Preparation method of naltrexone implants

Abstract

The present invention relates to a technical field of pharmaceutical preparation, in particular to a preparation method of naltrexone implants, including the following steps: (1) dissolving naltrexone and polylactic acid in an organic solvent to form naltrexone microspheres, and drying; (2) placing the naltrexone microspheres in a heated tableting mold for tableting, and obtaining naltrexone implant tablets; (3) dissolving the polylactic acid in the organic solvent to obtain a coating solution, and placing the coating solution in a coating pool, and then immersing the naltrexone implant tablets in the coating solution, and drying in a suspended state.

Claims

1. A preparation method of naltrexone implants, comprising the following steps: (1) preparing naltrexone microspheres: dissolving naltrexone and polylactic acid in a first organic solvent to form the naltrexone microspheres, and drying; (2) tableting: placing the naltrexone microspheres in a heated tableting mold for tableting, and obtaining naltrexone implant tablets; (3) coating: dissolving the polylactic acid in a second organic solvent to obtain a coating solution, and placing the coating solution in a coating pool, and then immersing the naltrexone implant tablets in the coating solution, and drying in a suspended state, wherein, in step (2), adding and mixing naltrexone crystals with the naltrexone microspheres before tableting, and then tableting in the heated tableting mold to obtain the naltrexone implant tablets, wherein, in step (3), setting a tube inside the coating pool, and immersing the tube in the coating solution before immersing the naltrexone implant tablets in the coating solution, and then pushing the naltrexone implant tablets through the tube which is disposed inside the coating pool and uniformly distributed with small holes, wherein the density of small holes on the tube is at least 100/30 cm tube length, the tube comprising small holes, an inlet, a body and an outlet, the body connects the inlet and the outlet, and the small holes, the inlet, the body and the outlet of the tube are immersed in the coating solution of the coating pool, wherein the coating time of the naltrexone implant tablets passing through a tube is 15-50 s, and the coating temperature is 33-40° C.

2. The preparation method of naltrexone implants of claim 1, wherein, in step (2), a mass ratio of the naltrexone microspheres to the naltrexone crystals is 100:10-20.

3. The preparation method of naltrexone implants of claim 1, wherein, in step (2), a mass ratio of the naltrexone microspheres to the naltrexone crystals is 100:12-15.

4. The preparation method of naltrexone implants of claim 1, wherein, in step (2), heating the tableting mold to 35-50° C.

5. The preparation method of naltrexone implants of claim 1, wherein, in step (2), heating the tableting mold to 37-40° C.

6. The preparation method of naltrexone implants of claim 1, wherein, in step (3), coating the naltrexone implant tablets by moving them from one end of the tube to the other end with an external driving force.

7. The preparation method of naltrexone implants of claim 1, wherein, the diameter of the inlet of the tube is 0.5-1.5 mm larger than the diameter of the outlet, and the diameter of the outlet of the tube is 1.5-2 mm larger than the diameter of the naltrexone implant tablets.

8. The preparation method of naltrexone implants of claim 1, wherein, the diameter of the inlet of the tube is 0.8-1.2 mm larger than the diameter of the outlet, and the diameter of the outlet of the tube is 1.5-1.8 mm larger than the diameter of the naltrexone implant tablets.

9. The preparation method of naltrexone implants of claim 1, wherein the coating time of the naltrexone implant tablets passing through a tube is 30 s, and the coating temperature is 37° C.

10. The preparation method of naltrexone implants of claim 1, wherein, in step (3), after drying in the suspended state at 18-24° C. for 15-45s, continuing to dry under vacuum at 30-50° C. for 48-50 h.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a sketch map of the coating pool and drying apparatus used in the coating process.

(2) FIG. 2 is the mean blood concentration-time curve of naltrexone in the plasma of the subjects after subcutaneous implantation of naltrexone implants in Test Example 2.

DESCRIPTION OF THE EMBODIMENTS

Example 1 Preparation Method of Naltrexone Implants

(3) The preparation steps are as follows:

(4) (1) Preparing naltrexone microspheres: dissolving the naltrexone and polylactic acid (molecular weight is 60,000) with a mass ratio of 1:1 in methylene chloride, and the concentration of the obtained solution is 20%; stirring at 37° C. to form microspheres suspended in solution, then filtering, and vacuum drying the microspheres.

(5) Wherein, the microspheres have a diameter of 50 to 200 μm.

(6) (2) Preparing naltrexone crystal: dissolving naltrexone hydrochloride in 20 times volume of water, and then mixing it with an equal volume of 3% NaHCO.sub.3 solution, extracting with dichloromethane for 3 times, and then concentrating and vacuum drying the extract, and finally obtaining the naltrexone crystal.

(7) Wherein, the naltrexone crystal has a length of 10 to 30 μm.

(8) (3) Tableting: mixing the naltrexone microspheres of step (1) and the naltrexone crystal of step (2) at a mass ratio of 100:10 to obtain the mixture of naltrexone microspheres, shocking while mixing, so that the crystal can uniformly distribute in the microspheres and form a dendritic shape; heating the tableting mold to 40° C., and tableting the mixture of naltrexone microspheres at a pressure of 13 KN to obtain a naltrexone implant tablet.

(9) (4) Coating: as shown in FIG. 1, dissolving the DL-polylactic acid with a molecular weight of 60,000 in dichloromethane to form a 6% coating solution, placing the solution in the coating pool 1, pushing the naltrexone implants 3 to the liquid tube 2 which is disposed inside the coating pool 1 and uniformly distributed with small holes, pushing the implants 3 from one end of the liquid tube 2 to the other end by an external force to coat the tablets; the coating time is 30 s, and the coating temperature is 37° C.; transferring the coated naltrexone implants to a suspension dryer 4, drying at 20° C. for 30 s, and then drying under vacuum at 40° C. for 48 h.

(10) In step (4), the density of small holes on the liquid tube 2 is 150/30 cm, the diameter from the inlet to the outlet of the liquid tube 2 is gradually reduced, and the inlet is 0.9 mm larger than the outlet; the diameter of the outlet of the liquid tube 2 is 1.5 mm larger than the diameter of the naltrexone implant 3.

Example 2 Preparation Method of Naltrexone Implants

(11) (1) Preparing naltrexone microspheres: dissolving the naltrexone and polylactic acid (molecular weight is 50,000) with a mass ratio of 0.6:1 in methylene chloride, and the concentration of the obtained solution is 20%; stirring at 35° C. to form microspheres suspended in solution, then filtering, and vacuum drying the microspheres.

(12) Wherein, the microspheres have a diameter of 50 to 180 μm.

(13) (2) Preparing naltrexone crystal: dissolving naltrexone hydrochloride in 16 times volume of water, and then mixing it with an equal volume of 4% NaHCO.sub.3 solution, extracting with dichloromethane for 3 times, and then concentrating and vacuum drying the extract, and finally obtaining the naltrexone crystal.

(14) Wherein, the naltrexone crystal has a length of 5 to 20 μm.

(15) (3) Tableting: mixing the naltrexone microspheres of step (1) and the naltrexone crystal of step (2) at a mass ratio of 100:15 to obtain the mixture of naltrexone microspheres, shocking while mixing, so that the crystal can uniformly distribute in the microspheres and form a dendritic shape; heating the tableting mold to 37° C., and tableting the mixture of naltrexone microspheres at a pressure of 11 KN to obtain a naltrexone implant tablet.

(16) (4) Coating: as shown in FIG. 1, dissolving the DL-polylactic acid with a molecular weight of 50,000 in dichloromethane to form a 6% coating solution, placing the solution in the coating pool 1, pushing the naltrexone implants 3 to the liquid tube 2 which is disposed inside the coating pool 1 and uniformly distributed with small holes, pushing the implants 3 from one end of the liquid tube 2 to the other end by an external force to coat the tablets; the coating time is 50 s, and the coating temperature is 33° C.; transferring the coated naltrexone implants to a suspension dryer 4, drying at 24° C. for 15 s, and then drying under vacuum at 30° C. for 50 h.

(17) In step (4), the density of small holes on the liquid tube 2 is 100/30 cm, the diameter from the inlet to the outlet of the liquid tube 2 is gradually reduced; the diameter of the outlet of the liquid tube 2 is 1.5 mm larger than the diameter of the naltrexone implant 3.

Example 3 Preparation Method of Naltrexone Implants

(18) (1) Preparing naltrexone microspheres: dissolving the naltrexone and polylactic acid (molecular weight is 70,000) with a mass ratio of 0.8:1 in methylene chloride, and the concentration of the obtained solution is 18%; stirring at 36° C. to form microspheres, which is suspended in solution, then filtering, and vacuum drying the microspheres.

(19) Wherein, the microspheres have a diameter of 50 to 200 μm.

(20) (2) Preparing naltrexone crystal: dissolving naltrexone hydrochloride in 18 times volume of water, and then mixing it with an equal volume of 3% NaHCO.sub.3 solution, extracting with dichloromethane for 3 times, and then concentrating and vacuum drying the extract, and finally obtaining the naltrexone crystal.

(21) Wherein, the naltrexone crystal has a length of 30 to 50 μm.

(22) (3) Tableting: mixing the naltrexone microspheres of step (1) and the naltrexone crystal of step (2) at a mass ratio of 100:14 to obtain the mixture of naltrexone microspheres, shocking while mixing, so that the crystal can uniformly distribute in the microspheres and form a dendritic shape; heating the tableting mold to 38° C., and tableting the mixture of naltrexone microspheres at a pressure of 15 KN to obtain a naltrexone implant tablet.

(23) (4) Coating: as shown in FIG. 1, dissolving the DL-polylactic acid with a molecular weight of 70,000 in dichloromethane to foci n a 7% coating solution, placing the solution in the coating pool 1, pushing the naltrexone implants 3 to the liquid tube 2 which is disposed inside the coating pool 1 and uniformly distributed with small holes, pushing the implants 3 from one end of the liquid tube 2 to the other end by an external force to coat the tablets; the coating time is 5 s, and the coating temperature is 40° C.; transferring the coated naltrexone implants to a suspension dryer 4, drying at 18° C. for 45 s, and then drying under vacuum at 50° C. for 50 h.

(24) In step (4), the density of small holes on the liquid tube 2 is 250/30 cm, the diameter at the inlet of the liquid tube 2 is 0.8 mm larger than the outlet; the diameter of the outlet of the liquid tube 2 is 1.8 mm larger than the diameter of the naltrexone implant 3.

Example 4 Preparation Method of Naltrexone Implants

(25) (1) Dissolving the naltrexone and polylactic acid (molecular weight is 70,000) with a mass ratio of 1.5:1 in methylene chloride, and the concentration of the obtained solution is 25%; stirring at 40° C. to form microspheres suspended in solution, then filtering, and vacuum drying the microspheres.

(26) Wherein, the microspheres have a diameter of 80 to 250 μm.

(27) (2) Dissolving naltrexone hydrochloride in 17 times volume of water, and then mixing it with an equal volume of 3.2% NaHCO.sub.3 solution, extracting with dichloromethane for 4 times, and then concentrating and vacuum drying the extract, and finally obtaining the naltrexone crystal.

(28) Wherein, the naltrexone crystal has a length of 2 to 15 μm.

(29) (3) Tableting: mixing the naltrexone microspheres of step (1) and the naltrexone crystal of step (2) at a mass ratio of 100:10 to obtain the mixture of naltrexone microspheres, shocking while mixing, so that the crystal can uniformly distribute in the microspheres and form a dendritic shape; heating the tableting mold to 35° C., and tableting the mixture of naltrexone microspheres at a pressure of 8 KN to obtain a naltrexone implant tablet.

(30) (4) Coating: as shown in FIG. 1, dissolving the DL-polylactic acid with a molecular weight of 90,000 in dichloromethane to form a 9% coating solution, placing the solution in the coating pool 1, pushing the naltrexone implants 3 to the liquid tube 2 which is disposed inside the coating pool 1 and uniformly distributed with small holes, pushing the implants 3 from one end of the liquid tube 2 to the other end by an external force to coat the tablets; the coating time is 35 s, and the coating temperature is 38° C.; transferring the coated naltrexone implants to a suspension dryer 4, drying at 25° C. for 35 s, and then drying under vacuum at 34° C. for 48 h.

(31) In step (4), the density of small holes on the liquid tube 2 is 200/30 cm, the diameter from the inlet to the outlet of the liquid tube 2 is gradually reduced, and the inlet is 1.2 mm larger than the outlet; the diameter of the outlet of the liquid tube 2 is 1.8 mm larger than the diameter of the naltrexone implant 3.

Example 5 Preparation Method of Naltrexone Implants

(32) (1) Dissolving the naltrexone and polylactic acid (molecular weight is 80,000) with a mass ratio of 1.8:1 in methylene chloride, and the concentration of the obtained solution is 22%; stirring at 37° C. to form microspheres suspended in solution, then filtering, and vacuum drying the microspheres.

(33) Wherein, the microspheres have a diameter of 80 to 200 μm.

(34) (2) Dissolving naltrexone hydrochloride in 15 times volume of water, and then mixing it with an equal volume of 4% NaHCO.sub.3 solution, extracting with dichloromethane for 3 times, and then concentrating and vacuum drying the extract, and finally obtaining the naltrexone crystal.

(35) Wherein, the naltrexone crystal has a length of 10 to 70 μm.

(36) (3) Tableting: mixing the naltrexone microspheres of step (1) and the naltrexone crystal of step (2) at a mass ratio of 100:10 to obtain the mixture of naltrexone microspheres, shocking while mixing, so that the crystal can uniformly distribute in the microspheres and form a dendritic shape; heating the tableting mold to 42° C., and tableting the mixture of naltrexone microspheres at a pressure of 14 KN to obtain a naltrexone implant tablet.

(37) (4) Coating: as shown in FIG. 1, dissolving the DL-polylactic acid with a molecular weight of 80,000 in dichloromethane to faun a 8% coating solution, placing the solution in the coating pool 1, pushing the naltrexone implants 3 to the liquid tube 2 which is disposed inside the coating pool 1 and uniformly distributed with small holes, pushing the implants 3 from one end of the liquid tube 2 to the other end by an external force to coat the tablets; the coating time is 40 s, and the coating temperature is 36° C.; transferring the coated naltrexone implants to a suspension dryer 4, drying at 23° C. for 40 s, and then drying under vacuum at 48° C. for 49 h.

(38) In step (4), the density of small holes on the liquid tube 2 is 300/30 cm, the diameter at the inlet of the liquid tube 2 is 1.5 mm larger than the outlet; the diameter of the outlet of the liquid tube 2 is 2 mm larger than the diameter of the naltrexone implant 3.

Example 6 Preparation Method of Naltrexone Implants

(39) (1) Dissolving the naltrexone and polylactic acid (molecular weight is 60,000) with a mass ratio of 1:1 in methylene chloride, and the concentration of the obtained solution is 20%; stirring at 37° C. to form microspheres suspended in solution, then filtering, and vacuum drying microspheres.

(40) Wherein, the microspheres have a diameter of 50 to 200 μm.

(41) (2) Tableting: heating the tableting mold to 40° C., and tableting the naltrexone microspheres at a pressure of 13 KN to obtain a naltrexone implant tablet.

(42) (4) Coating: as shown in FIG. 1, dissolving the DL-polylactic acid with a molecular weight of 60,000 in dichloromethane to form a 6% coating solution, placing the solution in the coating pool 1, pushing the naltrexone implants 3 to the liquid tube 2 which is disposed inside the coating pool 1 and uniformly distributed with small holes, pushing the implants 3 from one end of the liquid tube 2 to the other end by an external force to coat the tablets; the coating time is 30 s, and the coating temperature is 37° C.; transferring the coated naltrexone implants to a suspension dryer 4, drying at 20° C. for 30 s, and then drying under vacuum at 40° C. for 48 h.

(43) In step (4), the density of small holes on the liquid tube 2 is 150/30 cm, the diameter from the inlet to the outlet of the liquid tube 2 is gradually reduced, and the inlet is 0.9 mm larger than the outlet; the diameter of the outlet of the liquid tube 2 is 1.5 mm larger than the diameter of the naltrexone implant 3.

Contrast Example 1 Preparation Method of Naltrexone Implants

(44) Except that the tableting temperature is 50° C. in step (3), the other steps are the same as Example 1.

Contrast Example 2 Preparation Method of Naltrexone Implants

(45) Except that the microsphere is washed, the other steps are the same as Example 1, the prepare steps are as follows:

(46) (1) Preparing naltrexone microspheres: dissolving the naltrexone and polylactic acid (molecular weight is 60,000) with a mass ratio of 1:1 in methylene chloride, and the concentration of the obtained solution is 20%; stirring at 37° C. to form microspheres suspended in solution, then filtering, washing with distilled water and vacuum drying the microspheres.

(47) Wherein, the microspheres have a diameter of 50 to 200 μm.

(48) (2) Preparing naltrexone crystal: dissolving naltrexone hydrochloride in 20 times volume of water, and then mixing it with an equal volume of 3% NaHCO.sub.3 solution, extracting with dichloromethane for 3 times, and then concentrating and vacuum drying the extract, and finally obtaining the naltrexone crystal.

(49) Wherein, the naltrexone crystal has a length of 10 to 30 μm.

(50) (3) Tableting: mixing the naltrexone microspheres of step (1) and the naltrexone crystal of step (2) at a mass ratio of 100:10 to obtain the mixture of naltrexone microspheres, shocking while mixing, so that the crystal can uniformly distribute in the microspheres and form a dendritic shape; heating the tableting mold to 40° C., and tableting the mixture of naltrexone microspheres at a pressure of 13 KN to obtain a naltrexone implant tablet.

(51) (4) Coating: as shown in FIG. 1, dissolving the DL-polylactic acid with a molecular weight of 60,000 in dichloromethane to form a 6% coating solution, placing the solution in the coating pool 1, pushing the naltrexone implants 3 to the liquid tube 2 which is disposed inside the coating pool 1 and uniformly distributed with small holes, pushing the implants 3 from one end of the liquid tube 2 to the other end by an external force to coat the tablets; the coating time is 30 s, and the coating temperature is 37° C.; transferring the coated naltrexone implants to a suspension dryer 4, drying at 20° C. for 30 s, and then drying under vacuum at 40° C. for 48 h.

(52) In step (4), the density of small holes on the liquid tube 2 is 150/30 cm, the diameter from the inlet to the outlet of the liquid tube 2 is gradually reduced, and the inlet is 0.9 mm larger than the outlet; the diameter of the outlet of the liquid tube 2 is 1.5 mm larger than the diameter of the naltrexone implant 3.

Contrast Example 3 Preparation Method of Naltrexone Implants

(53) Except that the immersing time for the naltrexone implants to coat is 50 s, the other steps are the same as Example 1.

Contrast Example 4 Preparation Method of Naltrexone Implants

(54) Except that the coating time of the naltrexone implants is 45° C., the other steps are the same as Example 1.

Contrast Example 5 Preparation Method of Naltrexone Implants

(55) Except that the molecule weight of the naltrexone implant is 40,000, the other steps are the same as Example 1.

Contrast Example 6 Preparation Method of Naltrexone Implants

(56) Except that the mass ratio of naltrexone microspheres to naltrexone crystals is 100:5, the other steps are the same as Example 1.

Test Example 1 the Drug Content, Yield and Coating Thickness of Naltrexone Implants Prepared by the Above Methods

(57) Determining the drug content of the implants prepared in Examples 1-6 and Contrast Examples 1-6 according to the quality standard of naltrexone implants with the method of HPLC.

(58) At the same time, counting the number of finished products and defective products prepared by each process, and calculating the yield.

(59) TABLE-US-00001 TABLE 1 The drug content and yield of implants prepared by the different methods Drug Coating Groups Content ( % ) Yield (%) Thickness (mm) Example 1 49.1 94 0.0023 ± 0.0003 Example 2 45.5 96 0.0025 ± 0.0001 Example 3 52.7 93 0.0028 ± 0.0003 Example 4 45.6 95 0.0020 ± 0.0004 Example 5 54.5 92 0.0029 ± 0.0004 Example 6 39.1 80 0.0022 ± 0.0004 Contrast Example 1 38.5 53 0.0032 ± 0.0008 Contrast Example 2 26.7 72 0.0030 ± 0.0012 Contrast Example 3 38.8 72 0.010 ± 0.007 Contrast Example 4 39.7 71 0.0012 ± 0.010  Contrast Example 5 38.7 73 0.009 ± 0.017 Contrast Example 6 42.3 83 0.0031 ± 0.006 

Test Example 2 Clinical Results of Naltrexone Implants Prepared by Different Methods

(60) Subcutaneously implanting 10 tablets of the naltrexone implants prepared in Example 1, Example 6, Comparative Example 1 and Comparative Example 5 into the patients respectively. Determining the blood concentration after implantation and the results are shown in FIG. 2.

(61) The results show that the naltrexone implant tableting method of the present invention can effectively improve the sustained release of the drug and avoid the burst release due to collapse of the microspheres.

(62) The detailed description is intended to illustrate one of the preferred embodiments of the present invention. These examples are non-limiting and should not be construed as limiting any aspect of invention. It should be noted that any modification and equivalent replacement within the spirit and principle of the invention should be included in the protection scope of the invention.