KR19980067001A - New Flubiprofen Emulsion Injectable Composition - Google Patents

Abstract

The present invention relates to a fluvipropene emulsion injectable composition comprising fluvipropene, an oil, an emulsifier, and water.

The fluvipropene, oil and emulsifiers are mixed into one completely phase and then added to the water phase to spontaneously disperse in water to form a microemulsion of small particle size.

Description

New Flubiprofen Emulsion Injectable Composition

FIG. 1 shows the blood concentration-time curve obtained after intravenous administration of flubiprofen solubilized in the drug solution and emulsion of Experimental Example 3 to mice.

Figure 2 shows the particle size distribution after preparing an emulsion having the composition of Example 11 and stored for 6 months at 4 ℃.

The present invention relates to a novel flubiprofen emulsion injectable composition prepared by solubilizing flubiprofen in a microemulsion system.

Flubiprofen is a nonsteroidal anti-inflammatory medication used for mild and severe pain, rheumatoid arthritis, osteoarthritis, analgesia after extraction and dental surgery, and anti-inflammatory. It is used as an oral preparation such as tablets, capsules, and eye drops. .

When taken orally, the dose of this drug is 150 ~ 200mg per day and up to 300mg if necessary, but the gastrointestinal disorder is severe and it takes a long time to show its efficacy. This is urgent. Accordingly, to solve this drawback by developing flubiprofen as an injection, but the development of the injection is difficult because of low solubility in water.

To this end, in the Green Cross, Flurbiprofen axetil, 2- (2-fluoro-4-biphenylyl) propionic acid 1- (acetoxy) ethyl, is a flubipropene prodrug. Intravenous injection [Lipofen] with lipo-emulsification of ester] / Ropion : Developed as ((株) Green Cross / 日 硏 製藥 (日本)], long-lasting and reduced side effects, but flubiprofen precursor used in this preparation It is difficult to separate fluviprofen and fluviprofen axetyl, and it is expensive and has problems that rapid drug expression cannot be expressed, which is an advantage of injection.

In order to solve the above problems, the present inventors have studied the injection using fluviprofen itself without chemically modifying fluviprofen, and as a result, it has been prepared using a solubilization system prepared by applying an emulsion system to fluviprofen. Rubypropene emulsion injectable compositions have been developed.

An object of the present invention is to provide a flubiprofen emulsion injection composition.

The present invention is described in detail as follows.

The present invention relates to a fluvipropene emulsion injectable composition comprising 0.5 to 2.0% by weight of flubiprofen, 2 to 20% by weight of oil, 2 to 20% by weight of emulsifier, and 58 to 99.5% by weight of water.

The oil used in the present invention may be used singly or in combination with oils commonly used in preparations such as ethyl oleate, triglycerides, isopropyl myristate, vegetable oils (castor oil, soybean oil, corn oil, etc.), and the amount is an emulsion injection. 2-20 weight% is added with respect to a composition. At this time, when 2% by weight or less is used, it is difficult to dissolve flubiprofen, and at 20% by weight or more, the dose of the injection increases, which causes problems in administration.

Emulsifiers used in the present invention include polysorbates, spans, poloxamers, ethoxylated castor oil, hydroxylated castor oil, lecithin with a phosphatidylcholine content of 60%, 99% phosphatidylcholine (PC), phosphatidylglycerol (PG ), Phosphatidylethanolamine (PE) and its derivatives dimyristoyl phosphatidylcholine (DMPC), dipalmitoin phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), dimyristoyl phosphatidylethanolamine (DMPE), di Emulsifiers commonly used in formulations such as palmitoyl phosphatidylethanolamine (DPPE), dioleoyl phosphatidylethanolamine (DOPE), distearoyl phosphatidylethanolamine (DSPE), and phospholipid modified with polyethylene glycol can be used alone or in combination. have. And this amount adds 2-20 weight% with respect to an emulsion injection composition. If the added amount is less than 2% by weight, the formulation is less safe.

Phospholipids modified with polyethylene glycol for use in the present invention are 1,2-diacyl-sn-glycero-3-phosphoethanolamine-N- [polyethylene glycol 2000] and 1,2-diacyl-sn-glycer. 3-phosphoethanolamine-N- [polyethyleneglycol 5000] and its acyl group derivatives dimyristoyl (14: 0), dipalmitoyl (16: 0), distearoyl (18: 0), Dioleoyl (18: 1) and 1-palmitoyl-2-olioyl (16: 0-18: 1).

As the aqueous phase used in the present invention, a solution commonly used as an isotonic solution, such as 0.9% saline solution, 2.5% glycerol solution, 5% sorbitol solution, 5% dextrose solution, can be used.

The preparation method of the fluviprofen emulsion injection composition which consists of said composition is as follows.

The fluvipropene, oil and emulsifiers are mixed into one completely phase and then added to the water phase to spontaneously disperse in water to form a microemulsion of small particle size.

When using an emulsifier that is not dissolved in water due to low HLB, spontaneous dispersion may not be achieved.In this case, an oil phase is prepared by dissolving flubiprofen, an oil and an emulsifier in ethanol, and then an emulsifier having a high HLB value. Is dissolved in a solvent to prepare an aqueous phase. While stirring the aqueous phase slowly, the ethanol solution containing the oil phase was slowly dropped to prepare a slightly milky clear solution. The solution is removed under reduced pressure of ethanol to prepare an o / w microemulsion. The solution is centrifuged under low centrifugal force (about 200 g) to remove additives that do not form an emulsion, followed by filtration and filling into vials to prepare an emulsion injectable composition of flubiprofen. It is sterile by filtration but is sterilized if necessary.

When spontaneous dispersion is not performed, there is a method using a homogenizer, a method of using an ultrasonic grinder, a method using a microfluidizer, etc. in addition to the method using ethanol as described above.

Fluviprofen emulsion injection composition of the present invention is easy to manufacture and economical, and can be solubilized flubiprofen to reduce the volume to a single intravenous and intramuscular injection to human, excellent stability, It has the advantage of expressing quickly.

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples, but the present invention is not limited thereto.

[Examples 1-9]

A flubiprofen emulsion injection composition having the composition of Table 1 was prepared. The fluvipropene, oil and emulsifiers are mixed into one completely phase and then added to the aqueous phase to spontaneously disperse in water to form an emulsion of small particle size.

Table 1 Compositions of Examples 1 to 9 (Unit: weight%)

[Examples 10-18]

Flubiprofen emulsion injection composition having the composition of Table 2 was prepared by the method using ethanol.

Table 2 Compositions of Examples 10-18 (Unit: wt%)

Experimental Example 1

After mixing ethyl oleate and polysorbate 20, various amounts of flubiprofen were added thereto to take 500 mg of this mixture, and 5 ml of aqueous phase was added thereto, which was allowed to stand for several minutes at room temperature to spontaneously form an emulsion, followed by particle size. Was measured.

Table 3 When the weight ratio of ethyl oleate and tween 20 is 1: 3, the particle size of the emulsion prepared with the weight percent of fluviprofen and the aqueous phase in the mixture of ethyl oleate, tween 20 and flubiprofen Impact

* Figures in parentheses indicate the ratio of the mean value of the number distribution to the mean value of the weight distribution. The closer this value is to 1, the more evenly distributed it is.

The average particle size of the emulsion prepared in all compositions had a particle size capable of intravenous injection, and the particle size and solubility did not change significantly depending on the type of aqueous phase.

Experimental Example 2

The solubility of flubiprofen for each system listed below was calculated by measuring the absorbance at 280 nm using UV.

① distilled water

② Phosphate buffer solution at pH 7.4

③ 5% polysorbate 20 solution

④ ethyl oleate

⑤ 10-fold dilution of 1: 1 mixture of ethyl oleate and polysorbate 20 with water phase

(Composition of Example 3)

Experimental Example 3

The emulsion prepared in the composition of Example 6 was intravenously administered to an experimental rat in an amount of 2.5 mg / kg, and the results were compared with those dissolved in a buffer solution (2, Experimental Example 1.25 mg / ml).

The results are shown in FIG.

In comparison, the mean blood concentrations were similar. However, due to the solubilization effect of the emulsion, the drug can be dissolved in the phosphate buffer by about 8 times as much as the volume reduction effect. Could.

Experimental Example 4

The particle size distribution of the emulsion having the composition of Example 11 at 4 ° C. for 6 months is shown in FIG. 2. There were a few micelle-sized particles with small particle size, and the particle size distribution did not change compared to the initial stage of manufacture.

Claims (4)

Flubiprofen emulsion injectable composition containing 0.5 to 2% by weight of flubiprofen, 2 to 20% by weight of oil, 2 to 20% by weight of emulsifier, and 58 to 99.5% by weight of water. The fluviprofen emulsion injectable composition according to claim 1, wherein the oil is used alone or in combination with ethyl oleate, triglyceride, isopropyl myrilate and vegetable oil. The emulsifier according to claim 1, wherein the emulsifier is a polysorbate, span, poloxamer, ethoxylated castor oil, hydroxylated castor oil, lecithin with a content of 60%, 99% phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine And their derivatives dimyristoyl phosphatidylcholine, dipalmitoin phosphatidylcholine, distearoyl phosphatidylcholine, dimyristoyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolamine, dioleoyl phosphatidylethanolamine, distearoyl phosphatidylethanolamine Fluvopropene emulsion injection composition, characterized in that the polyethylene glycol modified phospholipids used alone or in combination. The phospholipid modified with polyethylene glycol is 1,2-diacyl-sn-glycero-3-phosphoethanolamine-N- [polyethylene glycol 2000] and 1,2-diacyl-sn-glycer. Rho-3-phosphoethanolamine-N- [polyethyleneglycol 5000] and its acyl group derivatives dimyristoyl, dipalmitoyl, distearoyl, dioleoyl, 1-palmitoyl-2-olioyl. Flubiprofen emulsion injection composition.