KR101561610B1 - Pharmaceutical formulation containing liposome nanoparticles that encapsulate poorly water soluble drug having good long stability and preparation method thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical composition having excellent long-term stability including liposome nanoparticles encapsulating an insoluble drug and a method for producing the same, wherein the size of the liposome nanoparticles encapsulating the poorly soluble drug according to the present invention is 30 -900 nm, the solubility of the pharmaceutical preparation containing the same is improved and the long-term stability is improved, so that the bioavailability of the drug can be improved. In addition, since the pharmaceutical preparation can be manufactured by an easy manufacturing method, it can be usefully applied to a poorly soluble drug that requires stability.

Description

TECHNICAL FIELD The present invention relates to a pharmaceutical composition containing liposomal nanoparticles encapsulating an insoluble drug and having excellent long-term stability and a method for producing the same.

The present invention relates to a pharmaceutical composition having excellent long-term stability including liposome nanoparticles encapsulating an insoluble drug and a method for producing the same.

The research areas of nanoparticles have been actively studied in medicine. Oral preparations for increasing the absorption rate, transdermal preparations for high permeability absorption, injection preparations for improving stability in target orientations or aqueous solutions, Permeation agents and the like.

Many of the drugs currently used as medicines have low bioavailability due to their low solubility when administered to a living body with poor solubility, and many of the candidate drug candidates under development are also difficult to formulate due to their poor solubility. Therefore, a variety of preparation methods for the solubilization of poorly soluble drugs have been studied, but their effects have been limited to a limited extent until now. Polymer nanoparticles are one of the important fields in drug delivery systems. Recently, nanoparticles using amphiphilic polymers have been studied.

Polymer nanoparticles are one of the important fields in drug delivery systems. Recently, nanoparticles using amphiphilic polymers have been studied. The amphipathic polymer in which the hydrophobic block and the hydrophilic block coexist forms a nanocomposite having a unique structure by the physical cohesive force such as intermolecular hydrophobic interaction and van der waals force in the aqueous solution. This shows that the hydrophobic block tends to aggregate in order to minimize contact with water. The hydrophobic aggregate thus formed forms a core and forms a polymeric micelle surrounding the hydrophilic block outside the hydrophobic block, Thereby increasing the solubility. Such polymeric micelles are widely used as formulations for the solubilization of insoluble drugs having a low water solubility and a low bioabsorption ratio by forming cores having a size of several tens to several hundreds of nanometers and encapsulating an insoluble drug therein.

However, based on the above-mentioned nano-based technology, it has been a great effort to deliver an anti-cancer drug which is difficult to heal, but it has not yet achieved remarkable results.

Currently on the market, docetaxel is an anticancer drug marketed by Sanofi-Aventis under the trade name Taxotere and has effects on non-small cell lung cancer, breast cancer, ovarian cancer and head and neck cancer. Docetaxel is a semisynthetic taxoid, which is strongly lipophilic and hardly soluble in water. Commercially available docetaxel is supplied as an injectable solution with a stock solution in Polysorbate 80 and a container containing 13% (W / W) ethanol. The two are mixed to give a pre-culture solution having a solubility of 10 mg / Mix (Pre-Mix) solution is prepared and diluted with physiological saline to be infused by Infusion. The injection solution prepared above should have a concentration of docetaxel of 0.3-0.9 mg / ml in the diluted perfusate, and a precipitate may be formed at the concentration of 0.9 mg / ml or more. In addition, the use of polysorbate 80 has the disadvantage of inducing anaphylaxis shock. In order to prevent such a shock, a steroid or an antihistamine should be pre-administered. In order to maintain the stability of docetaxel in an aqueous solution, alcohol is used as an organic solvent, and thus organic toxicity appears.

Patent Document 1 discloses a water-soluble compound of hydroxypropylbetacyclodextrin and hydroxypropylmethylcellulose (HPMC), polyethylene glycol (PEG) or polyvinylpyrrolidone (PVP) in order to stabilize and formulate a water insoluble compound docetaxel in aqueous solution The polymer was mixed with distilled water and dissolved to develop an injectable preparation, but failed in the bioequivalence test.

Patent Document 2 describes that the stability of an insoluble drug in a polymer aqueous solution is increased by using poloxamer, which is a triblock copolymer with polyethylene glycol. However, when a mixture of polyethylene glycol and poloxamer, which is a triblock copolymer, Can not completely dissolve and the stability is very low, so precipitation occurs from 2-3 hours. In addition, to prevent precipitation, an aqueous solution of lecithin was used to prevent precipitation. However, this method also produced precipitation within several days.

Therefore, it is urgently required to develop a nanoparticle which is simple in a manufacturing method and is stable in an aqueous solution or a solid state without using harmful organic solution or surfactant when manufacturing nanoparticles.

Accordingly, the present inventors have found that, in comparison with conventional formulations, the long-term stability is improved and the solubility is further increased, thereby improving the bioavailability of the drug, The present invention has been completed.

Korean Patent Publication No. 2007-0112725; Korean Patent Publication No. 2012-0046595.

It is an object of the present invention to provide a pharmaceutical composition with improved long-term stability comprising liposomal nanoparticles encapsulating an insoluble drug.

Another object of the present invention is to provide a method for preparing a pharmaceutical composition with improved long-term stability comprising the liposomal nanoparticles encapsulating the poorly soluble drug.

In order to achieve the above object,

Based on 1 part by weight of the poorly soluble drug,

1 - 10 parts by weight of a glycol solubilizer;

1 to 10 parts by weight of a triblock copolymer in the form of [polyethylene oxide (PEO) -polypropylene oxide (PPO) -polyethylene oxide (PEO)];

5 to 25 parts by weight of a phospholipid; And

And 10 to 60 parts by weight of glycerin; and a liposome nanoparticle encapsulating an insoluble drug having a particle size of 30 to 900 nm.

In addition, the present invention includes a step of ultrasonically treating or heating a poorly soluble drug by mixing it with a glycol solubilizer and a triblock copolymer of [polyethylene oxide (PEO) -polypropylene oxide (PPO) -polyethylene oxide (PEO)] One); And

(Step 2) of adding a solution prepared by dissolving a phospholipid in a glycerin-containing solution to the mixture of step 1 (step 2). A method for producing a preparation is provided.

The size of the liposome nanoparticles encapsulating the poorly soluble drug according to the present invention is 30-900 nm, which improves the solubility of the pharmaceutical preparation containing it and improves the bioavailability of the drug because of its excellent long-term stability. In addition, since the pharmaceutical preparation can be manufactured by an easy manufacturing method, it can be usefully applied to a poorly soluble drug that requires stability.

Fig. 1 is a photograph taken to visually confirm whether or not a liquid formulation of Example 4 of the present invention and a precipitate after dilution with liquid formulation, 2-fold, 4-fold, 8-fold and 16-fold were observed.
FIG. 2 is a graph showing the average particle size of a preparation diluted with 2-fold, 4-fold, 8-fold, and 16-fold formulations of Example 4 of the present invention.
FIG. 3 is a graph showing a two-week change in the mean particle size of the liquid liposome prepared in Example 4. FIG.
Fig. 4 is a graph showing the two-week change in the average particle size of the solid-state liposome prepared in Example 11. Fig.

Hereinafter, the present invention will be described in detail.

Based on 1 part by weight of the poorly soluble drug,

1 - 10 parts by weight of a glycol solubilizer;

1 to 10 parts by weight of a triblock copolymer in the form of [polyethylene oxide (PEO) -polypropylene oxide (PPO) -polyethylene oxide (PEO)];

5 to 25 parts by weight of a phospholipid; And

And 10 to 60 parts by weight of glycerin; and a liposome nanoparticle encapsulating an insoluble drug having a particle size of 30 to 900 nm.

Hereinafter, the pharmaceutical preparation according to the present invention will be described in detail.

In the pharmaceutical preparation according to the present invention, the poorly soluble drug may be used alone or in combination with a poorly soluble drug which is difficult to be solubilized, and is preferably an anticancer agent, a therapeutic agent for cardiovascular diseases and the like, and is preferably selected from docetaxel, paclitaxel, doxorubicin, cisplatin , It is more preferable to use alone or in combination with carbodiimide, carboplatin, 5-FU, etoposide, camptothecin, testosterone, estrogen, estradiol, triamcinolone acetonide, hydrocortisone, dexamethasone, prednisolone, betamethasone, cyclosporine, prostaglandin And docetaxel alone is most preferably used, but not limited thereto.

In the pharmaceutical preparation according to the present invention, the glycol solubilizing agent may be polyethylene glycol, propylene glycol, tetraglycol, or the like, preferably polyethylene glycol. The glycol solubilizer may be used in combination with glycofurol, polysorbate, cremophor, Solutol HS 15, and the like.

The glycol solubilizer is preferably contained in an amount of 1 to 10 parts by weight, more preferably 2 to 8 parts by weight, and most preferably 4 to 6 parts by weight, based on 1 part by weight of the poorly soluble drug.

When the glycerol solubilizer is contained in an amount of less than 1 part by weight based on 1 part by weight of the poorly soluble drug, dispersion of the poorly soluble drug is incomplete, resulting in difficulty in drug release. When the glycol solubilizer is contained in an amount exceeding 10 parts by weight, The improvement of the dissolution rate or the stability is insufficient and the reagent is wasted.

In the pharmaceutical preparation according to the present invention, the [PEO-PPO-PEO] type triblock copolymer residue plays a role of micelle formation. Examples of the triblock copolymer residues of the [PEO-PPO-PEO] type include Poloxamer 184, Poloxamer 185, Poloxamer 188, Poloxamer 124, Poloxamer 237, Poloxamer 338, Poloxamer 407, It is preferable to use SOMER 188.

In addition, the [PEO-PPO-PEO] type triblock copolymer is preferably contained in 1 to 10 parts by weight, more preferably 2 to 8 parts by weight, based on 1 part by weight of the poorly soluble drug.

When the triblock copolymer of [PEO-PPO-PEO] type is contained in an amount of less than 1 part by weight based on 1 part by weight of the tacky drug, a poorly soluble drug is precipitated quickly. When the triblock copolymer is contained in an amount exceeding 10 parts by weight, There is a problem that the size increases.

In the pharmaceutical preparation according to the present invention, the phospholipid functions to increase the stability of the micelle by enclosing the micelle in the phospholipid. Such phospholipids include lecithins, phosphatidylcholine, phosphatidylethanolamines, phosphatidylserines, phosphatidylglycerols, phosphatidylinositols, sterols, anionic lipids, cationic lipids, phosphatidylcholine, phosphatidylic acid, sphingomyelin, , Cardiolipin, phosphoinositide, acetic anhydride, lipid-PEG, saturated fatty acid-containing phospholipids, etc. may be used singly or in combination.

Specifically, the lecithins may be purified egg yolk lecithin, purified soybean lecithin and the like. The phosphatidylcholine may be selected from the group consisting of soybean phosphatidylcholine, yolk phosphatidylcholine, bovine phosphatidylcholine, dilauryl phosphatidylcholine, dimyristoylphosphatidylcholine, Tolyl phosphatidylcholine, distearoylphosphatidylcholine and the like can be used. The phosphatidylethanolamines include diaryloylphosphatidylethanolamine, dimyristoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, distearoylphosphatidylethanolamine, Dioleoylphosphatidylethanolamine and the like can be used.

The above phosphatidylserines may be used in combination with dilauroyl phosphatidylserine, dimyristoylphosphatidylserine, dipalmitoylphosphatidylserine, distearoylphosphatidylserine, and the like. The phosphatidylglycerols may be dilaurylphosphatidylglycerol , Di-myristoyl phosphatidyl glycerol, dipalmitoyl phosphatidyl glycerol, distearoyl phosphatidyl glycerol, and the like. The phosphatidyl inositols include di lauroyl phosphatidyl inositol, dimyristoyl phosphatidyl inositol, dipalmitoyl phosphatidyl inositol , Distearoylphosphatidylinositol, and the like.

Further, the sterols may be cholesterol, cholesterol hexasuccinate, 3? - [N- (N ', N'-dimethylaminoethane) carbamoyl] cholesterol, ergosterol, stigmasterol, lanosterol, The lipid may be selected from the group consisting of dipalmitoyl glycerophosphate, distearoyl glycerophosphoglycerol, dipalmiotyl isostatic acid, and the like. The cationic lipid may be selected from the group consisting of dioleic trimethylammonium propane, dimethyloctadecylammonium , Diol ricin phosphatylethanolamine, dialkyldimethylammonium propane, dialkyltrimethylammonium propane, and the like can be used.

The phospholipid is preferably contained in an amount of 5 to 25 parts by weight, more preferably 10 to 20 parts by weight, and most preferably 10 to 15 parts by weight, based on 1 part by weight of the poorly soluble drug.

When the phospholipid is contained in an amount of less than 5 parts by weight based on 1 part by weight of the poorly soluble drug, micelles are not sufficiently enclosed and a poorly soluble drug is precipitated. When the amount of the phospholipid is more than 25 parts by weight, The problem of enlargement occurs.

In the pharmaceutical preparation according to the present invention, the glycerin can be used without limitation as long as it can dissolve the phospholipid at a concentration of 1-70%. However, glycerin, alkoxyglycerol, glycerol monostearate, nitroglycerin, glycerol oleate, Glyceryl myristate, glyceryl stearate, glyceryl di-palmitate, glyceryl triolate, glyceryl myristate, glyceryl cocoate and the like are preferably used, and glycerin having a purity of 99.0% or more is more preferably used.

The glycerin is preferably contained in an amount of 10 to 60 parts by weight, more preferably 15 to 55 parts by weight, and most preferably 20 to 50 parts by weight based on 1 part by weight of the poorly soluble drug.

When the glycerin is contained in an amount less than 10 parts by weight based on 1 part by weight of the poorly soluble drug, the phospholipid is not sufficiently dispersed. When the glycerin is contained in an amount exceeding 60 parts by weight, the glycerin capacity is excessively used A sufficient sealing effect can not be expected.

The pharmaceutical preparations according to the present invention may be in the form of oral preparations, injections, mucosal preparations, inhalants, external preparations, percutaneous absorption preparations and the like, but they are not limited thereto, and oral preparations or injection preparations are preferable.

The pharmaceutical preparation according to the present invention may further comprise a pH adjusting agent for adjusting the acidity suitable for use as a preparation, and the pH adjusting agent may be those conventionally used in the art, preferably citric acid, malic acid , Lactic acid, fumaric acid, glycolic acid, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid and the like.

The pharmaceutical preparations according to the present invention may contain at least one excipient such as polyvinylpyrrolidone, glucose, phosphatide, polyhydric alcohol, sucrose, trehalose, mannitol, lactose, citric acid, mannitol, deck Those which can be used for pharmaceuticals such as monosaccharides, disaccharides, and trisaccharides, including sucrose, can be used.

As described above, the pharmaceutical preparation according to the present invention improves the solubility and the long-term stability, so that the bioavailability of the drug can be improved (see Experimental Examples 1 and 2).

In addition, the present invention relates to a method for preparing a pharmaceutical composition, comprising the steps of: (1) mixing an insoluble drug with a glycol dissolving agent and ultrasonic treatment or heating; And

(Step 2) of adding a solution prepared by dissolving a phospholipid in a glycerin-type mixture to the mixture of step 1, and a step (step 2) of adding a solution prepared by dissolving a phospholipid in glycerin- And a manufacturing method thereof.

Hereinafter, the manufacturing method according to the present invention will be described in detail.

First, in the method for producing a pharmaceutical preparation according to the present invention, step 1 is a step of mixing an insoluble drug with a glycol dissolving agent and ultrasonic treatment or heating.

Specifically, step 1 is a step of dissolving the poorly soluble drug in a glycerol dissolving agent for liposomizing, and a method of dissolving the insoluble drug by dissolving it through ultrasonic treatment may be used, but not limited thereto .

In the preparation method according to the present invention, the insoluble drug may be used alone or in combination with a poorly soluble drug which is difficult to be solubilized. An anticancer drug, a cardiovascular disease drug, and the like are preferable, and docetaxel, paclitaxel, doxorubicin, cisplatin, It is more preferable to use them alone or in combination with other drugs such as carboplatin, 5-FU, etoposide, camptothecin, testosterone, estrogen, estradiol, triamcinolone acetonide, hydrocortisone, dexamethasone, prednisolone, betamethasone, cyclosporin, prostaglandin , Docetaxel alone is most preferably used, but not limited thereto.

In the production method according to the present invention, the glycol solubilizing agent may be polyethylene glycol, propylene glycol, tetraglycol and the like, preferably polyethylene glycol. The glycol solubilizer may be used in combination with glycofurol, polysorbate, cremophor, Solutol HS 15, and the like.

The glycol solubilizer is preferably contained in an amount of 1 to 10 parts by weight, more preferably 2 to 8 parts by weight, and most preferably 4 to 6 parts by weight, based on 1 part by weight of the poorly soluble drug.

In the pharmaceutical preparation according to the present invention, the [PEO-PPO-PEO] type triblock copolymer residue plays a role of liposome formation. Examples of the triblock copolymer residues of the [PEO-PPO-PEO] type include Poloxamer 184, Poloxamer 185, Poloxamer 188, Poloxamer 124, Poloxamer 237, Poloxamer 338, Poloxamer 407, It is preferable to use SOMER 188.

In addition, the [PEO-PPO-PEO] type triblock copolymer is preferably contained in 1 to 10 parts by weight, more preferably 2 to 8 parts by weight, based on 1 part by weight of the poorly soluble drug.

Next, in the method for producing a pharmaceutical preparation according to the present invention, Step 2 is a step of adding a solution prepared by dissolving phospholipids in glycerin to the mixture of Step 1 to disperse the mixture.

Specifically, step 2 is a step of adding a solution in which phospholipids are dissolved in glycerin to improve the solubility and stability of the poorly soluble drug, thereby liposomizing the poorly soluble drug.

In the preparation method according to the present invention, the phospholipid is selected from the group consisting of lecithins, phosphatidylcholine, phosphatidylethanolamines, phosphatidylserines, phosphatidylglycerols, phosphatidylinositols, sterols, anionic lipids, cationic lipids, phosphatidylcholine, Phospholipids, dexamethasone, sphingomyelin, cephalin, cardiolipin, phosphoinositide, acetic anhydride, lipid-PEG, saturated fatty acid-containing phospholipids and the like.

Specifically, the lecithins may be purified egg yolk lecithin, purified soybean lecithin and the like. The phosphatidylcholine may be selected from the group consisting of soybean phosphatidylcholine, yolk phosphatidylcholine, bovine phosphatidylcholine, dilauryl phosphatidylcholine, dimyristoylphosphatidylcholine, Tolyl phosphatidylcholine, distearoylphosphatidylcholine and the like can be used. The phosphatidylethanolamines include diaryloylphosphatidylethanolamine, dimyristoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, distearoylphosphatidylethanolamine, Dioleoylphosphatidylethanolamine and the like can be used.

The above phosphatidylserines may be used in combination with dilauroyl phosphatidylserine, dimyristoylphosphatidylserine, dipalmitoylphosphatidylserine, distearoylphosphatidylserine, and the like. The phosphatidylglycerols may be dilaurylphosphatidylglycerol , Di-myristoyl phosphatidyl glycerol, dipalmitoyl phosphatidyl glycerol, distearoyl phosphatidyl glycerol, and the like. The phosphatidyl inositols include di lauroyl phosphatidyl inositol, dimyristoyl phosphatidyl inositol, dipalmitoyl phosphatidyl inositol , Distearoylphosphatidylinositol, and the like.

Further, the sterols may be cholesterol, cholesterol hexasuccinate, 3? - [N- (N ', N'-dimethylaminoethane) carbamoyl] cholesterol, ergosterol, stigmasterol, lanosterol, The lipid may be selected from the group consisting of dipalmitoyl glycerophosphate, distearoyl glycerophosphoglycerol, dipalmiotyl isostatic acid, and the like. The cationic lipid may be selected from the group consisting of dioleic trimethylammonium propane, dimethyloctadecylammonium , Diol ricin phosphatylethanolamine, dialkyldimethylammonium propane, dialkyltrimethylammonium propane, and the like can be used.

The phospholipid is preferably contained in an amount of 5 to 25 parts by weight, more preferably 10 to 20 parts by weight, and most preferably 10 to 15 parts by weight, based on 1 part by weight of the poorly soluble drug.

In the preparation method according to the present invention, the glycerin can be used without limitation as long as it can dissolve the phospholipid at a concentration of 1-70%. However, the glycerin can be used in the form of glycerin, alkoxyglycerol, glycerol monostearate, nitroglycerin, glycerol oleate, Glyceryl trioleate, glyceryl myristate, glyceryl cocoate and the like are preferably used, and glycerin having a purity of not less than 99.0% is most preferably used.

The glycerin is preferably contained in an amount of 10 to 60 parts by weight, more preferably 15 to 55 parts by weight, and most preferably 20 to 50 parts by weight based on 1 part by weight of the poorly soluble drug.

In the manufacturing method according to the present invention, the step of lyophilization after the step 2 may further comprise the step of preparing the liposome nanoparticles encapsulating the solid insoluble drug.

The preparation method according to the present invention can be applied to pharmaceutical preparations with improved long-term stability including liposomal nanoparticles encapsulating an insoluble drug that can be used in the form of oral agents, injections, mucosal agents, inhalants, external agents, Can be manufactured.

The preparation method according to the present invention may further comprise a pH adjusting agent for adjusting the acidity suitable for use as a preparation, and the pH adjusting agent may be those conventionally used in the art, preferably citric acid, malic acid, Lactic acid, fumaric acid, glycolic acid, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and the like.

The preparation method according to the present invention may be carried out by mixing at least one excipient such as polyvinylpyrrolidone, glucose, phosphatide, polyhydric alcohol, sucrose, trehalose, mannitol, lactose, citric acid, mannitol, dextrose Which can be used for pharmaceuticals such as monosaccharides, disaccharides, and trisaccharides.

The preparation method according to the present invention can prepare liposomic nanoparticles having a particle size of 30-900 nm in which a poorly soluble drug is encapsulated and improve the solubility of the pharmaceutical preparation containing the drug, Can be effectively used as a method for producing a pharmaceutical preparation which can improve the bioavailability of the pharmaceutical composition.

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.

The following Examples and Experimental Examples are merely illustrative of the present invention, and the present invention is not limited to the following Examples and Experimental Examples.

< Example  1> liquid phase Liposome  Nanoparticle

Dexamethasol (87 mg) was added to 110 mg of polyethylene glycol (PEG-400) to which pH adjuster (citric acid, 2.75 mg) had been added and then triblock copolymer F-68 (440 mg) And melted. Next, a solution (10.75 g) dissolved in glycerin (8 g) such that the concentration of lecithin (L-alpha-phosphatidylcholine, 2.75 g) as a phospholipid was 25 wt% was added to the mixed solution to prepare liquid liposome nanoparticles .

< Example  2> liquid phase Liposome  Nanoparticle

Except that polyethylene glycol (PEG-400) (220 mg) was used instead of polyethylene glycol (PEG-400) (110 mg) in Example 1 above.

< Example  3> Liquid phase Liposome  Nanoparticle

Except that polyethylene glycol (PEG-400) (330 mg) was used instead of polyethylene glycol (PEG-400) (110 mg) in Example 1 above.

< Example  4> Liquid phase Liposome  Nanoparticle

Except that polyethylene glycol (PEG-400) (440 mg) was used instead of polyethylene glycol (PEG-400) (110 mg) in Example 1 above.

< Example  5> Liquid phase Liposome  Nanoparticle

Except that polyethylene glycol (PEG-400) (550 mg) was used instead of polyethylene glycol (PEG-400) (110 mg) in Example 1 above.

< Example  6> Liquid phase Liposome  Nanoparticle

Except that polyethylene glycol (PEG-600) (440 mg) was used instead of polyethylene glycol (PEG-400) (110 mg) in Example 1 above.

< Example  7> Liquid phase Liposome  Nanoparticle

Except that polyethylene glycol (PEG-600) (550 mg) was used instead of polyethylene glycol (PEG-400) (110 mg) in Example 1 above.

< Example  8> solid phase Liposome  Nanoparticle

Dexamethasol (87 mg) was added to 110 mg of polyethylene glycol (PEG-400) to which a pH adjuster (compound name, 2.75 mg) had been added and then triblock copolymer F-68 (440 mg) Lt; 0 &gt; C. Next, a solution (10.75 g) prepared by dissolving lecithin (L-α-phosphatidylcholine, 2.75 g) as a phospholipid in glycerin (8 g) so as to have a concentration of 25% by weight was added to the mixed solution, and then dextrose 20 mL), cooled, and lyophilized to prepare solid-phase liposomal nanoparticles.

< Example  9> solid phase Liposome  Nanoparticle

The procedure of Example 8 was repeated except that polyethylene glycol (PEG-400) (220 mg) was used instead of polyethylene glycol (PEG-400) (110 mg).

< Example  10> solid phase Liposome  Nanoparticle

Except that polyethylene glycol (PEG-400) (330 mg) was used instead of polyethylene glycol (PEG-400) (110 mg) in Example 8 above.

< Example  11> solid phase Liposome  Nanoparticle

Except that polyethylene glycol (PEG-400) (440 mg) was used instead of polyethylene glycol (PEG-400) (110 mg) in Example 8.

< Example  12> solid phase Liposome  Nanoparticle

Except that polyethylene glycol (PEG-400) (550 mg) was used instead of polyethylene glycol (PEG-400) (110 mg) in Example 8.

< Example  13> solid phase Liposome  Nanoparticle

Except that polyethylene glycol (PEG-600) (440 mg) was used instead of polyethylene glycol (PEG-400) (110 mg) in Example 8.

< Example  14> solid phase Liposome  Nanoparticle

The procedure of Example 11 was repeated except that polyvinylidone (2 g) was used instead of dextrose (2 g).

< Example  15> Liquid phase Liposome  Nanoparticle

Except that F-68 (110 mg) was used instead of F-68 (440 mg) in Example 4 above.

< Example  16> liquid phase Liposome  Nanoparticle

The procedure of Example 4 was repeated except that F-68 (220 mg) was used instead of F-68 (440 mg).

< Example  17> Liquid phase Liposome  Nanoparticle

The procedure of Example 4 was repeated except that F-68 (330 mg) was used instead of F-68 (440 mg).

< Example  18> liquid phase Liposome  Nanoparticle

The procedure of Example 4 was repeated except that F-68 (550 mg) was used instead of F-68 (440 mg).

< Example  19> liquid phase Liposome  Nanoparticle

Except that F-127 (440 mg) was used instead of F-68 (440 mg) in Example 4 above.

< Example  20> liquid phase Liposome  Nanoparticle

The procedure of Example 4 was repeated except that F-127 (550 mg) was used instead of F-68 (440 mg).

< Example  21> liquid phase Liposome  Nanoparticle

(10.75 g) was dissolved in glycerol (7.3 g) such that the concentration of lecithin (3440 mg) was adjusted to 32% by weight in place of the solution (10.75 g) dissolved in glycerol so that the concentration of lecithin was 25% ) Was used as the starting material.

< Example  22> liquid phase Liposome  Nanoparticle

(10.75 g) was dissolved in glycerol (8.75 g) such that the concentration of lecithin (2150 mg) was 20% by weight instead of the solution (10.75 g) dissolved in glycerol so that the concentration of lecithin was 25% ) Was used as the starting material.

< Example  23> liquid phase Liposome  Nanoparticle

(10.75 g) was dissolved in glycerin (9.14 g) such that the concentration of lecithin (1610 mg) was 15% by weight instead of the solution (10.75 g) dissolved in glycerol so that the concentration of lecithin was 25% ) Was used as the starting material.

< Example  24> liquid phase Liposome  Nanoparticle

(10.75 g) was dissolved in glycerin (9.67 g) such that the concentration of lecithin (1075 mg) was 10 wt% instead of the solution (10.75 g) dissolved in glycerin so that the concentration of lecithin was 25 wt% ) Was used as the starting material.

< Example  25> liquid phase Liposome  Nanoparticle

(10.75 g) dissolved in glycerin (6.75 g) such that the concentration of lecithin (4300 mg) was 40% by weight instead of the solution (10.75 g) dissolved in glycerol so that the concentration of lecithin was 25% ) Was used as the starting material.

< Example  26> liquid phase Liposome  Nanoparticle

(10.75 g) was dissolved in glycerol (5375 mg) such that the concentration of lecithin (5375 mg) was 50% by weight instead of the solution (10.75 g) dissolved in glycerol so that the concentration of lecithin was 25% ) Was used as the starting material.

< Example  27> Liquid phase Liposome  Nanoparticle

(10.75 g) dissolved in glycerol such that the concentration of lecithin was 25% by weight in Example 4 was dissolved in glycerol (3225 mg) such that the concentration of lecithin (7525 mg) was 70% by weight ) Was used as the starting material.

< Comparative Example  1> liquid phase Liposome  Nanoparticle

Except that polyethylene glycol (PEG-400) (10 mg) was used instead of polyethylene glycol (PEG-400) (110 mg) in Example 1 above.

< Comparative Example  2> liquid phase Liposome  Nanoparticle

Except that polyethylene glycol (PEG-400) (1100 mg) was used instead of polyethylene glycol (PEG-400) (110 mg) in Example 1 above.

< Comparative Example  3> Liquid phase Liposome  Nanoparticle

A solution (10.75 g) of lecithin (1075 mg) dissolved in glycerol (9675 mg) such that the concentration of lecithin (1075 mg) was changed to 10 wt% instead of the solution (10.75 g) dissolved in glycerol so that the concentration of lecithin was 25% ) Was used as the starting material.

< Comparative Example  4> Liquid phase Liposome  Nanoparticle

(10.75 g) was dissolved in glycerin (7.2 mg) such that the concentration of lecithin (3547 mg) was 33% by weight instead of the solution (10.75 g) dissolved in glycerol so that the concentration of lecithin was 25% ) Was used as the starting material.

< Comparative Example  5> Liquid phase Liposome  Nanoparticle

(10.75 g) was dissolved in glycerin (6235 mg) such that the concentration of lecithin (4515 mg) was 42% by weight instead of the solution (10.75 g) dissolved in glycerol so that the concentration of lecithin was 25% ) Was used as the starting material.

< Comparative Example  6> Liquid phase Liposome  Nanoparticle

A solution (6.5 g) of lecithin (2070 mg) dissolved in glycerol (8708 mg) such that the concentration of lecithin (2042 mg) was changed to 19 wt% instead of the solution (10.75 g) dissolved in glycerol so that the concentration of lecithin was 25% ) Was used as the starting material.

The components of the pharmaceutical preparations prepared in Example 1-21 and Comparative Example 1-6 are shown in Table 1 below.

Docetaxel weight part Glycols
(Parts by weight) Tree block
Copolymer
(Parts by weight) lecithin
Weight portion glycerin
Weight portion shape Example 1 One PEG 400 (1.26) F-68 (5.05) 14.36 43.10 Liquid phase Example 2 One PEG 400 (2.53) F-68 (5.05) 14.36 43.10 Liquid phase Example 3 One PEG 400 (3.79) F-68 (5.05) 14.36 43.10 Liquid phase Example 4 One PEG 400 (5.05) F-68 (5.05) 14.36 43.10 Liquid phase Example 5 One PEG 400 (6.32) F-68 (5.05) 14.36 43.10 Liquid phase Example 6 One PEG 600 (5.05) F-68 (5.05) 14.36 43.10 Liquid phase Example 7 One PEG 600 (6.32) F-68 (5.05) 14.36 43.10 Liquid phase Example 8 One PEG 400 (1.26) F-68 (5.05) 14.36 43.10 Solid phase Example 9 One PEG 400 (2.53) F-68 (5.05) 14.36 43.10 Solid phase Example 10 One PEG 400 (3.79) F-68 (5.05) 14.36 43.10 Solid phase Example 11 One PEG 400 (5.05) F-68 (5.05) 14.36 43.10 Solid phase Example 12 One PEG 400 (6.32) F-68 (5.05) 14.36 43.10 Solid phase Example 13 One PEG 600 (5.05) F-68 (5.05) 14.36 43.10 Solid phase Example 14 One PEG 600 (6.32) F-68 (5.05) 14.36 43.10 Solid phase Example 15 One PEG 400 (5.05) F-68 (1.26) 14.36 43.10 Liquid phase Example 16 One PEG 400 (5.05) F-68 (2.53) 14.36 43.10 Liquid phase Example 17 One PEG 400 (5.05) F-68 (3.79) 14.36 43.10 Liquid phase Example 18 One PEG 400 (5.05) F-68 (6.32) 14.36 43.10 Liquid phase Example 19 One PEG 400 (5.05) F-127 (5.05) 14.36 43.10 Liquid phase Example 20 One PEG 400 (5.05) F-127 (6.32) 14.36 43.10 Liquid phase Example 21 One PEG 400 (5.05) F-68 (5.05) 18.39 39.10 Liquid phase Example 22 One PEG 400 (5.05) F-68 (5.05) 11.49 45.97 Liquid phase Example 23 One PEG 400 (5.05) F-68 (5.05) 8.62 48.85 Liquid phase Example 24 One PEG 400 (5.05) F-68 (5.05) 5.74 51.72 Liquid phase Example 25 One PEG 400 (5.05) F-68 (5.05) 18.39 27.58 Liquid phase Example 26 One PEG 400 (5.05) F-68 (5.05) 14.36 14.36 Liquid phase Example 27 One PEG 400 (5.05) F-68 (5.05) 24.13 10.34 Liquid phase Comparative Example 1 One PEG 400 (0.11) F-68 (5.05) 14.36 43.10 Liquid phase Comparative Example 2 One PEG 400 (12.64) F-68 (5.05) 14.36 43.10 Liquid phase Comparative Example 3 One PEG 400 (5.05) F-68 (5.05) 1.15 10.34 Liquid phase Comparative Example 4 One PEG 400 (5.05) F-68 (5.05) 1.15 33.33 Liquid phase Comparative Example 5 One PEG 400 (5.05) F-68 (5.05) 28.73 40.23 Liquid phase Comparative Example 6 One PEG 400 (5.05) F-68 (5.05) 14.36 60.34 Liquid phase

< Experimental Example  1> Evaluation of average particle size by dilution of liquid formulation

In order to determine the precipitation and average particle size of the liposomal nanoparticles encapsulating the poorly soluble drug according to the dilution concentration of the liquid preparation prepared in Example 4, the following experiment was conducted.

Specifically, five vials were prepared, and the liquid preparation (10 mL) prepared in Example 1, which was diluted by 2 times, 4 times, 8 times and 16 times with distilled water, was added to each vial, The results are shown in Fig. 1, and the results are shown in Table 1. The results are shown in Table 1. The results are shown in Table 1. The results are shown in Table 1. The results are shown in Table 1 by a particle size analyzer (manufacturer: Photal Otsuka electronics, model name: ELS-Z) using dynamic light scattering The particle size was measured and the results are shown in Fig.

Fig. 1 is a photograph taken to visually confirm whether or not a liquid formulation of Example 4 of the present invention and a precipitate after dilution with liquid formulation, 2-fold, 4-fold, 8-fold and 16-fold were observed.

FIG. 2 is a graph showing the average particle size of a preparation diluted with 2-fold, 4-fold, 8-fold, and 16-fold formulations of Example 4 of the present invention.

As shown in FIG. 1 and FIG. 2, it can be seen that the liquid preparation of Example 4 according to the present invention does not precipitate and exhibits a uniform particle size distribution, and the average particle size decreases as the dilution ratio increases.

From the above results, it can be seen that the glycerol solubilizer, the phospholipid and the lecithin glycerol solution of the pharmaceutical preparation according to the present invention had the average particle size of the liposomal nanoparticles encapsulating the poorly soluble drug uniformly dissolved therein and stably dissolved in the aqueous solution, It can be seen that no precipitate is formed.

Therefore, the pharmaceutical preparation according to the present invention forms liposomal nanoparticles encapsulating a poorly soluble drug using only a glycol dissolving agent, a phospholipid and a lecithin glycerol solution without using a harmful organic solvent or a surfactant, It was found that the problem of sedimentation of the soluble drug was improved.

< Experimental Example  2> Liposome  Evaluation of average particle size stability

The changes in the average particle size of the liposomes of the liquid liposome nanoparticles prepared in Examples 1 to 7, Examples 15 to 21 and Comparative Examples 1 to 6 and the solid liposome nanoparticles prepared in Examples 8 to 14 over time The average particle size of the liposome was measured immediately after production, 24 hours, 7 days, and 2 weeks by using a particle size analyzer (manufactured by Photal Otsuka electronics, model name: ELS-Z ), And the results are shown in Tables 2, 3, and 4. As shown in Fig.

0 hours 24 hours 7 days 14 days Example 1 130.1 132.5 146.4 158.2 Example 2 121.7 137.0 150.1 153.5 Example 3 126.2 127.1 138.2 137.5 Example 4 115.2 121.9 122.5 123.7 Example 5 121.1 130.3 135.1 137.6 Example 6 152.3 161.9 157.6 160.8 Example 7 150.5 153.6 162.0 162.9 Example 8 211.0 218.3 223.6 225.7 Example 9 201.6 213.7 227.3 230.9 Example 10 187.3 188.0 193.8 220.7 Example 11 159.2 166.2 164.2 166.1 Example 12 177.5 180.4 187.2 195.1 Example 13 190.2 200.8 206.7 223.9 Example 14 160.4 164.2 172.2 175.4 Example 15 157.8 162.1 164.5 190.2 Example 16 150.1 152.1 162.4 165.5 Example 17 142.2 153.1 152.0 156.7 Example 18 149.2 148.2 152.1 153.4 Example 19 128.2 139.5 143.3 145.2 Example 20 157.1 152.4 160.8 161.6 Example 21 137.1 138.5 142.1 143.9 Comparative Example 1 753.3 762.2 862.7 - Comparative Example 2 251.4 252.5 260.7 262.1 Comparative Example 3 601.0 660.7 700.4 - Comparative Example 4 253.5 252.6 257.1 658.6 Comparative Example 5 663.4 662.1 867.8 - Comparative Example 6 257.4 258.7 267.4 268.1

FIG. 3 is a graph showing a two-week change in the mean particle size of the liquid liposome prepared in Example 4. FIG.

Fig. 4 is a graph showing the two-week change in the average particle size of the solid-state liposome prepared in Example 11. Fig.

As shown in FIGS. 3 and 4, it can be seen that the average particle size of the liquid-phase liposomic nanoparticles prepared in Examples 1 to 7 and 15 to 21 was stable at 130 to 160 nm on average for two weeks, It was found that the average particle size of the solid-state liposomal nanoparticles prepared in Examples 8 to 14 was stably maintained at 160 to 240 nm for 2 weeks.

Therefore, the pharmaceutical preparation according to the present invention can maintain the size of the liposome nanoparticles encapsulating the poorly soluble drug for a long period of time by using only the glycol solubilizer, the triblock copolymer, the phospholipid and the lecithin glycerol solution without using a harmful organic solvent , It is stable, and it is understood that the precipitation problem of the poorly soluble drug as the active ingredient is improved.

Claims (10)

1 part by weight of the poorly soluble drug is mixed with 1-10 parts by weight of a glycol solubilizer and 1-10 parts by weight of a triblock copolymer (polyethylene oxide (PEO) - polypropylene oxide (PPO) -polyethylene oxide (PEO) Treating or heating (step 1); And
(Step 2) of adding a solution prepared by dissolving 5 to 25 parts by weight of a phospholipid in 10 to 60 parts by weight of glycerin to the mixture of step 1, Wherein the liposomal nanoparticles are encapsulated with an insoluble drug.
The method according to claim 1,
Wherein said insoluble drug is selected from the group consisting of docetaxel, paclitaxel, doxorubicin, cispletin, carboprotein, 5-FU, etoposide, camptothecin, testosterone, estrogen, estradiol, triamcinolone acetonide, hydrocortisone, dexamethasone, prednisolone, betamethasone, Cyclosporin, and prostaglandin. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt;
The method according to claim 1,
Wherein the glycol solubilizer is at least one selected from the group consisting of polyethylene glycol, propylene glycol, and tetraglycol.
The method according to claim 1,
Wherein the glycol solubilizer is a mixture of at least one selected from the group consisting of glycofurol, polysorbate, cremopore, and Solutol HS 15.
The method according to claim 1,
The triblock copolymer residues in the form of [polyethylene oxide (PEO) -polypropylene oxide (PPO) -Polyethylene Oxide (PEO)] include Poloxamer 184, Poloxamer 185, Poloxamer 188, Poloxamer 124, Poloxamer 237, 338, and Poloxamer 407. The method according to claim 33,
The method according to claim 1,
The phospholipid is selected from the group consisting of lecithins, phosphatidylcholine, phosphatidylethanolamines, phosphatidylserines, phosphatidylglycerols, phosphatidylinositols, sterols, anionic lipids, cationic lipids, phosphatidylcholine, phosphatidic acid, sphingomyelin, Wherein the phospholipid is at least one member selected from the group consisting of cardiolipin, phosphoinositide, acetal phosphate, lipid-PEG, and saturated fatty acid-containing phospholipids.
The method according to claim 1,
Wherein the glycerin family is selected from the group consisting of glycerin, alkoxyglycerol, glycerol monostearate, nitroglycerin, glycerol oleate, glyceryl stearate, glyceryldipyrinate, glyceryl trioleate, glyceryl myristate and glyceryl cocoate And at least one kind selected from the group consisting of:
delete The method according to claim 1,
The preparation method comprises the steps of: preparing a pharmaceutical composition comprising polyvinylpyrrolidone, glucose, a phosphatide, a polyhydric alcohol, and a monosaccharide, a disaccharide and a trisaccharide including sucrose, trehalose, mannitol, lactose, citric acid, mannitol, dextrose, One or more excipients selected from the group consisting of: And
Wherein at least one pH adjusting agent selected from the group consisting of citric acid, malic acid, lactic acid, fumaric acid, glycolic acid, acetic acid, hydrochloric acid, hydrobromic acid and sulfuric acid can be further used.
A liposomal nanoparticle prepared by the method of claim 1 encapsulating an insoluble drug having improved long term stability and a particle size of 30-900 nm.

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