Preparation Method of Drug-Containing Sustained Release Microparticles

Abstract

The present invention relates to a preparation method of drug-containing sustained release microparticles, the preparation method comprising the steps of: (a) dissolving a biodegradable polymer and a drug in a halogenated alkane solvent to form a drug-containing biodegradable polymer solution; (b) homogeneously mixing the drug-containing biodegradable polymer solution in a continuous phase containing a surfactant to form a dispersed phase; (c) maintaining an emulsion comprising the continuous phase and the dispersed phase at a temperature lower than the boiling point of the halogenated alkane solvent to form microparticles in the continuous phase; (d) primarily drying the microparticles; (e) mixing the primarily dried microparticles with an aqueous alcohol solution, and then maintaining the aqueous alcohol solution at a temperature no less than the boiling point of the halogenated alkane solvent to extract and evaporate the remaining halogenated alkane solvent from the microparticles; and (f) secondarily drying the obtained microparticles to produce drug-containing microparticles. The drug-containing sustained release microparticles prepared in accordance with the preparation method of the present invention minimize the hydrolysis of the biodegradable polymer in the microparticles, while easily removing the halogenated alkane solvent in the microparticles, and are thus capable of exhibiting excellent sustained drug release.

Claims

1. A preparation method of drug-containing sustained release microparticles, comprising: (a) dissolving a biodegradable polymer and a drug in a halogenated alkane solvent to form a drug-containing biodegradable polymer solution; (b) homogeneously mixing the drug-containing biodegradable polymer solution in a continuous phase containing surfactant to form a dispersed phase; (c) maintaining an emulsion including the continuous phase and the dispersed phase at temperature lower than the boiling point of the halogenated alkane solvent to form microparticles in the continuous phase; (d) primarily drying the microparticles; (e) mixing the primarily dried microparticles with an aqueous alcohol solution, and maintaining the aqueous alcohol solution at temperature above the boiling point of the halogenated alkane solvent to extract and evaporate the residual halogenated alkane solvent from the microparticles; and (f) secondarily drying the obtained microparticles to produce drug-containing microparticles.

2. The preparation method of drug-containing sustained release microparticles according to claim 1, wherein the biodegradable polymer is selected from the group consisting of polycaprolactone, lactic acid-caprolactone copolymer, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, and mixtures thereof.

3. The preparation method of drug-containing sustained release microparticles according to claim 1, wherein the drug is selected from the group consisting of anti-cancer drugs, antipsychotic drug, antihyperlipidemic drugs, antihypertensive drugs, antiepileptic drugs, drugs for treatment of diseases of the gastrointestinal system, anti-rheumatic drugs, antispasmodic drugs, antituberculosis drugs, muscle relaxant drugs, antiarrhythmic drugs, osteoporosis drugs, erectile dysfunction drugs, hemostatic drugs, antiviral drugs, hormone drugs, antibiotic drugs, antidiabetic drugs, antifungal drugs, antithrombotic drugs, antipyretic, anti-inflammatory and analgesic drugs, and mixtures thereof.

4. The preparation method of drug-containing sustained release microparticles according to claim 3, wherein the antipsychotic drug is selected from the group consisting of haloperidol, bromperidol, fluphenazine maleate, chlorpromazine, chlorpromazine hibenzate, sulpiride, carpipramine hydrochloride, carpipramine maleate, clocapramine hydrochloride, mosapramine hydrochloride, risperidone, clozapine, olanzapine, sertindole, and mixtures thereof.

5. The preparation method of drug-containing sustained release microparticles according to claim 1, wherein the halogenated alkane solvent is selected from the group consisting of dichloromethane, chloroform, chloroethane, dichloroethane, trichloroethane, and mixtures thereof.

6. The preparation method of drug-containing sustained release microparticles according to claim 1, wherein the surfactant is selected from the group consisting of a nonionic surfactant, an anionic surfactant, a cationic surfactant, and mixtures thereof.

7. The preparation method of drug-containing sustained release microparticles according to claim 1, wherein the continuous phase containing surfactant is a polyvinyl alcohol aqueous solution.

8. The preparation method of drug-containing sustained release microparticles according to claim 1, wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, and mixtures thereof.

9. The preparation method of drug-containing sustained release microparticles according to claim 1, wherein the primary drying and the secondary drying are performed by vacuum drying.

10. The preparation method of drug-containing sustained release microparticles according to claim 1, further comprising: between the step (c) and the step (d), removing the continuous phase through filtration and washing to obtain microparticles.

11. The preparation method of drug-containing sustained release microparticles according to claim 1, further comprising: between the step (e) and the step (f), removing the aqueous alcohol solution through filtration and washing to obtain microparticles.

12. The preparation method of drug-containing sustained release microparticles according to claim 1, wherein the drug-containing microparticles comprise 20 wt % to 99 wt % of biodegradable polymer per the total weight of the drug-containing microparticles.

Description

MODE FOR CARRYING OUT THE INVENTION

EXAMPLE

[0068] Although the present disclosure is hereinafter described in more detail through example according to the present disclosure and comparative example disaccording to the present disclosure, the scope of the present disclosure is not limited to the following example.

Example 1

[0069] 10 g PLGA (lactic acid-glycolic acid copolymer, a molar ratio of lactic acid and glycolic acid=75:25) as a biodegradable polymer and 8 g risperidone as a drug was dissolved in 40Ml dichloromethane (boiling point: 39.6° C.) solvent to prepare a drug-containing biodegradable polymer solution. Furthermore, 5L polyvinyl alcohol aqueous solution (concentration: 0.25 w/v %) was prepared using polyvinylalcohol as a surfactant and water as a continuous phase. Subsequently, the drug-containing biodegradable polymer solution was mixed with the polyvinyl alcohol aqueous solution and stirred at a high speed to form a dispersed phase in the form of droplets. Furthermore, an emulsion including the continuous phase and the dispersed phase was maintained at 15° C. for 2 to 3 hours, to allow the dichloromethane solvent to be extracted from the drug-containing biodegradable polymer solution in the form of droplets towards the polyvinyl alcohol aqueous solution, followed by solidification of the droplets, through which microparticles were formed in the continuous phase. Subsequently, the solidified microparticles were filtered and washed with water three times to remove polyvinylalcohol. Subsequently, filtering was performed again, through which the washed microparticles were obtained, and primarily dried under vacuum to evaporate moisture and dichloromethane remaining in the microparticles, yielding the primarily dried microparticles. The primarily dried microparticles were mixed with 500 mL aqueous ethanol solution (concentration: 25 v/v %) and stirred at 45° C. for 2 to 3 hours to extract dichloromethane remaining in the microparticles towards the aqueous ethanol solution, allowing the dichloromethane to evaporate. Subsequently, the aqueous ethanol solution including the microparticles was filtered, and the microparticles were washed with water three times to remove ethanol. Subsequently, filtering was performed again, through which the washed microparticles were obtained, and secondarily dried under vacuum to remove moisture, dichloromethane and ethanol remaining in the microparticles, yielding drug-containing sustained release microparticles.

Comparative Example 1

[0070] A drug-containing biodegradable polymer solution and 5 L polyvinyl alcohol aqueous solution were prepared by the same method as example 1. Subsequently, the drug-containing biodegradable polymer solution was mixed with the polyvinyl alcohol aqueous solution and stirred at a high speed to form a dispersed phase in the form of droplets. Furthermore, an emulsion including the continuous phase and the dispersed phase was maintained at 15° C. for 2 to 3 hours, to allow the dichloromethane solvent to be extracted from the drug-containing biodegradable polymer solution in the form of droplets towards the polyvinyl alcohol aqueous solution, followed by solidification of the droplets, through which microparticles were formed in the continuous phase. Subsequently, the continuous phase including the microparticles was stirred at 45° C. for 2 to 3 hours to evaporate dichloromethane from the microparticles, and the solidified microparticles were filtered and washed with water three times to remove the polyvinylalcohol. Subsequently, filtering was performed again to obtain the washed microparticles which were dried under vacuum to evaporate moisture and dichloromethane remaining in the microparticles, yielding drug-containing microparticles.

Comparative Example 2

[0071] A drug-containing biodegradable polymer solution and 5 L polyvinyl alcohol aqueous solution were prepared by the same method as example 1. Subsequently, the drug-containing biodegradable polymer solution was mixed with the polyvinyl alcohol aqueous solution and stirred at a high speed to form a dispersed phase in the form of droplets. Furthermore, an emulsion including the continuous phase and the dispersed phase was maintained at 15° C. for 2 to 3 hours, to allow the dichloromethane solvent to be extracted from the drug-containing biodegradable polymer solution in the form of droplets towards the polyvinyl alcohol aqueous solution, followed by solidification of the droplets, through which microparticles were formed in the continuous phase. Subsequently, the continuous phase including the microparticles was stirred at 45° C. for 2 to 3 hours to evaporate dichloromethane from the microparticles, so the microparticles were further solidified. Subsequently, the solidified microparticles were filtered and washed with water three times to remove polyvinylalcohol. Subsequently, filtering was performed again, through which the washed microparticles were obtained, and primarily dried under vacuum to evaporate moisture and dichloromethane remaining in the microparticles, yielding the primarily dried microparticles. The primarily dried microparticles were mixed with 500 mL aqueous ethanol solution (concentration: 25 v/v %), and stirred at 45° C. for 2 to 3 hours to extract residual dichloromethane from the microparticles towards the aqueous ethanol solution, allowing the dichloromethane to evaporate. Subsequently, the aqueous ethanol solution including the microparticles was filtered, and the microparticles were washed with water three times to remove ethanol. Subsequently, filtering was performed again, through which the washed microparticles were obtained, and secondarily dried under vacuum to remove moisture, dichloromethane and ethanol remaining in the microparticles, yielding drug-containing microparticles.

Test Example 1

Measurement of Weight Average Molecular Weight of Biodegradable Polymer in Microparticles

[0072] The weight average molecular weight of the biodegradable polymer (i.e., PLGA) in the drug-containing microparticles obtained in example 1 and comparative examples 1 and 2 was measured using high-performance liquid chromatography (Waters, GPC-150C Plus) as follows. Fractionation columns were connected in series in the order of Shodex GPC KF-G, 804, 803, 802 and 801. The column temperature was set to 50° C., the flow rate was 1.0 ml/min using tetrahydrofuran as mobile phase, and a differential refractometer was used as a detector. Subsequently, the weight average molecular weight of a test solution was calculated using weight average molecular weight calibration curves of each polystyrene standard solution.

Test Example 2

Measurement of an Amount of Solvent Remaining in Microparticles

[0073] Measurements of an amount of solvent remaining in the drug-containing microparticles obtained in example 1 and comparative examples 1 and 2 were performed by correctly transferinging 5ml of each of the test solution and the standard solution to headspace vials. Peak areas AT and AS of dichloromethane and ethanol in each of the test solution and the standard solution were measured and an amount of residual solvents in the obtained microparticles was calculated by the following equation.

[00001]$\mathrm{Amount}.Math..Math.\mathrm{of}.Math..Math.\mathrm{residual}.Math..Math.\mathrm{dichloromethane}.Math..Math.\mathrm{in}.Math..Math.\mathrm{microparticles}.Math..Math.\left(\mathrm{ppm}\right)=\frac{\mathrm{AT}}{\mathrm{AS}}\times \frac{\mathrm{WS}}{\mathrm{WT}}\times \frac{5}{20000}\times 1000000$

[0074] AT: Peak area of dichloromethane and ethanol in test solution

[0075] AS: Peak area of dichloromethane and ethanol in standard solution

[0076] WT: Harvested amount of obtained microparticles (g)

[0077] WS: Harvested amount of standard foam (g)

[0078] The test example measurement results of example 1 and comparative examples 1 and 2 are summarized in the following Table 1.

TABLE-US-00001 TABLE 1 Amount of residual Weight average molecular weight dichloromethane in of biodegradable polymer in microparticles (ppm) microparticles Example 1 0 139,876 Comparative 1 9222 127,588 example 2 0 88,963

[0079] As shown in Table 1, in the case of example 1, an emulsion including the continuous phase and the dispersed phase was maintained at temperature lower than the boiling point of the halogenated alkane solvent to form microparticles in the continuous phase, and the microparticles obtained by primary vacuum drying were mixed with an aqueous alcohol solution and maintained at temperature above the boiling point of the halogenated alkane solvent to remove the halogenated alkane solvent remaining in the microparticles by extraction and evaporation, followed by secondary vacuum drying, to completely remove the halogenated alkane solvent remaining in the microparticles while minimizing hydrolysis of the biodegradable polymer in the microparticles.

[0080] However, in the case of comparative example 1, dissimilar to example 1, the continuous phase including microparticles at temperature above the boiling point of the halogenated alkane solvent was maintained without primary vacuum drying and additional removal of the halogenated alkane solvent by the aqueous alcohol solution, to further solidify the microparticles, followed by vacuum drying to obtain microparticles, and it can be seen that the halogenated alkane solvent remaining in the microparticles is present in a large amount.

[0081] Furthermore, in the case of comparative example 2, dissimilar to example 1, before primary vacuum drying, the step for maintaining the continuous phase including microparticles at temperature above the boiling point of the halogenated alkane solvent to further solidify the microparticles was performed, and thus, the halogenated alkane solvent remaining in the microparticles was completely removed, but due to this, hydrolysis of the biodegradable polymer in the microparticles occurred, and it can be seen that the biodegradable polymer reduced in weight average molecular weight.

[0082] As described hereinabove, when drug-containing sustained release microparticles are prepared according to the preparation method of the present disclosure, the halogenated alkane solvent remaining in the microparticles can be completely removed, and in this process, molecular weight reduction resulting from hydrolysis of the biodegradable polymer in the microparticles can be minimized. Accordingly, the drug-containing sustained release microparticles prepared according to the preparation method of the present disclosure can completely remove the halogenated alkane solvent that is toxic and cause cancers, while maintaining the weight average molecular weight of the biodegradable polymer, thereby maintaining superior sustained drug release.