阅读说明：本技术 具有改善的储存稳定性的药物组合物及其制备方法 (Pharmaceutical composition with improved storage stability and method for preparing the same ) 是由 金峰五 闵范赞 金志英 金寭林 徐敏孝 李思元 李一雄 赵重雄 崔仁子 于 2016-07-28 设计创作，主要内容包括：本发明提供了一种通过升华来纯化包含亲水性嵌段和疏水性嵌段的两亲性嵌段共聚物的方法,含有该两亲性嵌段共聚物的水溶性差的药物的聚合物胶束型药物组合物,以及制备该药物组合物的方法。根据本发明,可以获得具有减少的相关化合物和改善的储存稳定性的水溶性差的药物的药物组合物。(The present invention provides a method for purifying an amphiphilic block copolymer comprising a hydrophilic block and a hydrophobic block by sublimation, a polymer micelle type pharmaceutical composition of a poorly water-soluble drug containing the amphiphilic block copolymer, and a method for preparing the pharmaceutical composition. According to the present invention, a pharmaceutical composition of a poorly water-soluble drug having reduced related compounds and improved storage stability can be obtained.)

1. A method for purifying an amphiphilic block copolymer comprising a hydrophilic block (A) and a hydrophobic block (B) by sublimation,

wherein the sublimation is carried out under a temperature condition of 80 ℃ to less than 120 ℃ and a vacuum pressure condition of 10 Torr or less.

2. The process according to claim 1, wherein the sublimation is carried out under temperature conditions of 80 ℃ to 100 ℃ and vacuum pressure conditions of 5 torr or less.

3. The method of claim 1, wherein the sublimation is carried out for a time of 10 to 74 hours.

4. The method of claim 1, wherein the hydrophilic block (a) is selected from the group consisting of polyethylene glycol or derivatives thereof, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylamide, and combinations thereof.

5. The method of claim 1, wherein the hydrophobic block (B) is selected from the group consisting of polylactide, polyglycolide, polymalic acid, polycaprolactone, polydioxan-2-one, polyamino acids, polyorthoesters, polyanhydrides, polycarbonates, and combinations thereof.

6. A pharmaceutical composition comprising the amphiphilic block copolymer of claim 5.

7. The pharmaceutical composition of claim 6, which is a polymeric micelle pharmaceutical composition.

8. The pharmaceutical composition of claim 7, further comprising a poorly water soluble drug.

9. A process for preparing a pharmaceutical composition comprising

(a) Purifying an amphiphilic block copolymer comprising a hydrophilic block (a) and a hydrophobic block (B);

(b) dissolving one or more poorly water-soluble drugs selected from paclitaxel and docetaxel and a purified amphiphilic block copolymer in an organic solvent; and

(c) adding an aqueous solvent to the solution obtained in step (b) to form polymeric micelles,

wherein the amphiphilic block copolymer is purified by the method of claim 1.

Technical Field

The present invention relates to a pharmaceutical composition having improved storage stability and a method for preparing the same, and more particularly to a pharmaceutical composition of a poorly water-soluble drug comprising an amphiphilic block copolymer, wherein the content of a specific related compound is maintained within a prescribed limit; and to a process for the preparation thereof.

Background

Dissolution of poorly water soluble drugs is a key technology for delivering drugs into the body via oral or parenteral administration. Such a dissolution method includes a method of adding a surfactant to an aqueous solution to form micelles, and then entrapping (entertaining) a poorly water-soluble drug therein. The amphiphilic block copolymer used as a surfactant comprises a hydrophilic polymer block and a hydrophobic polymer block. Since the hydrophilic polymer block directly contacts blood proteins and cell membranes in vivo, polyethylene glycol or monomethoxypolyethylene glycol, etc., having biocompatibility, have been used. The hydrophobic polymer block improves affinity with hydrophobic drugs, and thus has been used a biodegradable polylactide, polyglycolide, poly (lactic-glycolide), polycaprolactone, polyamino acid, polyorthoester, or the like. In particular, polylactide derivatives have been applied to drug carriers in various forms because they have excellent biocompatibility and are hydrolyzed into harmless lactic acid in vivo. Polylactide derivatives have different physical properties depending on their molecular weight, and various forms such as microspheres, nanoparticles, polymer gels, and implants have been developed.

6,322,805 discloses a composition for delivering a poorly water-soluble drug consisting of a polymer micelle type drug carrier and a poorly water-soluble drug, wherein the polymer micelle type drug carrier is formed of a diblock copolymer or a triblock copolymer which is not crosslinked by a crosslinking agent, consisting of at least one biodegradable hydrophobic polymer selected from the group consisting of polylactide, polyglycolide, poly (lactide-glycolide), polycaprolactone and derivatives thereof, and poly (alkylene oxide) as a hydrophilic polymer, wherein the poorly water-soluble drug is physically embedded in the drug carrier and dissolved, and wherein the polymer micelle type drug carrier forms a transparent aqueous solution in water and efficiently delivers the poorly water-soluble drug into the body. According to the above us patent, the polyethylene glycol-polylactide diblock copolymer is synthesized by the following steps: removing water from monomethoxypolyethylene glycol, adding stannous octoate dissolved in toluene thereto and removing toluene under reduced pressure, adding D, L-lactide to the resulting mixture and carrying out polymerization, adding chloroform to dissolve the resulting block copolymer, adding dropwise an excess of diethyl ether with stirring to form a precipitate, filtering the formed precipitate, and washing with diethyl ether several times. However, this method is difficult to use in large-scale production and therefore not commercially available. In addition, the ether used for purification may remain in the final polymer micelle composition.

8,853,351 discloses a method for preparing an amphiphilic block copolymer, which comprises (a) dissolving an amphiphilic block copolymer in a water-miscible organic solvent; (b) adding and mixing an aqueous solution of an alkali metal salt (sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or lithium carbonate) to the polymer solution obtained in step (a); (c) separating the organic and aqueous phases of the solution obtained in step (b) by salting out; and (d) separating the organic phase obtained in step (c) and removing the organic solvent therefrom to recover the polymer. However, this method involves complicated steps, requires additional steps to remove the alkali metal salt and the salt for salting out (sodium chloride or potassium chloride), and may have residual metal salt even after removing it.

The impurities of the drug must be strictly controlled in various aspects. In particular, in the case of impurities originating from an Active Pharmaceutical Ingredient (API), each country determines in its drug approval guidelines an upper limit for the amount of known or unknown impurities (related compounds) originating from the API in a pharmaceutical product. In addition, there are several internationally used standards, ICH guide Q3A being a representative one. In this guideline, the amount of each related compound in the drug is limited to at most 0.1% or 0.2% or the like at the time of approval of the drug, and information such as toxicity-related data or the like that should be specified is differently applied depending on the related compound exceeding the limited amount. This means that the amount of the relevant compound must be reduced in the process of preparing the drug, since it is unknown how the relevant compound of the drug acts in vivo. Therefore, the manufacturing method for reducing the related compounds and setting the upper limit of the amount thereof according to the characteristics (structure and toxicity) of each related compound are essential factors in the quality control of the drug.

Disclosure of Invention

Technical problem

It is an object of the present invention to provide a polymer micelle type pharmaceutical composition containing a poorly water-soluble drug of an amphiphilic block copolymer, which contains a specific compound of interest in an amount within a specified limit.

It is another object of the present invention to provide a method for preparing the pharmaceutical composition.

Means for solving the problems

One aspect of the present invention provides a polymeric micelle pharmaceutical composition comprising: a purified amphiphilic block copolymer comprising a hydrophilic block (a) and a hydrophobic block (B), and one or more poorly water-soluble drugs selected from paclitaxel and docetaxel, wherein the pharmaceutical composition contains less than 0.58 parts by weight of a related compound represented by the following formula 1, based on 100 parts by weight of an initial amount of the poorly water-soluble drug, when stored at 40 ℃ for 6 months:

[ formula 1]

Wherein:

R₁is H or COCH₃，R₂Is phenyl or OC (CH)₃)₃。

Another aspect of the present invention provides a method for preparing a polymeric micelle pharmaceutical composition, comprising: (a) purifying an amphiphilic block copolymer comprising a hydrophilic block (a) and a hydrophobic block (B); (b) dissolving one or more poorly water-soluble drugs selected from paclitaxel and docetaxel and a purified amphiphilic block copolymer in an organic solvent; and (c) adding an aqueous solvent to the solution obtained in step (b) to form polymeric micelles; the pharmaceutical composition contains the related compound represented by the above formula 1 in an amount of less than 0.58 parts by weight based on 100 parts by weight of the initial amount of the poorly water-soluble drug, when stored at 40 ℃ for 6 months.

Advantageous effects

According to the present invention, a pharmaceutical composition of a poorly water-soluble drug having reduced related compounds and improved storage stability can be obtained.

Drawings

FIG. 1 is a chromatogram obtained by HPLC analysis of a paclitaxel-containing polymer micelle composition subjected to an accelerated six-month test, used in Experimental example 1-1;

FIG. 2 is a chromatogram and a spectrum chart obtained by LC/MS/MS analysis of the related compound isolated in Experimental example 1-1 in Experimental example 1-2:

(a) RRT1.10 + -0.02 (1.08-1.12) (hereinafter RRT1.10 can be used interchangeably with RRT1.10 + -0.02);

(b) RRT 1.12 + -0.02 (1.10-1.14) (hereinafter RRT 1.12 may be used interchangeably with RRT 1.12 + -0.02);

FIG. 3 is a chromatogram obtained by HPLC analysis of the induced reaction product obtained in Experimental example 2:

(a) a polymeric micelle pharmaceutical composition containing paclitaxel,

(b) the amount of paclitaxel is such that the amount of paclitaxel,

(c) the reaction product of paclitaxel and L-lactide,

(d) the reaction product of paclitaxel and D-lactide;

FIG. 4 is a chromatogram obtained by LC/MS/MS analysis of the induced reaction product obtained in Experimental example 3:

(a) the amount of paclitaxel is such that the amount of paclitaxel,

(b) a reaction product of paclitaxel and L-lactide,

(c) a reaction product of paclitaxel and D-lactide;

FIG. 5 is a chromatogram obtained by HPLC analysis performed in Experimental example 4.

Detailed Description

The present invention is explained in more detail below.

The pharmaceutical composition of the present embodiment 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 comprises an a-B type diblock copolymer or a B-a-B type triblock copolymer consisting of a hydrophilic block (a) and a hydrophobic block (B).

According to one embodiment of the present invention, the amphiphilic block copolymer may comprise from 20 to 95 wt.%, more specifically from 40 to 95 wt.%, of the hydrophilic block, based on the total weight of the copolymer. Furthermore, the amphiphilic block copolymer can comprise 5 to 80 wt.%, more specifically 5 to 60 wt.%, of the hydrophobic block, based on the total weight of the copolymer.

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

According to an embodiment of the present invention, the hydrophilic block is a polymer having biocompatibility and may include one or more selected from the group consisting of polyethylene glycol or a derivative thereof, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylamide, and a combination thereof, and more particularly, it may include one or more selected from the group consisting of polyethylene glycol, monomethoxypolyethylene glycol, and a combination thereof. The number average molecular weight of the hydrophilic block can be 200-.

According to one embodiment of the invention, the hydrophobic block is a polymer having biodegradability and may be a polymer of monomers derived from alpha-hydroxy acids. Specifically, it may comprise one or more selected from the group consisting of polylactide, polyglycolide, polymalic acid, polycaprolactone, polydioxan-2-one, polyamino acids, polyorthoesters, polyanhydrides, polycarbonates, and combinations thereof, and more specifically, it may comprise one or more selected from the group consisting of polylactide, polyglycolide, polycaprolactone, polydioxan-2-one, and combinations thereof. The number average molecular weight of the hydrophobic block can be 200-.

According to one embodiment of the present invention, an amphiphilic block copolymer comprising a hydrophobic polymer block of a poly (alpha-hydroxy acid) may be synthesized by a known ring-opening polymerization method using a hydrophilic polymer having a hydroxyl group as an initiator and an alpha-hydroxy acid lactone monomer. For example, L-lactide or D, L-lactide can be polymerized by ring opening using hydrophilic polyethylene glycol or monomethoxy polyethylene glycol having a hydroxyl group as an initiator. Depending on the number of hydroxyl groups present in the hydrophilic block as initiator, a diblock copolymer or triblock copolymer may be synthesized. In the ring-opening polymerization, an organic metal catalyst such as tin oxide, lead oxide, tin octylate, antimony octylate, or the like can be used, and biocompatible tin octylate is preferably used in the preparation of the medical polymer.

In an embodiment of the present invention, a purified copolymer is used as the amphiphilic block copolymer. According to a preferred embodiment of the invention, the amphiphilic block copolymer is a copolymer which has been purified by sublimation.

The sublimation purification may be carried out at a temperature of preferably 80 ℃ or more and less than 120 ℃, more preferably 80 to 100 ℃, and at a pressure of preferably 10 torr or less, more preferably 5 torr or less, still more preferably 1 torr or less in a vacuum degree for preferably 10 to 74 hours, more preferably 10 to 48 hours, still more preferably 24 to 48 hours. Purification by sublimation under such conditions can minimize the change in molecular weight of the copolymer and remove impurities from the copolymer.

The pharmaceutical composition of the present embodiment comprises one or more poorly water-soluble drugs selected from paclitaxel and docetaxel as an active ingredient.

According to one embodiment of the present invention, the pharmaceutical composition may further comprise one or more poorly water-soluble drugs other than paclitaxel and docetaxel as an additional active ingredient. As such additional active ingredients, one or more taxane anticancer agents selected from 7-epitaxol, t-acetyl taxol, 10-deacetyltaxol, 10-deacetyl-7-epitaxol, 7-xylosyl taxol, 10-deacetyl-7-glutaryl taxol, 7-N, N-dimethylglycyl taxol, 7-L-alanyl taxol and cabazitaxel (cabazitaxel) can be used.

The pharmaceutical composition of the present embodiment may comprise 0.1 to 50 parts by weight, more specifically 0.5 to 30 parts by weight, of a poorly water-soluble drug, based on 100 parts by weight of the amphiphilic block copolymer. If the amount of the poorly water-soluble drug is too small compared to the amount of the amphiphilic block copolymer, the weight of the amphiphilic copolymer used per drug is high, and thus the reconstitution time may increase. On the other hand, if the amount of the poorly water-soluble drug is too large, there may be a problem that the poorly water-soluble drug rapidly precipitates.

As used herein, the "initial" amount of poorly water soluble drug refers to the weight of poorly water soluble drug incorporated when preparing the pharmaceutical composition.

In an embodiment of the present invention, when the pharmaceutical composition is stored under accelerated conditions (40 ℃) for 6 months, it contains, based on 100 parts by weight of the initial amount of the poorly water-soluble drug, less than 0.58 parts by weight of a related compound represented by the following formula 1:

[ formula 1]

Wherein:

R₁is H or COCH₃，R₂Is phenyl or OC (CH)₃)₃。

The compound of formula 1 may include a compound of formula 1a below, a compound of formula 1b below, or both:

[ formula 1a ]

[ formula 1b ]

In the above formulae 1a and 1b, R₁And R₂The definition of (a) is the same as that in the above formula 1.

According to an embodiment of the present invention, the poorly water-soluble drug is paclitaxel, and the related compound may include a compound represented by the following formula 1 c:

[ formula 1c ]

The compound of formula 1c may include a compound of formula 1d below, a compound of formula 1e below, or both: [ formula 1d ]

[ formula 1e ]

The pharmaceutical composition of the embodiment of the present invention may contain the related compound of formula 1 (particularly, formula 1c) below in an amount of less than 0.58 parts by weight, for example, 0.5 parts by weight or less, preferably 0.35 parts by weight or less, more preferably 0.2 parts by weight or less, still more preferably 0.1 parts by weight or less, most preferably 0.07 parts by weight or less, based on 100 parts by weight of the initial amount of the poorly water-soluble drug, when stored under accelerated conditions (40 ℃) for 6 months.

The pharmaceutical composition of the present embodiment may contain, when stored under accelerated conditions (40 ℃) for 6 months, the related compound of formula 1a (particularly, formula 1d) below in an amount of less than 0.22 parts by weight, for example, 0.2 parts by weight or less, preferably 0.15 parts by weight or less, more preferably 0.1 parts by weight or less, still more preferably 0.06 parts by weight or less, most preferably 0.05 parts by weight or less, based on 100 parts by weight of the initial amount of the poorly water-soluble drug.

The pharmaceutical composition of the present embodiment may contain, when stored under accelerated conditions (40 ℃) for 6 months, the related compound of formula 1b (particularly, formula 1e) below in an amount of less than 0.36 parts by weight, for example, 0.3 parts by weight or less, preferably 0.2 parts by weight or less, more preferably 0.1 parts by weight or less, still more preferably 0.04 parts by weight or less, most preferably 0.02 parts by weight or less, based on 100 parts by weight of the initial amount of the poorly water-soluble drug.

When stored under stringent conditions (80 ℃) for 3 weeks, the pharmaceutical composition of the embodiment of the present invention may contain the related compound of formula 1 (particularly, formula 1c) below in an amount of less than 0.45 part by weight, preferably 0.4 part by weight or less, more preferably 0.2 part by weight or less, and most preferably 0.16 part by weight or less, based on 100 parts by weight of the initial amount of the poorly water-soluble drug.

When stored under stringent conditions (80 ℃) for 3 weeks, the pharmaceutical composition of the embodiment of the present invention may contain the related compound of formula 1a (particularly formula 1d) below in an amount of less than 0.18 parts by weight, preferably 0.15 parts by weight or less, more preferably 0.1 parts by weight or less, most preferably 0.08 parts by weight or less, based on 100 parts by weight of the initial amount of the poorly water-soluble drug.

When stored under stringent conditions (80 ℃) for 3 weeks, the pharmaceutical composition of the embodiment of the present invention may contain the related compound of formula 1b (particularly formula 1e) below in an amount of less than 0.27 parts by weight, preferably 0.2 parts by weight or less, more preferably 0.1 parts by weight or less, most preferably 0.08 parts by weight or less, based on 100 parts by weight of the initial amount of the poorly water-soluble drug.

In an embodiment of the invention, a pharmaceutical composition containing a specific relevant compound in an amount within the specified limits is a commercially available composition, since it can be produced on a large scale.

In one embodiment, the pharmaceutical composition of the invention is completely free of ethers, such as diethyl ether.

In one embodiment, the pharmaceutical composition of the invention is completely free of metal salts, such as alkali metal salts and/or salts for salting out, such as NaCl or KCl.

The pharmaceutical composition of the present embodiment may be prepared by a method comprising the steps of: (a) purifying an amphiphilic block copolymer comprising a hydrophilic block (a) and a hydrophobic block (B); (b) dissolving one or more poorly water-soluble drugs selected from 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 polymeric micelles.

Purification of amphiphilic Block copolymer As described above, the polymeric micelles can be formed by conventional methods.

In the method of preparing the pharmaceutical composition of the present embodiment, as the organic solvent, for example, a water-miscible organic solvent selected from the group consisting of alcohols (e.g., ethanol), acetone, tetrahydrofuran, acetic acid, acetonitrile, and dioxane, and combinations thereof, may be used, but is not limited thereto. In addition, one selected from the group consisting of conventional water, distilled water for injection, physiological saline, 5% glucose, a buffer solution, and a combination thereof may be used as the aqueous solvent, but is not limited thereto.

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

In embodiments, the method may further comprise adding a lyophilization aid to lyophilize the micelle composition. Lyophilization aids may be added to the lyophilized composition to maintain a cake. In another embodiment, the lyophilization aid may be one or more selected from the group consisting of a sugar and a sugar alcohol. The sugar may be one or more selected from lactose, maltose, sucrose or trehalose. The sugar alcohol may be one or more selected from mannitol, sorbitol, maltitol, xylitol and lactitol. The lyophilization aid may also be used to promote uniform dissolution of the lyophilized polymeric micelle composition upon reconstitution. The content of the lyophilization aid may be 1 to 90 wt.%, particularly 1 to 60 wt.%, more particularly 10 to 60 wt.%, based on the total weight of the lyophilized composition.

The present invention is illustrated in more detail by the following examples. However, these examples are intended only to illustrate the present invention, and the examples do not limit the scope of the present invention in any way.