Metoprolol sustained-release composition and preparation method thereof

Abstract

The invention relates to a drug sustained-release composition, particularly a sustained-release composition comprising metoprolol and preparation method thereof. The invention also relates to a combination product comprising a sustained-release composition comprising metoprolol and a pharmaceutical composition comprising hydrochlorothiazide. The sustained-release composition comprising metoprolol according to the invention eliminates the phenomena of delayed release of such sustained-release compositions in the prior art, has a better drug release curve, and also have the advantages such as simple formula, easy operation, stable quality, strong controllability, and good reproducibility, and therefore have good application prospects.

Claims

1. A sustained-release composition consisting of a blank pellet core, an active constituent layer, and a sustained-release coating layer, characterized in that said active constituent layer consists of the active constituent and said sustained-release coating layer consists of the active constituent, a sustained release material, and optionally a pore-forming agent that is not the active constituent wherein said active constituent is selected from a free base of metoprolol, an optical isomer of metoprolol and a pharmaceutically acceptable salt of metoprolol, wherein the active constituent alone acts as a pore-forming agent, or the active constituent and the additional pore-forming substance co-act as a pore-forming agent, and, wherein the sustained-release material and the pore-forming agent in the sustained-release coating layer is in a weight ratio of from 1:0.1 to 1:0.4, and the active constituent and the additional pore-forming substance in the sustained-release coating layer, if present, is in a weight ratio of from 1:3 to 3:1.

2. The sustained-release composition according to claim 1, wherein said pharmaceutically acceptable salt of metoprolol is selected from the group consisting of metoprolol succinate, tartrate, fumarate, sorbate, laurate, and hydrochloride.

3. The sustained-release composition according to claim 1, wherein the sustained-release material is selected from the group consisting of a cellulose compound, Eudragit NE 30D, Eudragit RS 30D, Eudragit RL30D and a mixture thereof.

4. The sustained-release composition according to claim 1, wherein the sustained-release coating causes a weight gain of 20%60% of the sustained-release composition.

5. The sustained-release composition according to claim 1, wherein the active constituent in the active constituent layer accounts for 40%-70% of the total weight of the sustained-release composition.

6. The sustained-release composition according to claim 1, wherein said blank pellet core is a sucrose pellet core.

7. The sustained-release composition according to claim 1, wherein said blank pellet core has a particle size of 200 m900 m.

8. A method for preparing the sustained-release composition according to claim 1, comprising the following steps: 1) dissolving the active constituent in a suitable amount of a solvent to obtain a drug solution, and coating a blank pellet core with the drug solution to obtain a drug loaded pellet, and 2) dissolving a sustained-release coating material, the active constituent and optionally an additional pore-forming substance, as well as an adjuvant of the sustained-release coating layer adjuvant in a solvent to obtain a solution, and coating the drug loaded pellet obtained in the step 1) with the solution.

9. The method according to claim 8, wherein the solvent is selected from the group consisting of water, ethanol, propanol, propylene glycol, chloroform and a mixture thereof.

10. A pharmaceutical composition, comprising said sustained-release composition according to claim 1, and optionally a pharmaceutically acceptable carrier or excipient.

11. A combination product, comprising said sustained-release composition according to claim 1 and a pharmaceutical composition comprising hydrochlorothiazide.

12. The combination product according to claim 11, wherein said sustained-release composition and said pharmaceutical composition comprising hydrochlorothiazide can be capsulated into a capsule, or tableted into a tablet.

13. A method for treating a disease selected from hypertension, angina, myocardial infarction, hypertrophic cardiomyopathy, aortic dissection, arrhythmia, hyperthyreosis, or cardiac neurosis, comprising administering to a subject in need thereof a prophylactically or therapeutically effective amount of the sustained composition according to claim 1.

14. The sustained-release composition according to claim 1, wherein the additional pore-forming substance is hydroxypropyl cellulose.

15. A method for treating a disease selected from hypertension, angina, myocardial infarction, hypertrophic cardiomyopathy, aortic dissection, arrhythmia, hyperthyreosis, or cardiac neurosis, comprising administering to a subject in need thereof a prophylactically or therapeutically effective amount of the sustained composition according to claim 11.

16. The combination product according to claim 12, wherein said tablet is a conventional tablet, double-layer tablet, chewable tablet or orally disintegrating tablet.

17. The method according to claim 9, wherein said mixture is a mixture of water and ethanol.

Description

DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 illustrates the structure of the sustained-release pellet according to the invention;

(2) FIG. 2 illustrates the experiment on reproducibility of release curves of sustained-release pellets comprising metoprolol succinate in different batches in Example 6;

(3) FIG. 3 illustrates the comparison of release rate between the sustained-release pellet (in which the sustained-release film comprises the active constituent metoprolol succinate) prepared in Example 6 and the sustained-release pellet (in which sustained-release film comprises no active constituent metoprolol succinate) prepared in Comparative example 1;

(4) FIG. 4 illustrates the comparison of in vivo absorption dynamics between the sustained-release pellet (in which the sustained-release film comprises active constituent metoprolol succinate) prepared in Example 6 and the sustained-release pellet (in which the sustained-release film comprises no active constituent metoprolol succinate) prepared in Comparative example 1.

SPECIFIC MODES FOR CARRYING OUT THE INVENTION

(5) The embodiments of the invention are described in detail by reference to the following examples. However, it is understood by those skilled in the art that the following examples are used only for the purpose of illustrating the invention, rather than limiting the protection scope of the invention. When the conditions are not indicated in the Examples, the Examples are carried out under the conventional conditions or the conditions recommended by the manufacturers. The reagents or instruments used in the present invention, the manufacturers of which are not indicated, are the commercially available conventional products.

(6) Unless otherwise specified, the parameters in the following embodiments are calculated as follows.
Drug-loading percentage of pellet (%)=(W.sub.total weight of pelletW.sub.weight of blank pellet core)/W.sub.weight of raw material drug100%;
Weight gain caused by sustained-release coating (%)=(W.sub.total weight of pellet after sustained-release coatingW.sub.total weight of pellet before sustained-release coating)/W.sub.total weight of pellet after sustained-release coating100%;
Adhesion rate of pellet=(W.sub.total weight of pellet after sustained-release coatingW.sub.total weight of not adhered pellet)/W.sub.total weight of pellet after sustained-release coating100%.

(7) In the Examples of sustained-release pellets according to the invention, unless otherwise specified, the following methods are used in measurement. According to the first method (for use in sustained-release preparations or controlled-release preparations) of determination methods for release rate (Append. X D) in Chinese Pharmacopoeia (2010) Part II Appendix, the device of the second method (stirring paddle method) of determination methods for dissolution rate (Append. X C) in Chinese Pharmacopoeia (2010) Part II Appendix is used, water is used as dissolution medium, e.g., 500 ml water is used as dissolution medium of metoprolol succinate, or 1000 ml water is used as dissolution medium of hydrochlorothiazide, the temperature was set at 37 C., the rotation speed was set at 100 r/min, samples are taken at specified different time points (meanwhile an equal amount of medium is supplemented), and filtrated to obtain filtrates, and the filtrates are taken as test solutions and analyzed.

(8) The drug content of a sustained-release pellet comprising metoprolol is analyzed spectrophotometrically at 274 nm (Chinese Pharmacopoeia (2010) Part II Appendix IV A). Metoprolol succinate reference substance (purchased from market, USP standard reference substance) is measured by the same method, and cumulative released percentages of drug at different time points are calculated.

(9) The drug content of a pharmaceutical composition granule comprising hydrochlorothiazide is analyzed spectrophotometrically at 274 nm (Chinese Pharmacopoeia (2010) Part II Appendix IV A). Hydrochlorothiazide reference substance is measured by the same method, and cumulative released percentages of drug at different time points are calculated.

Example 1

(10) 800 g metoprolol succinate as raw material was weighed, and 1350 ml water was added to obtain a mixure. The resultant mixture was stirred and dissolved under heating, to obtain a drug-containing coating solution.

(11) 200 g sucrose pellet cores, 200 g starch pellet cores and 200 g microcrystalline cellulose pellet cores with a particle size of 200 m350 m were weighed, and were placed in a bottom-spray coating pan of fluidized bed to perform coating, respectively, wherein the temperature of air intake temperature was set at 70 C. to keep the temperature in the pan at 502 C., the pressure of air intake was set at 0.35 bar, the pressure of atomization was set at 1.5 bar, and the rate of liquid-spraying was set at 515 g/min (the rate of liquid-spraying could be adjusted depending on fluidized state). When the blank pellet cores were at a fluidized state, the drug-containing coating solution was bottom-sprayed onto the surface of blank pellet cores to perform drug loading. After drug loading was finished, the fluidized state was further kept at 70 C. for 5 min, to obtain metoprolol succinate loaded pellets with different particle sizes. The metoprolol succinate loaded pellets were passed through an 80 mesh screen and a 40 mesh screen, respectively, to discard fine power and adhered pellets, then weighed. The total weight of the drug-loading pellets, i.e., W.sub.total weight of pellet, was recorded, and the drug-loading percentage and adhesion rate of the drug loaded pellets were calculated. The results were shown in Table 1.

(12) TABLE-US-00001 TABLE 1 Results on coating and drug-loading of different blank pellet cores Investigation indexes Drug-loading Drug-loading Adhesion percentage of time rate Formula pellet (%) (min) (%) Formula 1 84.8 263 8.9 (sucrose pellet core) Formula 2 (starch pellet core) 95.7 205 3.1 Formula 3 (microcrystalline 95.8 190 2.8 cellulose pellet core)

Example 2

(13) Formula

(14) Formula of drug loaded pellet (drug sustained-release part) was as following:

(15) metoprolol succinate (g): 800;

(16) sucrose pellet core (200350 m) (g): 200.

(17) Formula of sustained-release coating layer (rapid-release part) was as following:

(18) TABLE-US-00002 Formula Ethyl cellulose (10 cps) Metoprolol succinate (No.) (g) (g) Formula 4 200 60 Formula 5 200 40 Formula 6 200 20

(19) Preparation method was as follows.

(20) (1) 800 g metoprolol succinate as raw material (synthesized by the processes described in the paper, Jiangxi Chemical Industry, 2003(1): 4-6) was weighed, and 1350 ml water was added to obtain a mixture. The resultant mixture was stirred and dissolved under heating at 60 C.70 C., and passed through a 200 mesh screen, to obtain a drug-containing coating solution.

(21) 200 g sucrose pellet cores with a particle size of 200 m350 m were weighed, and placed in a bottom-spray coating pan of fluidized bed to perform coating, wherein the temperature of air intake temperature was set at 70 C. to keep the temperature in the pan at 502 C., the pressure of air intake was set at 0.35 bar, the pressure of atomization was set at 1.5 bar, and the rate of liquid-spraying was set at 515 g/min (the rate of liquid-spraying could be adjusted depending on fluidized state). When the sucrose pellet cores were at a fluidized state, the drug-containing coating solution was bottom-sprayed onto the surface of sucrose pellet cores to perform drug loading. After drug loading was finished, the fluidized state was further kept at 70 C. for 5 min, and the resultant pellets were passed through an 80 mesh screen and a 40 mesh screen, respectively, to discard fine power and adhered pellets. Metoprolol succinate loaded pellets were obtained.

(22) (2) Ethyl cellulose (EC) at an amount as described in the above formula was weighed, and dissolved by adding a suitable amount of 95% ethanol, and metoprolol succinate at an amount as described in the above formula was then added and dissolved to obtain a sustained-release coating solution.

(23) (3) 500 g of each of the above obtained metoprolol succinate loaded pellets was weighed, and placed in a bottom-spray coating pan of fluidized bed to perform coating, respectively, wherein the temperature of air intake was set at 4045 C. to keep the temperature in the pan at 3035 C., the pressure of air intake was set at 0.35 bar, the pressure of atomization was set at 1.5 bar, and the rate of liquid-spraying was set at 312 g/min. When the drug loaded pellets were at a fluidized state, the above obtained three kinds of sustained-release coating solutions according to Formula 4, Formula 5 or Formula 6 were bottom-sprayed onto the surface of drug loaded pellets, respectively, to obtain sustained-release pellets containing metoprolol succinate, wherein the weight gains thereof cause by the sustained-release coatings were 33.1%, 31.6%, and 30.8%, which were corresponding to Formula 7, 8, and 9 in Table 2, respectively.

(24) The drug cumulative released percentages of the obtained sustained-release pellets containing metoprolol succinate were measured and shown in Table 2.

(25) TABLE-US-00003 TABLE 2 The results on cumulative released percentage of the sustained-release pellets containing ethyl cellulose (EC) and metoprolol succinate at different ratios Cumulative released percentage (%) Formula 1 h 4 h 8 h 12 h 16 h 20 h Formula 7 17.1 44.5 72.5 92.4 99.1 100.4 Formula 8 13.5 38.2 65.4 85.1 95.5 100.2 Formula 9 11.8 35.6 60.9 81.1 90.7 98.2

Example 3

(26) 500 g metoprolol succinate loaded pellets prepared by the method of Example 2 were subjected to sustained-release coating. The coating process was the same as the one in Example 2. As calculated based on the consumed volume of the coating solution, the sustained-release pellets having different weight gains caused by sustained-release coating (when the coating solution was consumed completely, the weight gain caused by coating was 40%) were obtained. Their drug cumulative released percentages were shown in Table 3.

(27) Formula of sustained-release coating layer was as following:

(28) ethyl cellulose (10 cps)(g): 200;

(29) metoprolol succinate (g): 45.

(30) TABLE-US-00004 TABLE 3 Evaluation results on cumulative released percentages of the sustained-release pellets having different coating weight gains cumulative released Weight gain caused by percentage (%) Formula sustained-release coating (%) 1 h 4 h 8 h 20 h Formula 10 20 25.4 52.6 85.7 99.9 Formula 11 25 21.2 46.9 75.1 99.3 Formula 12 35 16.1 40.7 63.5 98.7 Formula 13 40 14.2 33.9 56.4 95.6

Example 4

(31) 500 g metoprolol succinate loaded pellets prepared by the method of Example 2 were subjected to sustained-release coating. The coating process was the same as the one in Example 2. The formula of the sustained-release coating was as followed. As calculated based on the consumed volume of the coating solution, the sustained-release pellets having different weight gains caused by sustained-release coating were obtained. Their drug cumulative released percentages were shown in Table 4.

(32) Formula of sustained-release coating layer was as following:

(33) ethyl cellulose (10 cps)(g): 200;

(34) metoprolol succinate (g): 25;

(35) hydroxypropyl cellulose (Klucel LF) (g): 20.

(36) TABLE-US-00005 TABLE 4 Evaluation results on cumulative released percentages of the sustained-release pellets having different coating weight gains Cumulative released Weight gain caused by percentage (%) Formula sustained-release coating (%) 1 h 4 h 8 h 20 h Formula 14 20 20.7 45.9 74.3 96.6 Formula 15 25 16.1 40.5 62.2 95.9 Formula 16 35 12.2 31.3 52.4 91.4 Formula 17 40 10.1 27.6 50.4 87.5

Example 5

(37) Experiment on Reproducibility of Method for Preparing Metoprolol Succinate Loaded Pellet

(38) 800 g metoprolol succinate as raw material was weighed, and 1350 ml water was added to obtain a mixture. The resultant mixture was stirred and dissolved under heating at 60 C.70 C., and passed through a 200 mesh screen, to obtain a drug-containing coating solution.

(39) 200 g sucrose pellet cores with a particle size of 200 m350 m were weighed, and placed in a bottom-spray coating pan of fluidized bed to perform coating, wherein the temperature of air intake was set at 70 C. to keep the temperature in the pan at 502 C.), the pressure of air intake was set at 0.35 bar, the pressure of atomization was set at 1.5 bar, and the rate of liquid-spraying was set at 515 g/min (the rate of liquid-spraying could be adjusted depending on fluidized state). When the sucrose pellet cores were at a fluidized state, the drug-containing coating solution was bottom-sprayed onto the surface of sucrose pellet cores to perform drug loading. After drug loading was finished, the fluidized state was further kept at 70 C. for 5 min, and the resultant pellets were passed through an 80 mesh screen and a 40 mesh screen, respectively, to discard fine powder and adhered pellets. The metoprolol succinate loaded pellets were obtained and weighed. The total weight of pellets after drug loading, i.e., W.sub.total weight of pellets, was recorded, and the drug-loading percentage and yield of pellets were calculated, as shown in Table 5.

(40) TABLE-US-00006 TABLE 5 Results on reproducibility of method for preparing metoprolol succinate loaded pellets Amount of Amount of drug Drug-loading Sample Preparation scale Amount of main sucrose pellet loaded pellets percentage Yield batch (preparation unit/batch) drug (g/batch) core (g/batch) (g/batch) (%) (%) 1 16800 800 200 964 95.5 96.4 2 16800 800 200 962 95.2 96.2 3 16800 800 200 963 95.3 96.3 Note: the metoprolol succinate dose per unit of preparation is 47.5 mg; the yield is the amount of drug loaded pellets divided by the total amount of raw materials.

Example 6

(41) Experiment on Reproducibility of Method for Preparing Sustained-Release Pellet Comprising Metoprolol Succinate

(42) 200 g ethyl cellulose (10 cps) was weighed, and a suitable amount of 95% ethanol was added to obtain a mixture. The resultant mixture was stirred and dissolved under heating at 40 C.-50 C. About 50 g metoprolol succinate was added, and the resultant mixture was stirred and dissolved under heating at 40 C.-50 C. 95% ethanol was added to a final volume of 2152 ml, to obtain a sustained-release coating solution.

(43) 500 g metoprolol succinate loaded pellets prepared in Example 5 were placed in a bottom-spray coating pan of fluidized bed to perform coating, wherein the temperature of air intake was set at 4045 C. to keep the temperature in the pan at 3035 C.) the pressure of air intake was set at 0.35 bar, the pressure of atomization was set at 1.5 bar, and the rate of liquid-spraying was set at 312 g/min. When the drug loaded pellets were at a fluidized state, the sustained-release coating solution was bottom-sprayed onto the surface of metoprolol succinate loaded pellets, to obtain three batches of sustained-release pellets comprising metoprolol succinate, which had the weight gain caused by sustained-release coating of 32.1%, 31.8%, and 32.0%, respectively. The results were shown in Table 6. The release curves were shown in FIG. 2.

(44) TABLE-US-00007 TABLE 6 Experimental results on reproducibility of method for preparing sustained-release coating pellets comprising metoprolol succinate Sustained-release Amount of pellet Amount of drug Amount of succinate comprising Cumulative released Sample loaded pellets ethyl cellulose metoprolol metoprolol Yield percentage (%) batch (g/batch) (g/batch) (g/batch) (g/batch) (%) 1 h 4 h 8 h 20 h 1 500 200 46 736 98.7 12.4 39.2 68.5 99.4 2 500 200 46 733 98.3 13.1 41.6 69.5 99.8 3 500 200 46 735 98.5 12.9 39.1 68.8 99.4

Example 7

(45) Experiment on Release Difference of Unit Preparations

(46) Sustained-release pellets comprising metoprolol succinate prepared in Example 6 were filled into vacant gelatin capsules, to obtain sustained-release capsules comprising metoprolol succinate.

(47) Sustained-release pellets comprising metoprolol succinate of Formula 13 in Example 3, were homogeneously mixed with an equal amount of microcrystalline cellulose (PH102 type), and 0.3% sodium fumaryl stearate as lubricant was then added, then mixed well. The resultant mixture was pressed into tablets with a hardness of 10 kg-15 kg, to obtain sustained-release tablets comprising metoprolol succinate.

(48) 18 sustained-release capsules comprising metoprolol succinate and 18 sustained-release tablets comprising metoprolol succinate as prepared above were determined for their drug cumulative released percentages, and their relative standard deviation (RSD) was calculated. The results were shown in Table 7.

(49) TABLE-US-00008 TABLE 7 Evaluation results on cumulative released percentages of sustained-release capsule comprising metoprolol succinate and sustained-release tablet comprising metoprolol succinate Sustained-release capsule Sustained-release tablet comprising metoprolol comprising metoprolol succinate succinate Cumulative Cumulative Sampling time released RSD released RSD (h) percentage (%) (%) percentage (%) (%) 1 11.6 4.7 12.3 18.6 4 38.7 3.2 40.5 9.4 8 62.7 1.1 65.4 6.8 12 85.7 1.5 86.9 4.6 16 93.7 0.8 94.1 4.2 20 99.8 1.2 100.7 4.9

Example 8

(50) Formula 18

(51) Formula of drug loaded pellets (sustained-release part) was as following:

(52) metoprolol succinate (g): 770;

(53) microcrystalline cellulose (g): 200;

(54) hypromellose (g): 1.

(55) Formula of sustained-release coating layer (immediate-release part) was as following:

(56) ethyl cellulose (10 cps)(g): 200;

(57) metoprolol succinate (g): 30.

(58) Preparation Method:

(59) (1) 770 g metoprolol succinate passed through an 80 mesh screen was weighed, and homogeneously mixed with 180 g microcrystalline cellulose, then prepared into a suitable soft material with about 33 mL of 3% (W/V) hypromellose (HPMC) aqueous solution used as adhesive. The soft material was placed in a machine of extruding and round as ball to prepare pellets, wherein the speed of extruding was set at 30 rpm, the speed of round was set at 350 rpm, and the time for round as ball was 5 min. The prepared pellets were dried in an oven at 40 C. for 4 h, and screened to obtain the target pellets having a particle size of 400550 m, i.e., metoprolol succinate loaded pellets.

(60) (2) Ethyl cellulose (EC) at an amount as described in the above formula was weighed, and dissolved by adding a suitable amount of 95% ethanol, then metoprolol succinate at an amount as described in the above formula was added and dissolved to obtain a sustained-release coating solution.

(61) 500 g above prepared metoprolol succinate loaded pellets were placed in a bottom-spray coating pan of fluidized bed to perform coating, wherein the temperature of air intake was set 4045 C. to keep the temperature in the pan at 3035 C., the pressure of air intake was set at 0.35 bar, the pressure of atomization was set at 1.5 bar, and the rate of liquid-spraying was set at 312 g/min. When the drug loaded pellets were at a fluidized state, above prepared sustained-release coating solution was bottom-sprayed onto the surface of metoprolol succinate loaded pellets, to obtain sustained-release pellets comprising metoprolol succinate.

(62) The determined results on drug cumulative released percentage of the prepared sustained-release pellets comprising metoprolol succinate were shown in Table 8.

(63) TABLE-US-00009 TABLE 8 Evaluation results on cumulative released percentage of sustained-release pellets comprising metoprolol succinate Sampling time Cumulative released percentage (%) 1 h 11.2 4 h 31.8 8 h 56.5 12 h 78.4 16 h 95.5 20 h 99.7

Example 9

(64) Pharmaceutical Composition Granules Comprising Hydrochlorothiazide Prepared by Melt Method

(65) Formula 19 was as following:

(66) hydrochlorothiazide (g): 250;

(67) microcrystalline cellulose (g): 375 g;

(68) polyethylene glycol 6000 (g): 375 g.

(69) Preparation Method:

(70) hydrochlorothiazide was homogenously mixed with microcrystalline cellulose at an amount as described in the above formula to obtain a mixture. polyethylene glycol 6000 at an amount as described in the above formula was melted at 70 C., the mixture of hydrochlorothiazide and microcrystalline cellulose was added, then stirred homogeneously and immediately passed through a 20 mesh screen, to get the final product.

Example 10

(71) Pharmaceutical Composition Granules Comprising Hydrochlorothiazide Prepared by Hot-Melt Extrusion Method

(72) Formula 20 was as following:

(73) hydrochlorothiazide (g): 150;

(74) PVP-VA 64 (g): 350.

(75) Preparation Method:

(76) a hot-melt extruder was set at 180 C. for each region, at a speed of 25 rpm, and balanced for 30 min. Hydrochlorothiazide at an amount as described in the above formula was homogenously mixed with PVP-VA64 at an amount as described in the above formula, and placed in a loading hopper of the hot-melt extruder, then extruded into a shape of bar from the die hole after 1 min, caught in a stainless steel disc, left at room temperature for 4 h, and then crushed and passed through a 30 mesh screen, to obtain the final product.

Example 11

(77) Comparison of Dissolution Rate of Pharmaceutical Compositions Comprising Hydrochlorothiazide

(78) A suitable amount of pharmaceutical compositions comprising hydrochlorothiazide of Formula 19 and Formula 20 (corresponding to 10 mg hydrochlorothiazide) was weighed, respectively. According to the second method (stirring paddle method) for dissolution test (Append. C) in Chinese Pharmacopoeia (2010) Part II Appendix, 1000 ml water was used as dissolution medium, and dissolution rates were determined at different time points at 37 C., and under a speed of 50 r/min. 5 mL samples were taken at 5 min, 15 min, 30 min, 45 min and 60 min (meanwhile an equal amount of medium was supplemented), and filtrated to obtain a filtrate, and the filtrates are taken as test samples. Ultraviolet spectrophotometry (Chinese Pharmacopoeia (2010) Part II Appendix A) was used to determine absorbance at a wavelength of 272 nm. Hydrochlorothiazide reference substance was measured by the same method, and cumulative released percentages of the main drug hydrochlorothiazide at different time points were calculated by external standard method. The dissolution rates of pharmaceutical compositions comprising hydrochlorothiazide of Formula 19 and Formula 20 were shown in Table 9.

(79) TABLE-US-00010 TABLE 9 Cumulative released percentage of pharmaceutical compositions comprising hydrochlorothiazide of different formulas Cumulative released percentage (%) Formula No. 5 min 15 min 30 min 45 min 60 min Formula 19 5.5 8.9 13.7 45.6 56.7 Formula 20 15.6 30.4 56.3 62.5 75.7

Example 12

(80) Preparation of Metoprolol Succinate Sustained-Release/Hydrochlorothiazide Capsules

(81) The sustained-release pellets comprising metoprolol succinate prepared in Example 6, and pharmaceutical composition comprising hydrochlorothiazide prepared in Example 9, as calculated on basis of their contents, were mixed at a certain weight ratio, and filled into capsules, wherein each capsule contained 47.5 mg metoprolol succinate and 12.5 mg hydrochlorothiazide.

Example 13

(82) Preparation of Metoprolol Succinate Sustained-Release/Hydrochlorothiazide Capsules

(83) The sustained-release pellets comprising metoprolol succinate prepared in Example 8, and the pharmaceutical composition comprising hydrochlorothiazide prepared in Example 10, as calculated on basis of their contents, were mixed at a certain weight ratio, and filled into capsules, wherein each capsule contained 47.5 mg metoprolol succinate and 12.5 mg hydrochlorothiazide.

Comparative Example 1

(84) Formula 21:

(85) Formula of metoprolol succinate loaded pellet was as following:

(86) metoprolol succinate (g): 800;

(87) blank sucrose pellet core (200350 m) (g): 200.

(88) Formula of sustained-release layer was as following:

(89) ethyl cellulose (10 cps) (g): 200;

(90) hydroxypropyl cellulose (Klucel LF) (HPC) (g): 30.

(91) Preparation Method:

(92) (1) 800 g metoprolol succinate as raw material was weighed, and 1350 ml water was added to obtain a mixture. The resultant mixture was stirred and dissolved under heating at 60 C.-70 C., and passed through a 200 mesh screen, to obtain a drug-containing coating solution.

(93) 200 g sucrose pellet cores with a particle size of 200 m350 m were weighed, and placed in a bottom-spray coating pan of fluidized bed to perform coating, wherein the temperature of air intake was set at 70 C. to keep the temperature in the pan at 502 C., the pressure of air intake was set at 0.35 bar, the pressure of atomization was set at 1.5 bar, and the rate of liquid-spraying was set at 515 g/min (the rate of liquid-spraying could be adjusted depending on fluidized state). When the sucrose pellet cores were at a fluidized state, the drug-containing coating solution was bottom-sprayed onto the surface of sucrose pellet cores to perform drug loading. After drug loading was finished, the fluidized state was further kept at 70 C. for 5 min, and passed through an 80 mesh screen and a 40 mesh screen, respectively, to discard fine powder and adhered pellets, and metoprolol succinate loaded pellets were obtained.

(94) (2) Ethyl cellulose (EC) at an amount as described in the above formula was weighed, and dissolved by a suitable amount of 95% ethanol, and then hydroxypropyl cellulose (HPC) at an amount as described in the above formula was added and dissolved to obtain a sustained-release coating solution.

(95) (3) 500 g above prepared metoprolol succinate loaded pellets were weighed, and placed in a bottom-spray coating pan of fluidized bed to perform coating, wherein the temperature of air intake was set at 4045 C. to keep the temperature in the pan at 3035 C., the pressure of air intake pressure was set at 0.35 bar the pressure of atomization pressure was set at 1.5 bar and the rate of liquid-spraying was set at 312 g/min. When the drug loaded pellets were at a fluidized state, above prepared sustained-release coating solution was bottom-sprayed onto the surface of drug loaded pellets, to obtain sustained-release pellets comprising metoprolol succinate.

Experimental Example 1

(96) The sustained-release pellets prepared in Example 6, and the sustained-release pellets prepared in Comparative example 1 were taken. In accordance with the first method (for use in sustained-release preparations or controlled-release preparations) of determination methods for release rate (Append. D) in Chinese Pharmacopoeia (2010) Part II Appendix, the device of the second method (stirring paddle method) of determination methods for dissolution test (Append. C) in Chinese Pharmacopoeia (2010) Part II Appendix was used, 500 ml water was used as dissolution medium, the temperature was set at 37 C., the rotation speed was set at 100 r/min, and samples were taken at different time points (meanwhile an equal amount of medium was supplemented), and filtrated to obtain filtrates. The filtrates were taken as test samples. Ultraviolet spectrophotometry (Chinese Pharmacopoeia (2010) Part II Appendix A) was used to determine absorbance at a wavelength of 274 nm. Metoprolol succinate reference substance was measured by the same method, and cumulative released percentages of the drug at different time points were calculated. The results were shown in Table 10 and FIG. 3.

(97) TABLE-US-00011 TABLE 10 Evaluation results on cumulative released percentage of sustained-release pellets comprising metoprolol succinate Cumulative released percentage (%) Time (h) Formula of Comparative example 1 Formula of Example 6 1 0.70 4.50 2 3.32 12.82 4 19.20 33.61 6 36.06 51.21 8 51.23 65.91 10 65.25 74.93 12 75.62 80.12 16 87.09 86.95 20 91.41 89.79 24 92.56 91.68

(98) The results showed that the sustained-release pellets prepared by the present technical solution (Example 6) had the release rate increased significantly within 2 h compared to the pellets prepared by the traditional method (Comparative example 1), and eliminated the lagging phase brought about by the traditional preparation process.

Experimental Example 2

(99) Pharmacokinetic Study on Sustained-Release Pellets Comprising Metoprolol Succinate in Beagle Dogs

(100) Six beagle dogs were used in double periodic, randomized cross-over study design, and were orally administered once with an equal dose of experimental preparation (the sustained-release pellets comprising metoprolol succinate prepared in Example 6) and reference preparation (the sustained-release pellets comprising metoprolol succinate prepared in Comparative example 1), respectively. HPLC analytic method was used to determine the concentration of metoprolol succinate in blood plasma after administration. Data 9 processing was carried out by DAS2.0 program.

(101) Result

(102) After single oral administration of an equal dose of the experimental preparation and the reference preparation of sustained-release pellets comprising metoprolol succinate (95 mg), the time to peak (T.sub.max) was 0.920.58 h and 1.421.07 h, respectively; the peak concentration (C.sub.max) was 79.8719.98 ng.Math.ml.sup.1 and 78.7815.70 ng.Math.ml.sup.1, respectively; the plasma clearance half-life (T.sub.1/2) was 5.605.82 h and 6.394.61 h, respectively; and AUC.sub.0-t was 563.34203.46 ng.Math.h.Math.ml.sup.1 and 518.32111.19 ng.Math.h.Math.ml.sup.1, respectively. The drug concentration-time curve was shown in FIG. 4.

(103) Conclusion

(104) Compared with the reference preparation, single oral administration of an equal dose of the experimental preparation of sustained-release pellet comprising metoprolol succinate has following characteristics: (1) the bioavailability thereof was 108.52%25.34%, and (2) the time to peak thereof was about 30 min in advance.

(105) It can be seen by comparison that the sustained-release pellets prepared by the present invention solves the problem concerning the phenomena of delayed release of the traditional pellets coated by ethyl cellulose and hydroxypropyl cellulose in vivo and in vitro. The method is simple in process and has good reproducibility, and its production parameter can be controlled easily, and therefore, the method is favorable for industrial production.

(106) Although the embodiments of the invention are described in detail, a person skilled in the art would understand that according to all the already disclosed teachings, these details can be modified and replaced, and these alterations all fall in the protection scope of the invention. The scope of the invention is defined by the claims and any equivalent thereof.