.

The test preparation was tested by preparing the same process by changing the concentration of edetate to 0 (Comparative Example 6), 0.0008 (Example 1), 0.0009, 0.001% (Example 7), and 0.005% (Example 8). The experimental results are shown in Table 20.

TABLE 20

1) Edetate 0% (Comparative Example 6)

Test microorganism Number of bacteria per mL (cfu / mL) Early 24 hours 48 hours 7 days Pseudomonas Aruginosa 200 6.2 × 103 9.2 × 105 8.9 × 105 Candida Albican 150 5.2 × 102 8.8 × 103 9.9 × 103 Escherichia coli 190 9.7 × 103 8.2 × 104 8.9 × 105

2) Edetate 0.0008% (Example 1)

Test microorganism Number of bacteria per mL (cfu / mL) Early 24 hours 48 hours 7 days Pseudomonas Aruginosa 200 3.8 × 103 6.3 × 104 8.8 × 105 Candida Albican 150 3.1 × 102 2.5 × 102 1.3 × 103 Escherichia coli 190 1.8 × 103 3.2 × 103 7.3 × 105

3) Edetate 0.001% (Example 7)

Test microorganism Number of bacteria per mL (cfu / mL) Early 24 hours 48 hours 7 days Pseudomonas Aruginosa 200 2.4 × 103 6.8 × 104 8.3 × 105 Candida Albican 150 1.2 × 102 1.5 × 102 8.9 × 10 Escherichia coli 190 2.2 × 103 6.8 × 103 7.9 × 105

4) Edetate 0.005% (Example 8)

Test microorganism Number of bacteria per mL (cfu / mL) Early 24 hours 48 hours 7 days Pseudomonas Aruginosa 200 0 0 0 Candida Albican 150 0 0 0 Escherichia coli 190 0 0 0

From Table 20, it can be seen that the development of microorganisms is suppressed in the preparation containing diprivan and 0.005% of edtate as in Example 8. However, no inhibition of the growth of microorganisms was observed at 0.001%. Therefore, the formulation of the present invention was confirmed that does not affect the growth of microorganisms within the range of use of edtate secured pharmaceutical stability.

Claims (20)

Propofol at a concentration of 1-2% weight / volume (% w / v); Poloxamer 188 at a concentration above 10% w / vol 15% w / v; Macrogol 15 hydroxystearate at a concentration of 0.2-1% weight / volume; And An injectable composition with improved safety and stability comprising edetate at 0.0001 to 0.0008% weight / volume concentration. According to claim 1, The composition for injection is an injectable composition with improved safety and stability is a transparent microemulsion. The method of claim 2, The transparent microemulsion is an injection composition having improved safety and stability to maintain transparency even after autoclaving. According to claim 1, The edetate is a composition for injections that is improved safety and stability is a pharmaceutical stabilizing material to prevent yellowing. According to claim 1, Injectable composition with improved safety and stability further comprising an antioxidant. 6. The method of claim 5, The antioxidant is sodium ascorbate, the composition for injections with improved safety and stability. delete According to claim 1, Wherein the macrogol 15 hydroxystearate is 0.5 to 0.7% weight / volume concentration, the composition for injections with improved safety and stability. According to claim 1, Injectable composition with improved safety and stability, further comprising an osmotic modifier or pH adjuster. The method of claim 9, The osmotic modifier is glycerin, The pH adjusting agent is sodium hydroxide composition for injection and improved safety and stability. Dissolve poloxamer 188 in purified water at a concentration of more than 10% weight / volume up to 15% weight / volume, Add propofol at a concentration of 1-2% weight / volume (% w / v) at 60-70 ° C. and then stir, Macrogol 15 hydroxystearate and edetate are added to include macrogol 15 hydroxystearate at 0.2 to 1% weight / volume concentration and edetate at 0.0001 to 0.0008% weight / volume concentration at 1-30 ° C., adding a pH adjuster to adjust the pH to 8-8.5, The method for preparing the composition for injection of claim 1 comprising filtering the pH-adjusted solution and autoclaving to prepare a composition for adjusting the pH to 7 and a transparent microemulsion. delete delete delete delete 12. The method of claim 11, The edetate is a method for preparing an injectable composition which is a pharmaceutical stabilizing substance to prevent yellowing. 12. The method of claim 11, Before adjusting the pH to 8 to 8.5 by adding the pH adjusting agent, A method for producing an injectable composition further comprising adding an antioxidant. 12. The method of claim 11, Before adjusting the pH to 8 to 8.5 by adding the pH adjusting agent, A method for producing a composition for injection, further comprising adding an osmotic modifier. delete 12. The method of claim 11, The macrogol 15 hydroxystearate is 0.5 to 0.7% weight / volume of the composition for the preparation of injectables.