KR101787447B1 - Pharmaceutical composition with improved storage stability and method for preparing the same - Google Patents

Abstract

There is provided a pharmaceutical composition comprising a content of a specific soft substance below a reference and a process for producing the same.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pharmaceutical composition having improved storage stability and a method for preparing the same,

The present invention relates to a pharmaceutical composition with improved storage stability and a method for preparing the same, and more particularly, to a pharmaceutical composition for a poorly water-soluble drug comprising an amphiphilic block copolymer, And a process for producing the same.

Solubilization of water-soluble drugs is an essential technique for delivering drugs to the body via oral and parenteral administration. Such solubilization methods include adding a surfactant to an aqueous solution to form micelles and then incorporating the poorly soluble drugs. The amphiphilic block copolymer used as a surfactant is composed of a hydrophilic polymer block and a hydrophobic polymer block. Since the hydrophilic polymer block comes into direct contact with blood proteins and cell membranes in vivo, biocompatible polyethylene glycol or monomethoxypolyethylene glycol has been used. The hydrophobic polymer block improves the affinity with the hydrophobic drug and biodegradable polylactide, polyglycolide, poly (lactic-glycolide), polycaprolactone, polyamino acid or polyorthoesters have been used . Particularly, polylactide derivatives have excellent biocompatibility and are hydrolyzed into lactic acid which is harmless in the body, and thus they have been applied to drug carriers in various forms. Polylactide derivatives have various properties depending on their molecular weight and have been developed in the form of microspheres, nanoparticles, polymeric gels, and implant agents.

U.S. Patent No. 6,322,805 discloses a biodegradable hydrophobic polymer comprising at least one selected from the group consisting of polylactide, polyglycolide, polylactide glycolide, polycaprolactone and derivatives thereof and polyalkylene oxide as hydrophilic polymer Polymeric micellar drug carrier formed from a bi- or tri-biodegradable amphiphilic block copolymer, characterized in that it is not cross-linked by a cross-linking material, and is composed of a water-soluble drug physically encapsulated and solubilized in a drug carrier, Which is capable of transferring a drug into the body through the formation of a clear aqueous solution by dissolving the drug in the body. According to the above-mentioned US patent, after removing moisture from monomethoxy polyethylene glycol, stannous octoate dissolved in toluene is added, and then the pressure is reduced to remove toluene. D, L-lactide is added to the product to perform polymerization The resultant block copolymer was dissolved by adding chloroform, and then excess diethyl ether was added dropwise with continued stirring. The resulting precipitate was filtered and washed several times with diethyl ether to obtain a block copolymer of polyethylene glycol-polylactide double block copolymer . However, this method has a limitation that mass production is difficult and can not be used commercially.

Impurities in medicines must be strictly controlled in many ways. In particular, for impurities derived from active pharmaceutical ingredients (APIs), the national drug authorization guidelines specify the upper limit of the content of unknown or unknown API-derived compounds in the drug product. There are also internationally accepted standards, one of which is the ICH guideline Q3A. In this regulation, the content of the individual substances contained in the medicines is limited to 0.1% or 0.2% at the time of drug approval, and the information to be provided with the toxicity related data should be applied differently according to the substance exceeding the limit have. This suggests that the content of the drug substance should be reduced in the pharmaceutical manufacturing process because the drug substance does not know what kind of action it will have in the human body. Therefore, the manufacturing method for reducing these substances and the setting of the upper limit for the properties (structure and toxicity) of each substance are indispensable factors for the quality control of medicines.

It is an object of the present invention to provide a pharmaceutical composition comprising a polymeric micelle-type pharmaceutical composition of a water-insoluble drug comprising an amphiphilic block copolymer, wherein the content of the specific softening substance is below a reference level.

Another object of the present invention is to provide a method for producing the pharmaceutical composition.

According to an aspect of the invention there is provided a pharmaceutical composition comprising a purified amphiphilic block copolymer comprising a hydrophilic block (A) and a hydrophobic block (B), and at least one poorly soluble drug selected from the group consisting of paclitaxel and docetaxel, The polymeric micelle pharmaceutical composition comprising, when stored at 40 占 폚 for 6 months, a soft substance represented by the following formula (1): 0.2 parts by weight or less based on 100 parts by weight of the first water-insoluble drug;

 [Chemical Formula 1]

In this formula,

R ₁ is H or COCH ₃ , and R ₂ is phenyl or OC (CH ₃ ) ₃ .

According to another aspect of the present invention, there is provided a process for preparing an amphiphilic block copolymer comprising: (a) purifying an amphiphilic block copolymer comprising a hydrophilic block (A) and a hydrophobic block (B); (b) dissolving the at least one poorly soluble drug selected from the group consisting of paclitaxel and docetaxel and the purified amphiphilic block copolymer in an organic solvent; And (c) adding a water-soluble solvent to the solution obtained in step (b) to form polymeric micelles. When stored at 40 占 폚 for 6 months, the supersaturated substance represented by the formula (1) 0.2 parts by weight or less of the polymeric micelle composition.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to obtain a pharmaceutical composition of a water-insoluble drug capable of suppressing the production of a soft substance to improve storage stability.

1 is a chromatogram as a result of HPLC analysis of a polymeric micelle composition containing paclitaxel with 6-month accelerated test, which was used in Experimental Example 1 of the present invention.
2 shows the results of the product ion scans during the LC / MS / MS analysis of the flexible material obtained in Experimental Example 1 of the present invention (RRT 0.96 0.02 (0.94-0.98), hereinafter RRT 0.96 is used interchangeably) Respectively.
Figure 3 shows the results of LC / MS / MS analysis of the material obtained at the RRT 0.96 position from the mixture obtained by pyrolysis of paclitaxel in Experimental Example 2 of the present invention.
Figure 4 shows the results of the product ion scans during the LC / MS / MS analysis of the material obtained at the RRT 0.96 position from the mixture obtained by pyrolysis of paclitaxel in Experimental Example 2 of the present invention, together with the results of the polymeric micellar pharmaceutical composition will be.
(a) Analysis results of the 6-month accelerated test sample of the polymeric micelle pharmaceutical composition
(b) Analysis of the material obtained at the RRT 0.96 position from the mixture obtained by pyrolyzing the paclitaxel
FIG. 5 shows the ¹ H NMR analysis results of NMR analysis of the material obtained at the RRT 0.96 position from the mixture obtained by pyrolysis of paclitaxel in Experimental Example 2 of the present invention.
Figure 6 shows the ¹³ C NMR analysis results of the NMR analysis of the material obtained at the RRT 0.96 position from the mixture obtained by pyrolysis of paclitaxel in Experimental Example 2 of the present invention.
7 shows the result of COZY (Correlation Spectroscopy) analysis in NMR analysis of a substance obtained at a RRT 0.96 position from a mixture obtained by pyrolysis of paclitaxel in Experimental Example 2 of the present invention.
FIG. 8 shows results of HMBC (Heteronuclear Multiple Bond Correlation Spectroscopy) analysis during NMR analysis of the material obtained at the RRT 0.96 position from the mixture obtained by pyrolysis of paclitaxel in Experimental Example 2 of the present invention.
9 is a chromatogram of the result of HPLC analysis performed in Experimental Example 5 of the present invention.

Hereinafter, the present invention will be described in detail.

The pharmaceutical composition of the present invention comprises a purified amphiphilic block copolymer comprising a hydrophilic block (A) and a hydrophobic block (B).

According to one embodiment of the present invention, the amphiphilic block copolymer includes an A-B type diblock copolymer or a B-A-B type triblock copolymer composed of a hydrophilic block (A) and a hydrophobic block (B).

According to one embodiment of the present invention, the amount of the hydrophilic block of the amphiphilic block copolymer may be 20 to 95% by weight, more specifically 40 to 95% by weight, based on 100% Lt; / RTI > The content of the hydrophobic block in the amphiphilic block copolymer may be from 5 to 80% by weight, more specifically from 5 to 60% by weight, based on 100% by weight of the total of the copolymer.

According to one embodiment of the present invention, the number average molecular weight of the amphiphilic block copolymer may be 1,000 to 50,000 daltons, and more specifically 1,500 to 20,000 daltons.

According to one embodiment of the present invention, the hydrophilic block is a polymer having biocompatibility, specifically, a group consisting of polyethylene glycol or a derivative thereof, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylamide, and combinations thereof And more specifically, may include those selected from the group consisting of polyethylene glycol, monomethoxy polyethylene glycol, and combinations thereof. The number average molecular weight of the hydrophilic block may be 200 to 20,000 daltons, more specifically 200 to 10,000 daltons.

According to one embodiment of the present invention, the hydrophobic block may be a biodegradable polymer, and may be a polymer of an alpha (alpha) -hydroxy acid-derived monomer. Specific examples thereof include polylactide, polyglycolide, polymandelic acid , Polycaprolactone, polydioxan-2-one, polyamino acid, polyorthoesters, polyanhydrides, polycarbonates, and combinations thereof. More specifically, polylactide , Polyglycolide, polycaprolactone, polydioxan-2-one, and combinations thereof. The number average molecular weight of the hydrophobic block may be 200 to 20,000 daltons, and more specifically 200 to 10,000 daltons.

According to one embodiment of the present invention, an amphiphilic block copolymer comprising a hydrophobic polymer block of poly (alpha) -hydroxy acid) comprises a hydrophilic polymer having a hydroxyl group as an initiator and an alpha (alpha) -hydroxy Can be synthesized by a known ring-opening polymerization method using an acid lactone monomer. For example, L-lactide or D, L-lactide may be subjected to ring-opening polymerization using a hydrophilic polyethylene glycol having a hydroxyl group or monomethoxypolyethylene glycol as an initiator. It is possible to synthesize a double- or tri-block copolymer depending on the number of hydroxyl groups present in the initiator hydrophilic block. Organometallic catalysts such as tin oxide, lead oxide, tin octoate, and antimony octoate can be used for the ring-opening polymerization, and the production of medical polymers It is preferable to use Stannus octoate having biocompatibility.

In one example of the present invention, purified amphiphilic block copolymer is used. According to a preferred embodiment of the present invention, the amphiphilic block copolymer used in the present invention is purified by sublimation.

The purification by sublimation is preferably carried out at a temperature of 80 to 120 DEG C, more preferably 80 to 100 DEG C, and preferably a vacuum degree of 10 torr or less, more preferably 5 torr or less, still more preferably 1 torr or less Preferably 10 hours to 74 hours, more preferably 10 hours to 48 hours, still more preferably 24 hours to 48 hours. Performing purification by sublimation under these conditions can remove impurities from the copolymer while minimizing changes in the molecular weight of the copolymer.

The pharmaceutical compositions of the present invention comprise at least one poorly soluble drug selected from the group consisting of paclitaxel and docetaxel as active ingredients.

According to one embodiment of the present invention, the pharmaceutical composition of the present invention may further comprise a water-insoluble drug other than paclitaxel and docetaxel as additional active ingredients, such as 7-epipaclitaxel, , t-acetylpaclitaxel, 10-desacetylpaclitaxel, 10-desacetyl-7-epipaclitaxel, 7-xylosyl paclitaxel (7- xylosylpaclitaxel, 10-desacetyl-7-glutarylpaclitaxel, 7-N, N-dimethylglycylpaclitaxel and 7-L-alanyl Paclitaxel (7-L-alanylpaclitaxel) and carboxymethylcellulose can be used.

The content of the water-soluble drug contained in the pharmaceutical composition of the present invention may be 0.1 to 50 parts by weight, more specifically 0.5 to 30 parts by weight, based on 100 parts by weight of the amphiphilic block copolymer. If the content of the water-soluble drug is too small compared to the amphiphilic block copolymer, there may be a problem that the time for reconstitution prior to administration is increased because the weight ratio of the amphiphilic polymer used is larger than that of the unit drug. On the contrary, There may be a problem of rapid precipitation of the soluble drug.

In the present specification, the weight of the 'first' poorly soluble drug means the weight of the poorly soluble drug to be added in the production of the pharmaceutical composition.

In one example, the pharmaceutical composition of the present invention comprises, when stored for 6 months under accelerated conditions (40 ° C.), a softening agent represented by the following formula (1) in an amount of 0.2 parts by weight or less based on 100 parts by weight of the first water-insoluble drug.

[Chemical Formula 1]

In this formula,

R ₁ is H or COCH ₃ , and R ₂ is phenyl or OC (CH ₃ ) ₃ .

According to one embodiment of the present invention, the poorly soluble drug is paclitaxel, and the soft substance may comprise a compound represented by the following formula (1a):

[Formula 1a]

When the pharmaceutical composition of the present invention is stored for 6 months under accelerated conditions (40 DEG C), the amount of the flexible substance of formula (1) (especially formula (1a) is 0.2 parts by weight or less, preferably 0.18 parts by weight or less, More preferably 0.16 parts by weight or less, still more preferably 0.13 parts by weight or less, and most preferably 0.1 parts by weight or less.

In a preferred embodiment, the pharmaceutical composition of the present invention is characterized in that when stored for 6 months under accelerated conditions (40 ° C.), the flexible substance of Formula 1 (especially Formula 1a) is used in an amount of less than 0.15 parts by weight, . ≪ / RTI >

The pharmaceutical composition of the present invention is characterized in that, when stored for 3 weeks under severe conditions (80 ° C), the flexible substance represented by Formula 1 (particularly Formula 1a) is 1.2 parts by weight or less, preferably 0.9 parts by weight Or less, more preferably 0.7 parts by weight or less, still more preferably 0.4 parts by weight or less, and most preferably 0.2 parts by weight or less. In one example, the pharmaceutical composition of the present invention contains no ether, such as diethyl ether at all.

In a preferred embodiment, the pharmaceutical composition of the present invention may contain less than 1.12 parts by weight of the flexible substance of Formula 1 (especially Formula 1a) relative to 100 parts by weight of the initial water insoluble drug when stored for 3 weeks at harsh conditions (80 ° C) . In one example, the pharmaceutical compositions of the present invention contain no metal salts, such as alkali metal salts and / or precipitated salts, such as sodium chloride or potassium chloride.

In one example, the pharmaceutical composition of the present invention is a composition containing a specific softening substance below the reference content, and is a commercially available composition capable of mass production.

The pharmaceutical composition of the present invention comprises: (a) purifying an amphiphilic block copolymer comprising a hydrophilic block (A) and a hydrophobic block (B); (b) dissolving the at least one poorly soluble drug selected from the group consisting of paclitaxel and docetaxel and the purified amphiphilic block copolymer in an organic solvent; And (c) adding an aqueous solvent to the solution obtained in step (b) to form polymer micelles.

The purification of the amphiphilic block copolymer has been described above. Conventional methods can be used to form the polymer micelle.

In the method for preparing a pharmaceutical composition of the present invention, the organic solvent may be selected from water-miscible organic solvents such as alcohol, acetone, tetrahydrofuran, acetic acid, acetonitrile and dioxane and combinations thereof But is not limited thereto. The aqueous solvent may be selected from the group consisting of ordinary water, distilled water, distilled water for injection, physiological saline, 5% glucose, buffer, and combinations thereof, but is not limited thereto.

The method for preparing a pharmaceutical composition of the present invention may further comprise the step of removing the organic solvent after the step (a).

Hereinafter, the present invention will be described in more detail with reference to the following examples, which should not be construed as limiting the scope of the present invention.

[Example]

Manufacturing example  One: Monomethoxypolyethylene  Glycol and D, L - Lactide  (MPEG-PDLLA) and purified by the sublimation method

150 g of monomethoxy polyethylene glycol (mPEG, number average molecular weight = 2,000) was added to a 500 ml round-bottomed flask equipped with a stirrer, and water was removed by stirring at 120 ° C and vacuum for 2 hours. 0.15 g of Stannus octoate (Sn (Oct) ₂ ) dissolved in 200 μl of toluene was added into the reaction flask, and toluene was distilled off while stirring under vacuum for 1 hour. Then, 150 g of D, L-lactide was added and dissolved in a nitrogen atmosphere while stirring. After the D, L-lactide was completely dissolved, the reactor was sealed and polymerization was carried out at 120 ° C for 10 hours. After completion of the reaction, the mixture was directly connected with a vacuum pump while stirring the magnetically, and was refined for 7 hours by sublimation at less than 1 torr to obtain 262 g of mPEG-PDLLA in a molten state. ^The molecular weight (Mn: ~ 3740) was calculated by ¹ H-NMR analysis to determine the intensity based on -OCH ₃ which is the terminal group of monomethoxy polyethylene glycol.

Production Example 2: Purification of a double block copolymer (mPEG-PDLLA) by a sublimation method

30 g of mPEG-PDLLA obtained in the polymerization reaction step before the purification step of Preparation Example 1 was put in a one-necked flask and dissolved at 80 캜. The magnet was directly connected with a vacuum pump while stirring, and was refined for 24 hours and 48 hours by sublimation at less than 1 torr.

Production Example 3: Purification of a diblock copolymer (mPEG-PDLLA) by a sublimation method

The purification was carried out in the same manner as in Production Example 2, except that the purification temperature was changed to 100 캜.

Production Example 4: Purification of a double block copolymer (mPEG-PDLLA) by a sublimation method

The purification was carried out in the same manner as in Production Example 2, except that the purification temperature was 120 캜.

Manufacturing example  5: Aluminum oxide ( Al ₂ O ₃ (MPEG-PDLLA) by the adsorption method using

30 g of mPEG-PDLLA obtained in the polymerization reaction process before the purification process of Preparation Example 1 was put in a one-necked flask and dissolved by adding acetone (60 ml). Aluminum oxide (15 g) was added thereto and mixed thoroughly. A one-necked flask was installed in a rotary evaporator and mixed at 50 DEG C and 60 rpm for 2 hours. The solution was filtered again with PTFE filter (1 μm) at room temperature to remove aluminum oxide. The filtered acetone solution was purified by vacuum distillation of acetone at 60 ° C using a rotary evaporator to obtain purified mPEG-PDLLA. ¹ H-NMR analysis was conducted to calculate the molecular weight (Mn: ~ 3690) by calculating the intensity based on -OCH ₃ which is the terminal group of monomethoxy polyethylene glycol.

The molecular weight changes of mPEG-PDLLA according to the purification conditions in Production Examples 2 to 5 are shown in Table 1 below.

From the results of Table 1, it can be seen that the higher the purification temperature, the greater the decrease in the molecular weight of mPEG-PDLLA. As the purification conditions, 80 to 100 ° C for 24 to 48 hours, particularly 100 ° C for 24 hours, can be considered effective.

Example  One: Paclitaxel  -Containing polymeric micelle composition

1 g of paclitaxel and 5 g of mPEG-PDLLA obtained in Preparation Example 1 were quantitatively analyzed. To this, 4 ml of ethanol was added, and the mixture was stirred at 60 ° C until completely dissolved. Then, the ethanol was distilled off under reduced pressure at 60 ° C for 3 hours using a rotary vacuum distillation apparatus equipped with a round bottom flask. Thereafter, the temperature was lowered to 50 캜, 140 ml of purified water at room temperature was added, and the reaction was allowed to proceed until a clear solution of blue light was formed, thereby forming a polymer micelle. Then, 2.5 g of anhydrous lactose was added thereto as a lyophilization agent to completely dissolve it. The mixture was filtered using a filter having a pore size of 200 nm, and then lyophilized to prepare a polymeric micelle composition containing powdery paclitaxel.

Example  2: Paclitaxel  -Containing polymeric micelle composition

A polymeric micelle composition containing paclitaxel was prepared in the same manner as in Example 1, except that purified mPEG-PDLLA was used in Production Example 3 for 24 hours.

Example  3: Paclitaxel  -Containing polymeric micelle composition

A polymeric micelle composition containing paclitaxel was prepared in the same manner as in Example 1, except that mPEG-PDLLA purified in Preparation Example 5 was used

Experimental Example  One: In liquid chromatography method  by Flexible material  detach

16.7 ml of deionized water (DW) was added to a vial containing 100 mg of the polymeric micelle composition containing paclitaxel with a 6-month accelerated test (temperature: 40 ° C) and completely dissolved. The entire amount of this solution was transferred to a 20 ml volume flask, And adjusted to 20 ml (5.0 mg / ml). 2 ml of this solution was put into a 10 ml volume flask, and adjusted to 10 ml with acetonitrile (1 mg / ml). The above-mentioned composition was separated and collected by using the following liquid chromatography.

Liquid chromatographic method  Condition

1) Column: Poroshell 120 PFP (4.6 × 150 mm, 2.7 μm, Agilent)

2) mobile phase: A: DW / B: acetonitrile

3) Flow rate: 0.6 ml / min

4) Injection amount: 10 μl

5) Detector: Ultraviolet absorptiometer (measuring wavelength: 227 nm)

The chromatogram of the result of HPLC analysis is shown in Fig.

Experimental Example  2. Paclitaxel  Pyrolysis experiment

In Experimental Example 1, it was very difficult to directly test the suppositories obtained from the paclitaxel-containing polymer nanoparticle composition with many polymers. As a result of the qualitative analysis in the preliminary experiment using LC / MS / MS, the suppository was a compound in which water was bound to paclitaxel. Therefore, a test was conducted to confirm whether a suppository was produced by applying heat to paclitaxel by adding water molecules. First, 1 g of paclitaxel was allowed to stand at 170 ° C for 2 to 3 hours, then completely dissolved in 45 ml of acetonitrile, and then 5 ml of DW was added. This solution was used to separate and separate RRT 0.96 supernatant from prep LC.

Experimental Example  3. LC / MS / MS Flexible material  Qualitative analysis

(RRT: 0.96 0.02 (0.94-0.98)) isolated in Experimental Examples 1 and 2 were analyzed by liquid chromatography and mass spectrometry (LC / MS / MS). HPLC analysis showed HPLC peaks at the same positions as RRT 0.96 in the polymer micelle composition (FIG. 4). LC / MS / MS analysis of this material was also performed. First, MS scan showed m / z 894.1amu [M + H2O + Na] ⁺ in both materials (Figs. 2 and 3). The product ion scans were then carried out and the results are shown in FIG. The results of the RRT 0.96 suppository produced in the polymer nanoparticle composition containing paclitaxel accelerated for 6 months were also shown. As a result, it was confirmed that RRT 0.96 fractions after the pyrolysis of paclitaxel in Experimental Example 2 had the same structure as that of the suppositories at the RRT 0.96 position after 6 months of acceleration of the polymeric micelle composition.

In the following measurement, LC / MS / MS was measured using a liquid chromatography 1200 series and Agilent's Electrospray Ionization Mass Spectrometer 6400 Series. The analysis conditions are as follows.

Liquid chromatographic method  Condition

1) Column: Poroshell 120 PFP (4.6 × 150 mm, 2.7 μm, Agilent)

2) mobile phase: A: DW / B: acetonitrile

3) Flow rate: 0.6 ml / min

4) Injection amount: 10 μl

5) Detector: Ultraviolet absorptiometer (measuring wavelength: 227 nm)

Electrospray ionization mass spectrometer conditions

1) Ionization: Electrospray Ionization, Positive (ESI +)

2) MS Method: MS2 scan / Product ion scan

3) Ion source: Agilent Jet Stream ESI

4) Nebulizer gas (pressure): Nitrogen (35psi)

5) Ion spray voltage: 3500 V

6) Drying gas temperature (flow rate): 350 ° C (7L / min)

7) Sheath gas temperature (flow rate): 400 ° C (10 L / min)

8) Fragmentor: 135V

9) Nozzle voltage: 500V

10) Cell accelerator voltage: 7V

11) EMV: 0V

12) Collision energy: 22V

13) Precursor ion: m / z 836.2

14) Mass scan range: m / z 100 ~ 1500

The analytes separated from the detection step were set to flow into a mass spectrometer. At this time, the detection ion of the flexible substance was subjected to qualitative analysis by selecting the characteristic ion [M + Na] of the mass spectrum.

Experimental Example  4. Paclitaxel By pyrolysis  From the resulting mixture RRT  NMR analysis of the material obtained at the 0.96 position

The material obtained at the RRT 0.96 position from the mixture obtained by pyrolysis of paclitaxel in Experimental Example 2 was analyzed by NMR. The result of ¹ H NMR analysis in NMR analysis is shown in FIG. 5, the result of ¹³ C NMR analysis is shown in FIG. 6, the result of COZY (Correlation Spectroscopy) analysis is shown in FIG. 7, and the result of HMBC (Heteronuclear Multiple Bond Correlation Spectroscopy) Respectively.

According to the analysis result, the substance obtained at the RRT 0.96 position from the mixture obtained by pyrolysis of paclitaxel (i.e., the substance (RRT: 0.96 + 0.02 (0.94 ~ 0.98)) was confirmed to be a compound in which water was bonded to paclitaxel.

Form in which one molecule of water is bonded to paclitaxel: C ₄₇ H ₅₃ NO ₁₅ (871.94 g / mol)

Nuclear magnetic resonance spectroscopy conditions

One. ^One H

1) NMR equipment: Brucker DRX-900 equipped with a temperature controller

2) Sample / Solvent: 1 ~ 10mg sample / 0.6mL chloroform- d in 5mm OD NMR tube (In all NMR experiments, same sample was used)

3) Probehead: Brucker 5mm CPTCI

4) Proton 90 ° degree pulse width / Excitation angle / Acquisition time: 7.4 μsec / 30 ° / 3.3 sec

5) Relaxation delay / Number of scan: 2.0 sec / 16

2. ¹³ C

1) Probehead: Brucker 5mm CPTCI

2) Carbon 90 ° degree pulse width / Excitation angle / Acquisition time: 11.8 μsec / 30 ° / 0.58 sec

3) Relaxation delay / Number of scan: 3.0 sec / 656

3. COZY

1) NMR equipment: Brucker DRX-900

2) Probehead: Brucker 5mm CPTCI

3) Pulse sequence: cosygpqf pulse sequence

4) Proton 90 ° degree pulse width / Acquisition time: 7.4 μsec / 0.13 sec

5) Relaxation delay / Number of scans / Number of experiments for? ₁ : 1.5 sec / 4/320

4. HMQC

1) NMR equipment: Brucker DRX-900

2) Probehead: Brucker 5mm CPTCI

3) Pulse sequence: hsqcedetgpsisp pulse sequence

4) Proton 90 ° degree pulse width / Carbon 90 ° degree pulse width / Acquisition time: 7.4 μsec / 11.8 μsec / 0.12 sec

5) Relaxation delay / Number of scans / Number of experiments for? ₁ : 1.0 sec / 4/320

6) Temperature / 1/2 (J _CH ): 300K / 3.5 msec

5. HMBC

1) NMR equipment: Brucker DRX-900

2) Probehead: Brucker 5mm CPTCI

3) Pulse sequence: hmbcgplpndqf pulse sequence

4) Proton 90 ° degree pulse width / Carbon 90 ° degree pulse width / Acquisition time: 7.7 μsec / 11.8 μsec / 0.12 sec

5) Relaxation delay / Number of scans / Number of experiments for? ₁ : 1.5 sec / 4/320

6) Temperature / 1/2 (J _CH ): 283K / 3.5 msec

Experimental Example  5: Drug-containing polymer Micelle Under severe (80 ° C) conditions  Storage stability comparison experiment

Each of the polymer micelle compositions of the paclitaxel prepared in Examples 1 to 3 was stored in an oven at 80 DEG C for 3 weeks, and then the content of the suppositories was compared by HPLC analysis of the composition. The test solution was prepared by dissolving the micellar composition in an aqueous 80% acetonitrile solution and diluting the solution to 600 ppm of paclitaxel concentration. The spectrum of the result of the HPLC analysis is shown in FIG. 9, and the change of the content (%) of the flexible substance according to the time of harsh experiment is shown in Table 2 below.

HPLC  Condition

Column: 2.7 mu m particle diameter, poroshell 120PFP (4.6 x 150 mm, 2.7 mu m) (Agilent column)

Mobile phase condition

Detector: Ultraviolet absorptiometer (227 nm)

Flow rate: 0.6 ml / min

Content (%) of individual flexible substances = 100 (Ri / Ru)

Ri: the area of the individual flexible substances detected in the test solution analysis

Ru: sum of all peak areas detected in the test solution analysis

It can be seen from Table 2 and FIG. 9 that the stability of the polymeric micellar composition of Example 2 or 3 is improved compared to the composition of Example 1, and the decrease in the content of paclitaxel is relatively small, Can be maintained more stably.

Experimental Example  6: drug-containing polymer Micelle  Storage stability comparison experiment under acceleration (40 ℃)

The polymeric micelle composition of the paclitaxel prepared in Example 1 was tested in the same manner as in Experimental Example 5, except that the composition was stored in a stability tester at 40 ° C for 6 months. Table 3 shows changes in the content (%) of the flexible material with the acceleration test time.

The above experimental results show the average value of the contents of each substance and paclitaxel in the experiments conducted on three or more polymeric micelle compositions of different batches. On the other hand, the amount of each of the flexible materials showed a difference among the batches, and the following shows the case where the batch with the largest number of the flexible substances is detected.

Quality control of medicines emphasized not only the average value but also the highest value for a specific impurity, so it was necessary to improve the quality of the composition so that these values could be fundamentally lowered.

Through the experiment 5, it was proved that the pharmaceutical composition of the polymer micelle of Example 2 or 3 exhibited a lower content of the softener than that of the composition of Example 1. As a result, it was confirmed that when stored at accelerated storage temperature (40 ° C) for 6 months It can be deduced that the composition of Example 2 or 3 has a lower content than that of the composition of Example 1 shown in Table 3 above.

Claims (16)

(B) selected from the group consisting of a hydrophilic block (A) selected from the group consisting of polyethylene glycol, monomethoxy polyethylene glycol and combinations thereof, and a polylactide, a polyglycolide, and a combination thereof, And at least one water-miscible drug selected from the group consisting of paclitaxel and docetaxel. When stored at 40 DEG C for 6 months, the soft substance represented by the following formula (1) is dissolved in an amount of 0.2 By weight, based on the total weight of the polymeric micelle pharmaceutical composition:
[Chemical Formula 1]

In this formula,
R ₁ is H or COCH ₃ , and R ₂ is phenyl or OC (CH ₃ ) ₃ . The composition of claim 1, wherein the compound of formula (I) is a compound of formula
[Formula 1a]

The composition of claim 1 comprising 0.18 parts by weight or less of the flexible material of formula (1) relative to 100 parts by weight of the initial water insoluble drug. 4. The composition of claim 3 comprising 0.16 parts by weight or less of the flexible material of formula (1) relative to 100 parts by weight of the initial water miscible drug. 5. The composition of claim 4 comprising 0.13 parts by weight or less of the flexible material of formula (1) relative to 100 parts by weight of the first poorly soluble drug. 6. A composition according to claim 5 comprising up to 0.1 part by weight of the flexible material of formula (1) relative to 100 parts by weight of the initial poorly soluble drug. 2. The composition of claim 1 comprising up to 1.2 parts by weight, relative to 100 parts by weight of the initial poorly soluble drug, of the flexible material of formula (1) when stored at 80 DEG C for 3 weeks. 8. The composition according to any one of claims 1 to 7, wherein the hydrophilic block (A) is polyethylene glycol or monomethoxy polyethylene glycol and the hydrophobic block (B) is a polylactide. The composition according to any one of claims 1 to 7, wherein the hydrophilic block (A) has a number average molecular weight of 200 to 20,000 daltons and the hydrophobic block (B) has a number average molecular weight of 200 to 20,000 daltons. 8. The composition according to any one of claims 1 to 7, wherein the amphiphilic block copolymer is purified by sublimation. 11. The composition according to claim 10, wherein the sublimation is carried out under a temperature condition of 80 to 120 DEG C and a vacuum degree of 10 torr or less. 12. The composition of claim 11, wherein the sublimation is performed for 10 to 74 hours. delete delete delete delete

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