JP2002179562A - Stable painless propofol fat emulsion for intravenous injection - Google Patents

Abstract

PROBLEM TO BE SOLVED: To enhance the storage stability of a propofol fat emulsion containing lidocaine in order to reduce vascular pains during injection which are adverse effects of a propofol fat emulsion for intravenous injection. SOLUTION: This fat emulsion is obtained by previously adding lidocaine to an oily phase ingredient containing the propofol, emulsifying the resultant mixture in water, providing an emulsion, previously adding a surfactant having >=10 HLB as a stabilizer to an aqueous phase or subsequently adding the surfactant to the resultant emulsion and regulating the pH of the emulsion within the range of 3.0-6.5 in the presence of the stabilizer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an intravenous fat emulsion of propofol. In particular, the present invention relates to a technique for preventing the instability of a preparation by adding lidocaine to alleviate vascular pain that occurs as a side effect during intravenous injection of the preparation.

[0002] Propofol (chemical name 2,6-diisopropylphenol) is an oil-soluble drug that is insoluble in water, and is therefore used as a fat emulsion as a general anesthetic for intravenous injection and recently as a sedative for intravenous injection. . This fat emulsion has features such as rapid induction of anesthesia, rapid arousal, nausea after awakening, and little discomfort such as vomiting, and is widely used in surgical operations.In recent years, it has been used for sedation in intensive care units, etc. It has also been used. However, many side effects of propofol fat emulsion, in which strong vascular pain develops frequently at the time of intravenous injection, have been reported. W. Klement, J.M. O. A
rndt: British Journal of A
Naethsia, 1991; 67: 281-284.

Various methods for alleviating this vascular pain include intravenous cooling at 4 ° C., co-injection with lidocaine hydrochloride or nafamostat mesilate, intravenous injection of narcotics such as fentanyl a few minutes before administration. It has been known. However, these methods have no sufficient effect when used alone,
It is complicated and lacks convenience. Of these, co-injection with lidocaine hydrochloride, specifically, about 1 volume of 1% or 2% lidocaine hydrochloride injection solution is aseptically mixed with 9 volumes of commercially available 1% propofol emulsion in an injection cylinder, and quickly intravenously injected This method is the most commonly used method clinically because it is relatively simple and a relatively good effect of reducing vascular pain is obtained. However, the mixing of the lidocaine hydrochloride injection into the fat emulsion significantly impairs the stability of the emulsion, and the fat particles aggregate and coarsen to a size unsuitable for intravenous administration. Must be administered within

[0004] Therefore, it is desired to provide a propofol fat emulsion for intravenous injection which contains lidocaine in advance for pain relief but is stable for long-term storage.

[0005]

SUMMARY OF THE INVENTION The present invention meets the above needs. Therefore, the present invention forms an o / w emulsion containing propofol and lidocaine for analgesia, and the emulsion contains HLB10 contained in an aqueous phase as a stabilizer.
A stable intravenous painless propofol fat emulsion for intravenous injection, wherein the pH is adjusted to 3.0 to 6.5 in the presence of the above hydrophilic surfactant.

[0006]

[Detailed Description] As described above, it has long been reported that the stability of an emulsion is rapidly lost when a lidocaine hydrochloride injection is mixed with a commercially available intravenous propofol fat emulsion.
E. FIG. E. FIG. M. Lilliy, et al. , Anaet
hsia, 1996; 51: 815-818. In our follow-up tests, 2% lidocaine hydrochloride injection was added to 1/10 volume or 1 /
It was recognized that when 20 volumes were added and mixed, the liquidity of the mixed solution changed to acidic, and the particle size of the emulsion increased rapidly. At this time, 60% of the added lidocaine (1/10
(By volume) or 62.5% (by 1/20 volume) was present in the aqueous phase. FIG. 1 is a graph showing the change over time in the particle diameter when 1/10 volume is added.

[0007] Therefore, lidocaine (refers to a free base; the same applies to others) together with propofol is dissolved in the oil phase component in advance so that the final concentration of lidocaine in the preparation is 0.05 to 0.25% (w / v). This was emulsified to form an emulsion, and the pH of the emulsion at that time was 8.0 to 8.0.
In the range of 8.5, the stability of the emulsion was satisfactory.
However, the proportion of added lidocaine present in the aqueous phase was only 10
%. In order for lidocaine to effectively alleviate the vascular pain caused by intravenous injection of the emulsion, it is considered that its concentration in the aqueous phase must have reached an effective concentration. Was determined in the aqueous phase (partition ratio), and the results shown in FIG. 2 were obtained. According to this, at a pH of 7.0 or more, the proportion present in the aqueous phase is 50% or less of the added amount,
It was 80% or more on the acidic side, especially at pH 6.0 or less.

In order to examine the storage stability of this pH-adjusted emulsion, the above emulsion was adjusted to pH 5.5 and allowed to stand at room temperature, the particle size of the emulsion increased with time. After 24 hours, the emulsion became oily. It was found that the phase separated into a phase and an aqueous phase. FIG.
reference.

The present inventors have considered that the decrease in stability caused by adjusting the pH of the emulsion to the acidic side can be prevented by the use of a stabilizer, and propol 1w
/ V%, lidocaine 0.2 w / v% fat emulsion (containing 10% soybean oil as a base) was prepared, and various surfactants were added thereto to a final concentration of 0.15 w / v%. After adjusting the pH to 5.5 with hydrochloric acid, the mixture was allowed to stand at room temperature for 3 hours, and the average particle size was measured. The results shown in Table 1 were obtained.

Table 1 Effect of stabilizer at pH 5.5: ─────────────────────────────────── Stabilizer HLB Particle size (μm) Effect ─────────────────────────────────── No additive / No treatment (PH 8.4) ０．１ 0.146 ── No addition (control: pH 5.5) ── 3.906 × polysorbate 80 15 0.161 〇 HCO-60 (polyoxyethylene 14 0.190 レ ン) Ren (60) cured castor Oil) sodium lauryl sulfate 40 0.153 {benzalkonium chloride} 0.231 {monooxy fatty acid polyoxy 17 0.174} ethylene sorbitan monodecaglyceryl monolaurate 15.5 0.168 {polyoxyethylene (15) o 160 .165 Rail ether sorbitan monooleate 8.6 3.599 x sorbitan sesquioleate 4.5 4.099 x glyceryl monostearate 4.0 3.105 x oxyethyl monooleate 9.5 3.322 x n (5) Glyceryl ───────────────────────────────────

[0011] From these results, HLB as a stabilizer
Ten or more hydrophilic (water-soluble) surfactants were found to be effective. HLB as a stabilizer for confirmation
In emulsions containing 10 or more hydrophilic surfactants, the ratio of added lidocaine in the aqueous phase to p
Examination of the effect of H revealed that before the pH adjustment (pH 8.3), less than 15% of the added amount of lidocaine was present in the aqueous phase, but at pH 5.5, 85% or more of the added amount was in the aqueous phase. Existed inside. This means that the present invention makes it possible for the first time to maintain lidocaine concentration in the aqueous phase at a level effective for soothing without adversely affecting the stability of the emulsion.

The propofol fat emulsion for intravenous injection of the present invention is prepared by emulsifying a predetermined amount of an oil phase component in which propofol and lidocaine have been previously dissolved in distilled water for injection, adding a stabilizer thereto, and adjusting the pH to 3.0. To 6.5, preferably in the range of 4.0 to 5.5. Instead of adding a stabilizer after emulsification, a stabilizer may be added to distilled water for injection in advance, and the oil phase component may be emulsified therein. In any case, it is necessary that a stabilizer is present during pH adjustment.

Propofol fat emulsion for intravenous injection is commercially available, and its production method is also known. The method for producing a fat emulsion according to the present invention comprises adding lidocaine to an oil phase component in advance, adding a stabilizer to an aqueous phase before emulsification or an emulsion after emulsification, and finally adjusting the pH of the emulsion. Except for the above, known methods can be used.

The base of the oil phase component is a vegetable oil. Refined soybean oil is common, but other vegetable oils such as cottonseed oil and olive oil may be used. The oil phase component further contains an emulsifier.
The emulsifier used for this purpose is generally a natural phospholipid such as egg yolk lecithin. Lecithin is insoluble in water and is clearly distinguished from the stabilizers used in the present invention and cannot fulfill its function. Phospholipid is vegetable oil 10
It is used in an amount of 5 to 50 parts by weight per 0 parts by weight. The phospholipids are dissolved in the vegetable oil with warming if necessary with propofol and lidocaine. After emulsifying this oil phase component in distilled water for injection, a surfactant having an HLB of 10 or more is added to the emulsion as a stabilizer, or the oil phase component is emulsified in distilled water for injection in which the stabilizer has been previously dissolved. I do. Finally, the pH of the emulsion is adjusted to 3.0 to 6.5 to prepare the intravenous propofol fat emulsion of the present invention. Since the fat particle diameter of the fat emulsion must be very small (0.3 μm or less), it is preferable to once coarsely emulsify and then further reduce the fat particles using an ultrahigh-pressure emulsifier or the like.

The final concentration of each component in the final product is 5-20 w / v% vegetable oil, 0.5-5.0 wt / v phospholipid.
%, Propofol 0.5-2.0 wt / v%, lidocaine 0.1-0.5 wt / v%, stabilizer 0.05-
0.5 wt / v% is preferred and typically, vegetable oil 1
0 wt / v%, phospholipid 1.2 wt / v%, propofol 1.0 wt / v%, lidocaine 0.2 wt / v%,
It will contain 0.2-0.3 wt / v% stabilizer. The emulsion may contain a non-electrolyte tonicity agent such as glycerin for tonicity.

[0016]

The following examples are for illustrative purposes and are not limiting.

EXAMPLE 1 25 g of refined soybean oil and 3 g of refined egg yolk lecithin (manufactured by Kewpie Co., Ltd.) were mixed at 70 ° C., and the mixture was further heated at 70 ° C. while propofol (manufactured by Cilag) 2.5
g and 0.5 g of lidocaine (manufactured by Sigma) were mixed to prepare an oil phase component. Separately, 213 g of distilled water for injection heated to 75 ° C. and 5.5 g of concentrated glycerin were mixed, and 0.375 g of polyoxyethylene (60) hydrogenated castor oil (HCO-60 manufactured by Nikko Chemical) was added and dissolved.
While stirring this aqueous solution with a homomixer, the upper oil phase component was gradually added to carry out coarse emulsification. The obtained coarse emulsion was circulated three times under a pressure of 2500 kg / cm ² using an ultra-high pressure emulsifier (Mini DeBEE manufactured by BEE Japan) to obtain a fine emulsion. This emulsion was adjusted to pH 5.5 with 10% lactic acid to obtain a target intravenous propofol fat emulsion. This formulation was subjected to a stability test at room temperature, and the results shown in FIG. 4 were obtained. The change in the average particle diameter with time after pH adjustment was slight.

Example 2 The oil phase component of Example 1 was gradually added to a mixture of 211 g of distilled water for injection heated to 75 ° C. and 5.5 g of concentrated glycerin, and coarsely emulsified while stirring with a homomixer. This coarse emulsion was weighed at 2000 kg / c using the above ultra-high pressure emulsifier.
A fine emulsion was obtained by circulating 4 times under a pressure of m ² . 10% polysorbate 8 is added to 100 ml of this fine emulsion.
After adding 2.0 ml of 0 aqueous solution, pH was adjusted with 0.1N hydrochloric acid.
It was adjusted to 5.0 to obtain the desired intravenous propofol fat emulsion. FIG. 4 shows the results of a stability test similarly performed. The change over time in the average particle diameter after pH adjustment was slight.

[Brief description of the drawings]

FIG. 1 is a graph showing the change over time in the particle size when a 2% lidocaine hydrochloride injection is mixed with a commercially available intravenous propol fat emulsion.

FIG. 2 is a graph showing the relationship between lidocaine partition ratio in an aqueous phase and pH of a propol fat emulsion obtained by dissolving lidocaine in an oil phase component in advance and emulsifying the same.

FIG. 3. p of fat of Propol fat in the absence of stabilizer
The graph which shows the time-dependent change of the particle diameter in H5.5.

FIG. 4. pH of Propol fat emulsion in the presence of stabilizer
The graph which shows the time-dependent change of the particle diameter in 5.5 or 5.0.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Hitoshi Yasuda 26-7 Ichibancho, Kadoma-shi, Osaka F-term in Central Research Laboratory of Towa Pharmaceutical Co., Ltd. 4C076 AA16 BB13 CC01 DD63 EE53 FF56 FF67 GG41 4C206 AA01 AA02 CA16 GA31 NA08 ZA04 ZA08

Claims (5)

[Claims] 1. An o / w type emulsion containing propol and an effective soothing amount of lidocaine. The emulsion has a pH of 3 in the presence of a hydrophilic surfactant having an HLB of 10 or more contained in an aqueous phase as a stabilizer. A stable, intravenous, painless propofol fat emulsion which is adjusted to 0.0 to 6.5. 2. A final concentration of 5-20 w / v vegetable oil.
%, Phospholipids 0.5 to 5.0 w / v%, propofol 0.5 to 2.0 w / v%, lidocaine 0.1 to 0.5 w
2. The fat emulsion according to claim 1, which contains t / v% and a stabilizer of 0.05 to 0.5 wt / v%. 3. The fat emulsion according to claim 2, further comprising a non-electrolyte tonicity agent. 4. The fat emulsion according to claim 1, wherein the oil component has an average particle size of 0.3 μm or less. 5. An oil phase component comprising a vegetable oil and a phospholipid, in which a predetermined amount of propofol and a soothing effective amount of lidocaine are dissolved in advance and emulsified in water. Add a stabilizing effective amount, or emulsify in water containing a stabilizing effective amount of the surfactant beforehand, and finally,
The method for producing a stable intravenous painless propofol fat emulsion for intravenous injection, wherein the pH is adjusted to 3.0 to 6.5.