KR20150030971A - oil-in water emulsion composition of the water-insoluble pharmaceutical compounds and the method for preparing the same - Google Patents

Abstract

The present invention relates to an aqueous emulsion composition of a poorly soluble drug and a process for producing the same. The aqueous liquid emulsion composition of the present invention can be used as a conventional liposome form or emulsified form to disperse a poorly soluble drug stably without using a solubilizing agent which is toxic or has side effects in comparison with a method in which a poorly soluble drug is solubilized And can disperse a remarkably large amount of poorly soluble drugs.

Description

TECHNICAL FIELD [0001] The present invention relates to an aqueous emulsion composition for preparing a water-insoluble drug, and an oil-in-water emulsion composition for the water-insoluble pharmaceutical compound and a method for preparing the same.

The present invention relates to an aqueous emulsion composition of a poorly soluble drug and a process for producing the same.

In general, poorly soluble drugs can exhibit pharmacological action only in a dissolved state, so solubilization of the drug is closely related to the drug efficacy. Therefore, poorly soluble drugs are absolutely necessary for the solubilization step.

If an insoluble non-soluble drug is taken orally, it is not dispersed as a single molecule in the gastrointestinal tract and is not absorbed at all because it exists as a large aggregate.

Furthermore, if it is used as eye drops or injections, the insoluble compound crystallizes and clogs the blood vessels, causing blood clots, which can lead to a great risk of life. In particular, stable solubilization techniques for insoluble compounds used in eye drops and injections are the most important technologies .

Solubilization of poorly soluble medicines means that the poorly soluble medicines are efficiently encapsulated in the carrier and made into a colloidal state or a state sealed with fine particles without being precipitated in the aqueous solution. In order to solubilize a poorly soluble drug, a suitable solvent and a solubilizing agent for dissolving the poorly soluble drug are essentially used before being emulsified in water. To date, the solubilizer most commonly used for solubilization is a surfactant.

Surfactants are amphoteric compounds in which lipophilic groups and hydrophilic groups are present together in the molecule. In terms of different classes of surfactants, the first classifications are as follows; Surfactants are classified into cationic surfactants, anionic surfactants and amphoteric surfactants.

Examples of the cationic surfactant include high-grade halides, saccharide ammonium salts and alkylpyridinium salts, and anionic surfactants include soaps and alkylbenzenesulfonic acid salts, and amphoteric surfactants include phospholipids and the like.

When the surfactant is put into water, the hydrophobic hydrocarbon chains themselves gather in the water because of the hydrophobicity, and the hydrophilic groups meet in the shape of spheres to meet the water. The poorly soluble compound forms a micelle which is mainly distributed in the hydrophobic hydrocarbon chain. The micelles thus formed are arranged in accordance with the type of solubilizing agent, such as a spherical shape, a cylinder-shaped one-side long implementation, a circular disk-shaped circular shape, or the like.

The micelle thus formed can be formed variously according to the temperature, the concentration of the self-association, the structure of the solubilizing agent, and the like.

The second category is as follows; Solubilizing agents may be divided into water-soluble and water-insoluble.

Examples of the water soluble solubilizing agent include propylene glycol type, glycerin, polyethylene glycol (PEG) type, poloxamer type, polysorbate type, cyclodextrin type, phospholipid type such as lecithin, Examples of zero oil include castor oil, olive oil and soybean oil, and examples of the acid include oleic acid and soybean fatty acid.

Generally, an emulsion is a liquid-liquid dispersion system in which two liquids which are not mixed with each other are dispersed in another liquid in the form of small droplets with a constant ratio, that is, in a state in which one or more liquid phases, , Which generally have various size distributions ranging from tens of nanometers to tens of micrometers.

The emulsions are classified in various physicochemical terms, and in this patent generally Table 1 below is applied.

In Table 1, micro-emulsions and emulsions are classified in various aspects. Micro-emulsions are referred to as micro-emulsions when the mean diameter of droplets is 20-500 nm on the appearance side. The average particle diameter of the dispersed phase is 500 nm or more It is called an emulsion.

Compared to microemulsions, emulsions have the advantage of significantly increasing the amount of insoluble drugs absorbed into the body by increasing the content of insoluble drugs trapped within the particles at a constant volume.

However, such emulsions are generally thermodynamically unstable compared to microemulsions and are thermodynamically stable, such as flocculation, sedimentation, creaming, Ostwald ripening and coalescence. State, it may eventually be recrystallized or phase-separated.

Therefore, in the production of a thermodynamically stable emulsion state, it is very difficult to solve technical problems.

Accordingly, in the case of an emulsion, a method of preventing the emulsion particles from being separated by various routes such as coagulation, sedimentation, creaming, particle growth and adhesion, and preventing recrystallization of a poorly soluble drug from precipitating and ultimately producing a stabilized emulsion It is an urgent situation.

Some of the conventional techniques are as follows.

According to Patent Document 10-2006-0045910 related to a method of stabilizing an emulsion, a polymer solution prepared by dissolving and dispersing a bisphosphonate in an aqueous solution containing a water-soluble polymer and a hydrophilic surfactant is dissolved in a solution containing a biodegradable polymer and a hydrophobic surfactant Containing polymer microparticles prepared by adding a primary emulsion solution (W / O) to a polymer solution prepared by adding a secondary organic solvent to a primary organic solvent and dispersing the primary emulsion solution in an external continuous phase, , And an injection agent having a sustained effect for treating or preventing a bone related disease.

In addition, Patent Document 10-2004-0042152 also describes an invention relating to a polymer microparticle capable of continuous drug release and a method for producing the same.

However, in the conventional method, the solubilizing agent used in the poorly soluble medicines may cause toxicity or side effects to the patient, and the manufacturing process is complicated or the expensive equipment is often used.

Accordingly, the inventors of the present invention have invented a novel homogenization method which has not been known in the prior art for a poorly soluble drug through much time and effort, and invented a technique for manufacturing a more stable emulsion than the prior art.

Korean Patent Laid-Open Publication No. 10-2006-0045910 Korean Patent Publication No. 10-2004-0042152

It is an object of the present invention to provide an aqueous liquid emulsion composition of a poorly soluble drug.

It is also an object of the present invention to provide a method for producing an aqueous emulsion composition of an insoluble drug.

In order to achieve the object of the present invention,

(a) mixing a surfactant having at least two alkyl chains in the hydrophobic portion, an organic solvent having polarity, and a poorly soluble drug;

(b) injecting the mixture into an inline mixer;

(c) preparing a pre-emulsion by mixing at least 0.1 g of the poorly soluble medicament for at least 0.2 hours under a condition of 100 bar or more and 2,000 bar or less per unit area of the in-line mixer; And

(d) adding the pre-emulsion to water

Soluble emulsion composition of a poorly soluble drug and a process for producing the same.

The aqueous liquid emulsion composition of the present invention is advantageous in that it is capable of dispersing a remarkably large amount of a poorly soluble drug in comparison with a conventional method of solubilizing a poorly soluble drug in liposome form or emulsion form, . In addition, the aqueous emulsion composition of the present invention has a remarkably lower adverse effect than the conventional solubilizing agent used in a poorly soluble medicament, and uses a surfactant having little toxicity, thereby reducing side effects or toxicity .

Fig. 1 is an electron micrograph of the compositions of Example 4 and Comparative Example 4 of the present application. Fig.
2 is a diagram showing a structure and a principle of an inline mixer.

Hereinafter, the present invention will be described in detail.

The present invention

(a) mixing a surfactant having at least two alkyl chains in the hydrophobic portion, an organic solvent having polarity, and a poorly soluble drug;

(b) injecting the mixture into an inline mixer;

(c) preparing a pre-emulsion by mixing at least 0.1 g of the poorly soluble medicament for at least 0.2 hours under a condition of 100 bar or more and 2,000 bar or less per unit area of the in-line mixer; And

(d) adding the pre-emulsion to water

Soluble emulsion composition of a poorly soluble drug and a process for producing the same.

The aqueous emulsion composition of the poorly soluble drug may have an average diameter of 0.5 to 30 mu m per unit. If the diameter is less than 0.5 占 퐉 or exceeds 30 占 퐉, stabilization of the composition of the present invention may be degraded.

This corresponds to a size of several tens to hundreds of times larger than the conventional liposome using nano units. This means that the amount of the insoluble drug contained per unit is markedly increased. Therefore, a remarkably large amount of poorly soluble drugs can be dissolved in an aqueous solution as compared with the prior art.

As used herein, the term " poorly soluble "means from" slightly soluble "to" substantially insoluble "in Table 1 below, which is used to indicate the solubility of the drug in the Korean Pharmacopoeia 9 edition. Solubility refers to the degree to which the drug dissolves within 30 minutes when it is mixed with powder, if it is solid, into a solvent, and shake vigorously at 20 ± 5 ° C for 30 seconds every 5 minutes.

Terms Amount of solvent required to dissolve 1 g or 1 mL of solute It melts well.
It melts well.
Melt
It melts a little.
It is difficult to melt.
It is very difficult to melt.
It is almost insoluble. Less than 1 mL
1 mL or more and less than 10 mL
10 mL or more and less than 30 mL
30 mL or more and less than 100 mL
100 mL or more and less than 1000 mL
1000 mL or more and less than 10000 mL
More than 10000 mL

Herein, the meaning of emulsion stabilization may mean a storage stability according to temperature, an increase in stability against gravity or centrifugal force.

As used herein, a pre-emulsion may refer to a solid, a liquid or a mixture thereof that forms an emulsion when dispersed in a solvent containing water.

In the present specification, an emulsion may mean a state in which one of two liquids which do not melt each other is dispersed in a state of small particles on the other side.

As used herein, the term "dissolves" includes conventional dissolution, emulsification, and liposomal forms.

When mixing the step a), the poorly soluble drug and the surfactant having two or more alkyl chains in the hydrophobic part are preferably mixed in a weight ratio of 0.00001: 10 to 10: 0.00001.

When the mixing ratio of the poorly soluble drug and the surfactant having two or more alkyl chains in the hydrophobic part does not correspond to the above ratio, the aqueous emulsion composition of the poorly soluble drug of the present invention is not formed There is a possibility that it will not.

When the step a) is mixed, the poorly soluble drug and the organic solvent having polarity may be mixed in a weight ratio of 0.00001: 10 to 10: 0.00001.

If the mixing ratio of the poorly soluble drug and the polar organic solvent does not correspond to the above ratio, the aqueous emulsion composition of the poorly soluble drug of the present invention may not be formed.

The surfactant having two or more alkyl chains in the hydrophobic part included in the aqueous emulsion composition of the poorly soluble drug of the present invention is preferably egg yolk lecithin, soybean lecithin or hydrogenated lecithin, more preferably egg yolk lecithin, The surfactant is not limited to a surfactant having two or more alkyl chains in the hydrophobic portion.

The organic solvent having a polarity of the present invention is preferably an organic material having two or more groups of ethanol or an acid (-OH) group. The organic material having two or more hydroxyl (OH) groups may be specifically polyols, and more specifically, glycerin, 1,3-butylene glycol, propylene glycol, dipropylene glycol, and ethylene glycol, polyethylene glycol, diethoxydiglycol , Ethoxydiglycol, butoxydiglycol, and the like.

As used herein, the term "inline mixer" refers to a device in which a fixed device twisted 180 " left < / RTI > CIRCULATION, and RADIAL MIXING can occur either sequentially or simultaneously.

The aqueous emulsion composition of the insoluble drug of the present invention is achieved through specific manufacturing conditions in an inline mixer. Through a number of experiments, the inventors of the present invention have found that the poorly soluble drug should be homogenized by mixing with a surfactant having two or more alkyl chains and an organic solvent having polarity in an inline mixer in order to stably disperse the poorly soluble drug Respectively.

That is, the aqueous liquid emulsion composition of the present invention can be easily dispersed because of the specificity of the composition formed according to the preparation method. Therefore, the method of manufacturing the emulsion composition of the present invention It should be identified as a part.

The inline mixer includes a mixed blade structure. The number of unit blades constituting the mixed blade structure may be 1 to 50, and the number of each blade of the unit blade may be 20 or less.

As used herein, the term " blend mixture "means that blades are passed through so that the passing liquid can be homogenized in the form of 2 ⁿ , 3 ⁿ , 4 ⁿ , 5 ⁿ , Which means that the solution is conceptually divided into numerous parts each passing through the unit of each blade by passing through a pipe line disposed therein in such a form that it can be fixed or moved repeatedly by dividing the space that is repeatedly divided.

The structure and principle of the inline mixer are shown in FIG.

Through such mixing, the aqueous emulsion composition of the insoluble drug of the present invention is mixed in a very homogeneous form and the resulting composition is homogeneous such that the average particle size of the composition is within ± 200% of the diameter standard.

The compensation mixture should be performed under the condition that the force per unit area in the inline mixer is 100 bar or more and 2,000 bar or less. If the mixing is carried out under a condition that the force per unit area of the inline mixer is less than 100 bar, there is a fear that the aqueous emulsion composition of the poorly soluble medicament of the present invention is not formed. If it exceeds 2,000 bar, .

In general, when the poorly soluble drug is mixed with 0.1 g or more, the blending mixing time is maintained within a range of 100 bar to 2,000 bar per unit area in the inline mixer, It should be over 0.2 hours. Even when the poorly soluble drug is mixed with 0.1 g or more, the aqueous emulsion composition of the poorly soluble drug of the present invention may not be formed if it is blended within 0.2 hours. When the amount of the poorly soluble medicines is decreased, the mixing time is reduced, and when it is increased, the mixing time is increased.

In preparing the aqueous emulsion composition for an insoluble drug of the present invention, a fatty acid may be further mixed in the step a). The fatty acid is preferably at least one selected from the group consisting of caprylic acid, stearic acid, palmitic acid, myristic acid, lauric acid and oleic acid.

In the aqueous emulsion composition of the present invention, the poorly soluble medicines include meloxicam, celecoxib, itraconazole, docetaxel, capecitabine, traboprost, isoflavone, paclitaxel, diclofenac sodium, ginsenoside Rg1, alendronate , Docetaxel, dexacin, latanoprost, bimatoprost, tacrolimus, atorvastatin calcium, rosuvastatin calcium, entecavir, cyclosporin A, amphotericin B, omega 3 and ursodeoxycholic acid But the present invention is not limited thereto.

The solubility of the poorly soluble drug in water is 1 (w / w)% or less.

Hereinafter, the present invention will be described in more detail by way of examples. It is to be understood, however, that the scope of the present invention is not limited to these embodiments.

Examples 1 to 15

Hydrogenated lecithin and propylene glycol, propylene glycol, diethylene glycol, benzyl alcohol, ethoxydiglycol or ethanol were put into a kneader and mixed at 25 ± 5 ° C for 0.5 hour according to the composition shown in Table 3, and lecithin And a solvent were prepared. Thereafter, the insoluble drug described in Table 3 was added and then mixed again for 0.5 hour to prepare a second mixture immediately before mixing through an inline mixer.

The prepared second mixture was placed in an inline mixer, and the preform was prepared by mixing the mixture for 0.5 hour or 1 hour so that the applied force per unit area was 300 bar.

The prepared pre-emulsion was added to distilled water for injection and mixed as shown in Table 3 to prepare an emulsion.

Table 3 summarizes the above contents.

Example Poorly soluble medicines
Preemulsion (%) usage menstruum Surfactants Compensation time (hours) Example 1 Urushode deoxycholic acid
(UDCA)
6.25% 10g Propylene glycol
88.75 & Lecithin (PC95%)
5% One Example 2 Cyclosporine A
2% 10g Propylene glycol
93% Lecithin (PC95%)
5% One Example 3 Decker Shin
26% 10g Propylene glycol
69% Lecithin (PC95%)
5% One Example 4 Latano Frost
2% 0.1 g Propylene glycol
93% Lecithin (PC95%)
5% 0.5 Example 5 Traboproth
2% 0.1 g Propylene glycol
93% Lecithin (PC95%)
5% 0.5 Example 6 Docetaxel (trihydrate)
10% 0.1 g Diethylene glycol
85% Lecithin (PC95%)
5% 0.5 Example 7 Bimatofrost
2% 0.1 g Propylene glycol
93.% Lecithin (PC95%)
5% 0.5 Example 8 Amphotericin B
10% 0.1 g Diethylene glycol
85% Lecithin (PC95%)
5% 0.5 Example 9 Itraconazole
50% 10g Benzyl alcohol
49% Lecithin (PC95%)
One% One Example 10 Isoflavone
34% 10g Diethylene glycol
61% Lecithin (PC95%)
5% One Example 11 Meloxicam
20% 10g Ethoxydiglycoll
75% Lecithin (PC95%)
5% One Example 12 Celecoxib
50% 10g ethanol
49% Lecithin (PC95%)
One% One Example 13 Ginsenoside Rg1
10% 0.1 g Propylene glycol
85% Lecithin (PC95%)
5% One Example 14 Tacrolimus
2% 0.1 g Propylene glycol
93% Lecithin (PC95%)
5% 0.5 Example 15 Paclitaxel
6% 0.1 g Propylene glycol
89% Lecithin (PC95%)
5% 0.5

Comparative Example  1 to 15

The same procedure as in Examples 1 to 15 was carried out except that the mixture was mixed in a general mixer (Tokushu kika model 2.5) according to the composition shown in Table 3.

Experimental Example 1

The emulsions prepared by the methods of Examples 1 to 15 were measured using an Olympus Microscope Bx-41 and High Resolution Adapter Specifications.

The above results are summarized as follows.

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Example 15 size
(nm) 850 750 890 580 600 730 620 910 1050 980 1100 1250 1060 890 870

Experimental Example 2

The compositions prepared in Experimental Examples 1 to 15 and Comparative Examples 1 to 15 were stored for 1 to 90 days in a thermostatic chamber at 4, 20, 38, and 50 ° C, and the change with time was measured.

A sample was taken at each time point and visually confirmed whether the poorly soluble drug was recrystallized and precipitated in the emulsion.

The above results are summarized as follows.

1 day 2 days 5 days 7 days 15th 30 days 60 days 90 days Examples 1 to 15 4 ℃ X X X X X X X O
Examples 1, 3,
9, 10, 25 ℃ X X X X X X O
Examples 1, 3,
9, 10, O
Examples 1, 3,
9, 10, 37 ℃ X X X X X X X X 50 ℃ X X X X X X X X 1 day 2 days 5 days 7 days 15th 30 days 60 days 90 days Comparative Examples 1 to 15 4 ℃ X X X X X X O
Comparative Examples 1, 3,
9, 10, 11,
12,13 O
Comparative Examples 1, 3,
9, 10, 11,
12,13 25 ℃ X X X X X O
Comparative Examples 1, 3,
9, 10, 11,
12,13 O
Comparative Examples 1, 3,
9, 10, 11,
12,13 O
Comparative Examples 1, 3,
9, 10, 11,
12,13 37 ℃ X X X X O
Comparative Examples 1, 3,
9, 10, 11,
12,13 O
Comparative Examples 1, 3,
9, 10, 11,
12,13 O
Comparative Examples 1, 3,
9, 10, 11,
12,13 O
Comparative Examples 1, 3,
9, 10, 11,
12,13 50 ℃ X X O
Comparative Examples 1, 3,
9, 10,
O
Comparative Examples 1, 3,
9, 10, 11,
12,13 O
Comparative Examples 1, 3,
9, 10, 11,
12,13 O
Comparative Examples 1, 3,
9, 10, 11,
12,13 O
Comparative Examples 1, 3,
9, 10, 11,
12,13 O
Comparative Examples 1, 3,
9, 10, 11,
12,13

Experimental Example 3

The composition prepared in Example 4 and Comparative Example 4 was centrifuged at room temperature for 10 minutes to 30 minutes using a high-speed centrifuge (Hanil Combi 514R), and the change with time was measured.

After centrifugation, samples were taken and visually confirmed by phase separation.

The above results are summarized as follows.

time 8,500 RPM 9,500 RPM 10,000 RPM 13,000 RPM Example 4 10 minutes stability stability stability stability 20 minutes stability stability stability stability 30 minutes stability stability stability stability Comparative Example 4 10 minutes stability stability Phase separation Phase separation 20 minutes stability Phase separation Phase separation Phase separation 30 minutes stability Phase separation Phase separation Phase separation

Experimental Example 4

The emulsion of Example 4 and Comparative Example 4 was photographed using an optical electron microscope (Olympus Microscope Bx-41) and is shown in Fig.

1, it can be seen that the emulsion of Example 4 has a droplet stably formed in a spherical shape, and the emulsion of Comparative Example 4 has irregularities such as a large number of linear and unstable droplets as well as a spherical droplet It was confirmed that the droplet was formed.

Claims (16)

(a) mixing a surfactant having at least two alkyl chains in the hydrophobic portion, an organic solvent having polarity, and a poorly soluble drug;
(b) injecting the mixture into an inline mixer;
(c) preparing a pre-emulsion by mixing at least 0.1 g of the poorly soluble medicament for at least 0.2 hours under a condition of 100 bar or more and 2,000 bar or less per unit area of the in-line mixer; And
(d) adding the pre-emulsion to water
≪ RTI ID = 0.0 > 1, < / RTI >
The aqueous liquid emulsion composition according to claim 1, wherein the aqueous liquid emulsion has an average diameter of 0.5 to 30 탆.
The method according to claim 1, wherein in step (a), the poorly soluble drug and the surfactant having at least two alkyl chains in the hydrophobic part are mixed at a weight ratio of 0.00001: 10 to 10: 0.00001. Emulsion composition.
The aqueous emulsion composition of claim 1, wherein the poorly soluble drug and the organic solvent having polarity are mixed in a weight ratio of 0.00001: 10 to 10: 0.00001 in step a).
The method of claim 1, wherein in step (a), the poorly soluble drug and the surfactant having two or more alkyl chains in the hydrophobic part are mixed at a weight ratio of 0.00001: 10 to 10: 0.00001, and are mixed with an insoluble drug and an organic solvent Is mixed at a weight ratio of 0.00001: 10 to 10: 0.00001.
The aqueous liquid emulsion composition according to claim 1, wherein the surfactant having at least two alkyl chains in the hydrophobic part is at least one selected from the group consisting of egg yolk lecithin, soybean lecithin and hydrogenated lecithin.
The aqueous liquid emulsion composition according to claim 1, wherein the organic solvent having polarity is an organic substance having two or more groups of ethanol or a hydroxyl group (-OH).
The aqueous liquid emulsion composition according to claim 7, wherein the polar organic solvent is a polyol.
[Claim 7] The method according to claim 7, wherein the polar organic solvent is selected from the group consisting of glycerin, 1,3-butylene glycol, propylene glycol, dipropylene glycol, and ethylene glycol, polyethylene glycol, diethoxydiglycol, ethoxydiglycol, butoxydiglycol Wherein the emulsifiable concentrate is at least one selected from the group consisting of water,
The aqueous liquid phase emulsion composition of claim 1, wherein the inline mixer comprises a mixed blade structure.
The aqueous liquid phase emulsion composition according to claim 1, wherein the average particle size of the aqueous liquid emulsion composition of the poorly soluble drug is within ± 200% of the diameter standard.
The aqueous emulsion composition according to claim 1, wherein the fatty acid is further mixed in step (a).
[Claim 14] The aqueous liquid emulsion composition according to claim 12, wherein the fatty acid is at least one selected from the group consisting of caprylic acid, stearic acid, palmitic acid, myristic acid, lauric acid and oleic acid.
The method of claim 1, wherein the poorly soluble drug is selected from the group consisting of meloxicam, celecoxib, itraconazole, docetaxel, capecitabine, traboprost, isoflavone, paclitaxel, diclofenac sodium, ginsenoside Rg1, alendronate, docetaxel, At least one selected from the group consisting of ranoflavin, latanoprost, bimatoflost, tacrolimus, atorvastatin calcium, rosuvastatin calcium, entecavir, cyclosporin A, amphotericin B, omega 3 and ursodeoxycholic acid ≪ / RTI > by weight of the composition.
The aqueous liquid emulsion composition according to claim 1, wherein the poorly soluble drug has a solubility in water of 1 w / w% or less.
(a) mixing a surfactant having at least two alkyl chains in the hydrophobic portion, an organic solvent having polarity, and a poorly soluble drug;
(b) injecting the mixture into an inline mixer;
(c) preparing a pre-emulsion by mixing at least 0.1 g of the above-mentioned poorly soluble medicament by mixing at least 0.2 hours of maintaining the force per unit area of the in-line mixer at 100 bar or more and 2,000 bar or less; And
(d) adding the pre-emulsion to water
Wherein the aqueous emulsion composition is prepared by dissolving the aqueous emulsion composition in an aqueous medium.

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