Solid particle, preparation method therefor, and pharmaceutical composition containing solid particle

Abstract

A solid particle, a preparation method therefor, and a pharmaceutical composition. The solid particle comprises a porous solid particle and a non-aqueous liquid formula. The non-aqueous liquid formula comprises 0.10-4.00 wt % of a hydrophobic active pharmaceutical agent, 28.00-99.90 wt % of a hydrophobic solubilizing solution, 0-70.00 wt % of a non-ionic surfactant, and 0-1.00 wt % of an antioxidant. The hydrophobic solubilizing solution comprises a medium-chain monoglyceride and diglyceride, and/or a propylene glycol fatty acid monoester.

Claims

1. A solid microparticle, which comprises 0.33% hydrophobic active pharmaceutical ingredient, 5.00% to 24.75% hydrophobic liquid solubilizer, 4.50% to 19.80% nonionic surfactant, 0 to 0.60% antioxidant, and 66.67% to 75.00% porous solid particles, wherein the percentages refers to the weight percentages accounting for the solid microparticle; the porous solid particles comprise calcium hydrogen phosphate; the hydrophobic liquid solubilizer comprises propylene glycol monocaprylate type II, propylene glycol monolaurate type II or caprylic capric mono-/di- glyceride type I; and the hydrophobic active pharmaceutical ingredient is dutasteride, wherein the solid microparticle is made into hard capsules and releases dutasteride about 11% to 30% faster than that of dutasteride soft gelatin capsule within 0 to 15 minutes.

2. The solid microparticle as claimed in claim 1, wherein the content of the hydrophobic liquid solubilizer is 11.50% to 24.75%.

3. The solid microparticle as claimed in claim 1, wherein the content of the hydrophobic liquid solubilizer is 13.20% to 24.75%, and the percentages refer to the weight percentages accounting for the solid microparticle.

4. The solid microparticle as claimed in claim 1, wherein the content of the nonionic surfactant is 8.25% to 19.80%, and the percentages refer to the weight percentages accounting for the solid microparticle.

5. The solid microparticle as claimed in claim 1, wherein the content of the nonionic surfactant is 8.25% to 16.50%, and the percentages refer to the weight percentages accounting for the solid microparticle.

6. The solid microparticle as claimed in claim 1, wherein when the content of the antioxidant is not 0, the content of the antioxidant is 0.025% to 0.60%, and the percentages refer to the weight percentages accounting for the solid microparticle.

7. The solid microparticle as claimed in claim 1, wherein the content of the porous solid particles is 66.67% to 70.00%, and the percentages refer to the weight percentages accounting for the solid microparticle.

8. The solid microparticle as claimed in claim 1, wherein, the nonionic surfactant is PEGylated nonionic surfactant or polyol nonionic surfactant.

9. The solid microparticle as claimed in claim 1, wherein the antioxidant is dibutylhydroxytoluene or butylhydroxyanisole.

10. The solid microparticle as claimed in claim 1, wherein the porous solid particles have a specific surface area of >30 m.sup.2/g, and adsorb at least 0.40 mL/g the non-aqueous liquid formula while maintaining flowability simultaneously.

11. The solid microparticle as claimed in claim 8, wherein the PEGylated nonionic surfactant is polyoxyethylene 35 castor oil or caprylocaproyl polyoxylglycerides, and the polyol nonionic surfactant is polysorbate 80.

12. The solid microparticle as claimed in claim 8, the nonionic surfactant is PEGylated nonionic surfactant.

13. The solid microparticle as claimed in claim 8, wherein the solid microparticle is selected from any one of the following combinations: (1) the solid microparticle comprises 24.75% propylene glycol monocaprylate type II, 8.25% caprylocaproyl polyoxylglycerides, and 66.67% calcium hydrogen phosphate; (2) the solid microparticle comprises 16.50% propylene glycol monocaprylate type II, 16.50% caprylocaproyl polyoxylglycerides, and 66.67% calcium hydrogen phosphate; (3) the solid microparticle comprises 13.20% propylene glycol monocaprylate type II, 19.80% caprylocaproyl polyoxylglycerides, and 66.67% calcium hydrogen phosphate; (4) the solid microparticle comprises 24.75% propylene glycol monocaprylate type II, 8.25% polyoxyethylene 35 castor oil, and 66.67% calcium hydrogen phosphate; (5) the solid microparticle comprises 16.50% propylene glycol monocaprylate type II, 16.50% polyoxyethylene 35 castor oil, and 66.67% calcium hydrogen phosphate; (6) the solid microparticle comprises 13.20% propylene glycol monocaprylate type II, 19.80% polyoxyethylene 35 castor oil, and 66.67% calcium hydrogen phosphate; (7) the solid microparticle comprises 24.50% propylene glycol monocaprylate, 8.17% polyoxyethylene 35 castor oil, 0.33% dibutylhydroxytoluene, and 66.67% calcium hydrogen phosphate; and (8) the solid microparticle comprises 16.34% propylene glycol monocaprylate, 16.33% polyoxyethylene 35 castor oil, 0.33% dibutylhydroxytoluene, and 66.67% calcium hydrogen phosphate, wherein the percentages refer to the weight percentages accounting for the solid particle.

14. A pharmaceutical composition comprising the solid microparticle as claimed in claim 1 and tamsulosin.

15. The pharmaceutical composition as claimed in claim 14, wherein the pharmaceutical composition is in hard capsule form.

16. The pharmaceutical composition as claimed in claim 14, wherein the tamsulosin is tamsulosin sustained-release pellets or tamsulosin hydrochloride sustained-release pellets.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a dutasteride dissolution curve figure of each formulation in embodiment 4 and the commercial product Avodart® in a dissolution medium at pH=3.

(2) FIG. 2 is a dutasteride dissolution curve figure of each formulation in embodiment 5 and the commercial product Avodart® in a dissolution medium at pH=3.

(3) FIG. 3 is a dutasteride dissolution curve figure of formulation in embodiment 6 and the commercial product Avodart® in a dissolution medium without pepsin at pH=1.

(4) FIG. 4 is a dutasteride dissolution curve figure of formulation in embodiment 6 and the commercial product Avodart® in a dissolution medium containing pepsin at pH=1.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

(5) The present invention is further described by the following embodiments. The present invention is not limited to the scope of the embodiments. The experimental methods without indicating specific conditions are performed under conventional methods and conditions, or according to product specifications.

Embodiment 1

(6) The hydrophobic liquid solubilizers were mixed with Fujicalin at a weight ratio of 2:1, and the flowability of the solid microparticles were estimated by measuring the tap density and bulk density of the solid microparticles.

(7) The compression index (C.I.) and Hausner ratio (H.R.) could be calculated according to the following formula.
C.I.=100×((V.sub.0−V.sub.f)/V.sub.0)
H.R.=V.sub.0/V.sub.f

(8) Wherein V.sub.0 and V.sub.f are the bulk density and the tap density of the solid microparticles, respectively.

(9) U.S. Pharmacopeia Chapter 39 <1174 “Powder Flow”> shows the correlation between the powder flowability with the compressibility index and the Hausner ratio (Table 1).

(10) TABLE-US-00001 TABLE 1 Flowability and the corresponding compressibility index and Hausner ratio Compressibility index (%) Flowability Hausner ratio ≤10 Excellent 1.00-1.11 11-15 Good 1.12-1.18 16-20 Fair, no assistance needed 1.19-1.25 21-15 Passable, may shake 1.26-1.34 26-31 Poor-must shake, vibrate 1.35-1.45 32-37 Very poor 1.46-1.59 >38 Very,very poor >1.60

(11) The measurement results are shown in Table 2. All hydrophobic liquid solubilizers, including propylene glycol monolaurate (type II) (LAUROGLYCOL 90), propylene glycol monocaprylate (type II) (CAPRYOL 90), caprylic capric mono-/di-glyceride (type I) (Capmul MCM), etc., showed excellent flowability.

(12) TABLE-US-00002 TABLE 2 Flowability of the solid microparticles Weight ratio of Fujicalin/ non- com- Hydrophobic aqueous Silicon Bulk Tap pres- liquid liquid dioxide density density sibility Hausner No. solubilizer formula (%) (g/mL) (g/mL) index ratio Embodiment Propylene glycol 2:1 0 0.685 0.748 8.50 1.09 1-1 monolaurate (type II) (LAUROGLYCOL 90) Embodiment Propylene glycol 2:1 0 0.690 0.771 10.5 1.12 1-2 monocaprylate (type II) (CAPRYOL 90) Embodiment Caprylic capric 2:1 0 0.690 0.759 9.0 1.10 1-3 mono-/di- glyceride (type I) (Capmul MCM)

Embodiment 2

(13) Capryol 90 and Kolliphor® ELP were mixed at a weight ratio of 1:1, mixed with Fujicalin, and then mixed with silicon dioxide at different weight ratios. The flowability of the solid microparticles were estimated by measuring the tap density and the bulk density of the solid.

(14) According to the measurement results shown in Table 3, silicon dioxide-free solid microparticles with a Fujicalin to non-aqueous liquid formula weight ratio of 2:1 or 3:1 had excellent flowability.

(15) TABLE-US-00003 TABLE 3 Flowability of the solid microparticles Weight ratio of Fujicalin/non- aqueous Silicon Bulk Tap liquid dioxide density density compressibility Hausner No. formula (%) (g/mL) (g/mL) index ratio Embodiment 2-1 2:1 1.0 0.629 0.718 12.5 1.14 Embodiment 2-2 2:1 0.25 0.675 0.749 10.0 1.11 Embodiment 2-3 2:1 0 0.696 0.765 9.0 1.10 Embodiment 2-4 3:1 0 0.627 0.681 8.0 1.09 Comparative 1:0 0 0.479 0.529 9.5 1.10 embodiment 1

Embodiment 3

(16) When the solid microparticles were prepared, the content of each component might be as shown in the following table, the percentages referred to the weight percentages accounting for solid microparticles.

(17) TABLE-US-00004 TABLE 4 Hydrophobic active Hydrophobic Porous pharmaceutical liquid Nonionic solid No. agent solubilizer surfactant Antioxidant particles Embodiment 0.33% 35.00% / / 64.67% 3-1 dutasteride CAPRYOL 90 Fujicalin Embodiment 0.33% 35.00% / 0.10% BHT 64.57% 3-2 dutasteride CAPRYOL 90 Fujicalin Embodiment 0.33% 35.7% / 0.30% BHT 63.67% 3-3 dutasteride CAPRYOL 90 Fujicalin Embodiment 0.33% 35.00% / 0.10% BHT 34.57% 3-4 dutasteride CAPRYOL 90 Fujicalin and 30% silicon dioxide Embodiment 0.33% 25.00% 5.00% / 69.67% 3-5 dutasteride CAPRYOL 90 Kolliphor ®ELP Fujicalin Embodiment 0.33% 25.00% 5.00% / 69.67% 3-6 dutasteride CAPRYOL 90 LABASOL Fujicalin ALF Embodiment 0.33% 25.00% 5.00% / 69.67% 3-7 dutasteride CAPRYOL 90 Polysorbate 80 Fujicalin TM Embodiment 0.33% 25.00% 5.00% 0.10% BHT 69.57% 3-8 dutasteride CAPRYOL 90 Kolliphor ® ELP Fujicalin Embodiment 0.33% 25.00% 5.00% 0.10% BHT 69.57% 3-9 dutasteride CAPRYOL 90 LABASOL Fujicalin ALF Embodiment 0.33% 25.00% 5.00% 0.10% BHT 69.57% 3-10 dutasteride CAPRYOL 90 Polysorbate 80 Fujicalin TM Embodiment 0.33% 25.00% 5.00% 0.10% BHT 69.57% 3-11 dutasteride CAPRYOL 90 Polysorbate 80 Neusilin TM Embodiment 0.10% 39.90% 15.00% / 45.00% 3-12 dutasteride CAPRYOL 90 Polysorbate 80 Fujicalin TM Embodiment 0.50% 20.00% 10.00% / 69.50% 3-13 dutasteride CAPRYOL 90 Polysorbate 80 Fujicalin TM Embodiment 0.50% 11.50% 13.00% / 75.00% 3-14 dutasteride CAPRYOL 90 Polysorbate 80 Fujicalin TM Embodiment 0.50% 25.00% 4.50% / 70.00% 3-15 dutasteride Capmul MCM Kolliphor ® ELP Fujicalin Embodiment 0.50% 12.00% 13.00% / 74.50% 3-16 dutasteride CAPRYOL 90 Kolliphor ® ELP Fujicalin Embodiment 0.50% 15.00% 15.00% / 69.50% 3-17 dutasteride CAPRYOL 90 Kolliphor ® ELP Fujicalin Embodiment 0.50% 25.00% 15.00% / 59.50% 3-18 dutasteride CAPRYOL 90 Kolliphor ® ELP Fujicalin Embodiment 0.50% 30.00% 20.00% / 49.50% 3-19 dutasteride CAPRYOL 90 Kolliphor ® ELP Fujicalin Embodiment 0.50% 19.50% 40.00% / 40.00% 3-20 dutasteride CAPRYOL 90 Kollipho ® r ELP Fujicalin Embodiment 0.50% 30.00% 9.50% / 60.00% 3-21 dutasteride Capmul MCM Kolliphor ® ELP Fujicalin Embodiment 0.50% 31.50% 18.00% / 50.00% 3-22 dutasteride LAUROGLYC LABASOL Fujicalin OL90 ALF Embodiment 0.50% 36.50% 23.00% / 40.00% 3-23 dutasteride LAUROGLYC LABASOL Fujicalin OL90 ALF Embodiment 0.50% 36.40% 23.00% 0.10% BHT 40.00% 3-24 dutasteride LAUROGLYC LABASOL Fujicalin OL90 ALF Embodiment 0.50% 35.50% 23.00% 0.30% BHT 40.70% 3-25 dutasteride LAUROGLYC LABASOL Fujicalin OL90 ALF

(18) The obtained solid microparticles with dutasteride solid microparticle formulas shown in Table 4 had a Hausner ratio of 1.00 to 1.18 and good flowability.

(19) The obtained solid microparticles with dutasteride solid microparticle formulas shown in Table 4 were made into hard capsule formulations according to the preparation method of embodiment 4, and the dissolution thereof were detected according to the detection method in embodiment 4. They had about the same dissolutions as that of the formulation A-2, and could release about 18% to 25% faster than the reference listed formulation Avodart® within 0-15 minutes.

Embodiment 4

(20) Dutasteride solid microparticle hard capsules were prepared, the formulations of the Dutasteride were shown as follows:

(21) TABLE-US-00005 TABLE 5 Compositions of the hard capsules in embodiment 4 Formulation Formulation Formulation Formulation AB A-1 A-2 A-3 wt/ wt/ wt/ wt/ / wt capsule wt capsule wt capsule wt capsule Component % mg % mg % mg % mg Dutasteride 0.33 0.50 0.33 0.50 0.33 0.50 0.33 0.50 CAPRYOL 33.00 50.00 24.75 37.50 16.50 25.00 13.20 20.00 90 LABASOL / / 8.25 12.50 16.50 25.00 19.80 30.00 ALF Fujicalin 66.67 101.00 66.67 101.00 66.67 101.00 66.67 101.00 Total 100.00 151.50 100.00 151.50 100.00 151.50 100.00 151.50

(22) Preparation process of the capsules: (1) prescribed amounts of dutasteride and CAPRYOL 90 were mixed and vortexed for 5 minutes; (2) a prescribed amount of surfactant LABASOL ALF was added to obtain a clear solution; (3) the solution was mixed with porous particles to obtain solid microparticles capable of flowing freely; (4) 151 mg solid microparticles were filled into #2 hard capsules. Each capsule contained 0.5 mg dutasteride.

(23) Measurement of dissolution:

(24) The obtained hard capsules of each formula in this embodiment and commercially available Avodart® were stirred at 75 rpm according to USP II (paddle method) with 900 mL 0.001N HCl, 1% cetyltrimethylammonium bromide (CTAB) solution as a dissolution medium at a temperature of 37±0.5° C., and sampled at 15 min, 30 min, 45 min, and 60 min. The obtained sample solutions were filtered with a 0.45 μm filter membrane, and quantitatively detected by an HPLC method. The dissolution of dutasteride were calculated. The chromatographic conditions are shown in Table 6, and the dissolution data are shown in FIG. 1.

(25) TABLE-US-00006 TABLE 6 HPLC chromatographic conditions Instrument Waters LC aqueous liquid chromatography with automatic sampling, injection and UV detection Column Thermo AQUASIL C18 0.46*150 mm, 5 μm Operation parameters: Mobile phase: acetonitrile, methanol and water (40:20:35) Injection volume: 100 μL Flow rate: 2.0 mL/min Column temperature: 35° C. Detector wavelength: UV 240 nm

(26) Conclusion: the formulations AB, A-1, A-2 and A-3 of the present invention could release about 18% to 25% faster than the reference listed formulation Avodart® within 0-15 minutes.

Embodiment 5

(27) The formulas of dutasteride formulations are shown as follows:

(28) TABLE-US-00007 TABLE 7 compositions of hard capsules in embodiment 5 / Formulation B-1 FormulationB-2 Formulation B-3 Component wt % wt/capsule mg wt % wt/capsule mg wt % wt/capsule mg Dutasteride 0.33 0.50 0.33 0.50 0.33 0.50 CAPRYOL 90 24.75 37.50 16.50 25.00 13.20 20.00 Kolliphor ® 8.25 12.50 16.50 25.00 19.80 30.00 ELP Fujicalin 66.67 101.00 66.67 101.00 66.67 101.00 Total 100.00 151.50 100.00 151.50 100.00 151.50

(29) The preparation process and dissolution rate detection were the same as those in embodiment 4. The dissolution data are shown in FIG. 2.

(30) Conclusions: the formulations B-1, B-2 and B-3 of the present invention could release about 11% to 30% faster than that of the reference listed formulation Avodart® within 0 to 15 min, and the formulations B-1 and B-2 could release a little faster than Avodart® within 0 to 60 min.

Embodiment 6

(31) The formulation B-2 obtained in embodiment 5 and commercially available Avodart® were stirred at 75 rpm according to USP II (paddle method) with 900 mL 0.1N HCl 1% cetyltrimethylammonium bromide (CTAB) solution as a dissolution medium at a temperature of 37±0.5° C. The dissolution medium might or might not contain 0.40% pepsin.

(32) The detection method was the same as that in embodiment 4. The dissolution data are shown in FIGS. 3 and 4.

(33) Conclusions:

(34) FIG. 3 showed that the formulation B-2 obtained in the embodiment 5 had faster release rate and cumulative dissolution than Avodart® in the dissolution medium without pepsin.

(35) FIG. 4 showed that the formulation B-2 obtained in the embodiment 5 had about the same dissolution curves of hard capsules and soft capsules as those of Avodart® in the dissolution medium containing pepsin.

(36) Compared with Avodart® gelatin soft capsules, dutasteride in the hard capsules of the formulation B-2 showed more consistent dissolution rates without being influenced by the presence of pepsin in the dissolution medium, which might be caused by the potential cross-linking of the Avodart® soft gelatin capsules, resulting in that the dissolution of the medicament depended on pepsin.

Embodiment 7

(37) According to the formula and preparation method of embodiment 5, 171.6 mg tamsulosin sustained-release pills and 150 mg dutasteride solid microparticles (formulation B-2) were prepared and filled together into 0 #hard gelatin capsules. Each capsule contained 0.4 mg tamsulosin and 0.5 mg dutasteride.

Embodiment 8

(38) The formulations of the dutasteride were shown as follows:

(39) TABLE-US-00008 TABLE 8 Compositions of hard capsules in embodiment 8 Formulation B-4 Formulation B-5 Component wt % wt/capsule mg wt % wt/capsule mg Dutasteride 0.33 0.50 0.33 0.50 CAPRYOL 90 24.50 37.12 16.34 24.76 Kolliphor ® ELP 8.17 12.38 16.33 24.74 Fujicalin 66.67 101.00 66.67 101.00 BHT 0.33 0.50 0.33 0.50 Total 100.00 151.50 100.00 151.50

(40) The preparation process and detection of dissolution were the same as those in the embodiment 4.

(41) The dissolution data of the formulation B-4 was similar to that of the formulation B-1 in the embodiment 5, and the dissolution data of the formulation B-5 was similar to that of the formulation B-2 in the embodiment 5.

Comparative Embodiment 2

(42) The dutasteride solid microparticle hard capsules were prepared according to the formulas in the table below. The preparation process and detection method were the same as those in the embodiment 4. Captex® 355 are triglycerides of caprylic acid (C.sub.8) and capric acid (C.sub.10).

(43) TABLE-US-00009 TABLE 9 Component wt % wt/capsule mg Dutasteride 0.33 0.50 CAPRYOL 90 24.75 37.50 Captex ® 355 8.25 12.50 Fujicalin 66.67 101.00 Total 100.00 151.50

(44) When the hydrophobic liquid solubilizer comprised medium-chain triglycerides, the self-emulsifying property of the prepared dutasteride solid microparticles were significantly lower than that of the dutasteride solid microparticles of the present application, and the dissolution rate thereof was also significantly lower than that of the dutasteride solid microparticles of the present application.

(45) Although the specific embodiments of the present invention are described above, those skilled in the art should understand that these are merely for illustration, and that various changes or modifications may be made to these embodiments without departing from the principle and essence of the present invention. Therefore, the protection scope of the present invention is defined by the appended claims.