Instant release pharmaceutical preparation of anticoagulant and preparation method therefor

Abstract

The present invention relates to the technical field of medicine and relates to an instant release pharmaceutical preparation of an anticoagulant and a preparation method therefor. The instant release pharmaceutical preparation of an anticoagulant comprises a vicagrel compound or a pharmaceutically acceptable form thereof, the preparation is a tablet or a capsule, the vicagrel or the pharmaceutically acceptable form thereof is provided at a suitable particle size, and the D90 thereof <50 μm. With regard to the drug-containing particles obtained by the present invention, a pharmaceutical preparation formed therefrom exhibits rapid release characteristics in an in vitro dissolution test and exhibits considerable advantages in pharmacokinetics in vivo, showing a greater degree (AUC) and rate (C.sub.max) of drug absorption. Further provided by the present invention is a method for preparing an instant release pharmaceutical preparation of an anticoagulant; according to the formulation of the drug-containing particles as disclosed by the present invention, a capsule or tablet instant release preparation having excellent stability may be obtained by means of a combination of optional preparation steps.

Claims

1. An instant release pharmaceutical preparation wherein the preparation is a tablet or a capsule, and comprises the following components: a) a vicagrel compound, or a pharmaceutically acceptable salt thereof in the range 0.5%-30% wt of the tablet or capsule filling; b) one or more fillers in the range of 1%-95% wt of the tablet or capsule filling, wherein the filler is selected from microcrystalline cellulose, lactose, starch, pregelatinized starch, mannitol or sorbitol; c) one or more binders in the range of 0%-20% wt of the tablet or capsule filling, wherein the binder is selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone or ethyl cellulose; d) one or more disintegrants in the range of 0%-20% wt of the tablet or capsule filling, wherein the disintegrant is selected from low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, or crospovidone; e) one or more glidants/lubricants in the range of 0%-5% wt of the tablet or capsule filling, wherein the glidant/lubricant is selected from hydrogenated vegetable oil, silicon dioxide, magnesium stearate or sodium stearyl fumarate; and f) one or more stabilizers selected from fumaric acid, citric acid, hydrogenated castor oil, hydrogenated soybean oil, or glyceryl behenate, wherein the weight ratio of the one or more stabilizers to the tablet or capsule filling is 0.2-5:100; wherein the vicagrel compound or the pharmaceutically acceptable salt thereof is provided in form of particles, wherein 90% of said particles have a diameter (D90) of less than 50 μm.

2. The preparation according to claim 1, wherein the preparation consists of the following components: a) the vicagrel compound or a pharmaceutically acceptable salt thereof in the range of 0.5%-30% wt of the tablet or capsule filling; b) the fillers in the range of 1%-95% wt of the tablet or capsule filling; c) the binders in the range of 0%-20% wt of the tablet or capsule filling; d) the disintegrants in the range of 0%-20% wt of the tablet or capsule filling; e) the glidants/lubricants in the range of 0%-5% wt of the tablet or capsule filling; and f) the stabilizers in the range of 0.2%-5% wt of the tablet or capsule filling; wherein the sum of the percentages of all components being 100%.

3. The preparation according to claim 1, wherein the D90 is less than 30 μm.

4. The preparation according to claim 3, wherein the D90 is less than 15 μm.

5. A method for preparing the instant release pharmaceutical preparation according to claim 1, comprising the following steps: a) providing micronized active ingredient powders of vicagrel with a D90 less than 50 μm, wherein the active ingredient powder of vicagrel refers to a micronized form of vicagrel compounds or a pharmaceutically acceptable salt thereof; b) mixing the vicagrel active ingredient powders with (i) one or more fillers; (ii) one or more binders; (iii) one or more disintegrants; (iv) one or more glidants/lubricants to make drug-containing particles; and adding one or more stabilizers to the drug-containing particles and then filling and tableting to obtain vicagrel capsules or tablets, wherein a weight ratio of the stabilizers to the drug-containing particles is 0.2-5:100.

6. The preparation method according to claim 5, wherein for the tablet obtained in c), a coating step is further taken to obtain a coated vicagrel tablet, and a coating component does not contain polyethylene glycol and talc.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a dissolution curve of a vicagrel preparation at different particle sizes.

(2) FIG. 2 is a blood drug concentration curve of M9-2 in dogs after administration of a vicagrel preparation prepared with different particle sizes. A: D90=23 μm; B: D90=86 μm; C: D90=9 μm; and D: D90=49 μm.

(3) FIG. 3 is a blood drug concentration curve of M15-1 in dogs after administration of a vicagrel preparation prepared with different particle sizes. A: D90=23 μm; B: D90=86 μm; C: D90=9 μm; and D: D90=49 μm.

(4) FIG. 4 is a blood drug concentration curve of M15-2 in dogs after administration of a vicagrel preparation prepared with different particle sizes. A: D90=23 μm; B: D90=86 μm; C: D90=9 μm; and D: D90=49 μm.

DETAILED DESCRIPTION OF THE INVENTION

(5) The Detailed Description is given below. It should be understood that the present invention is not limited to these specific embodiments. Those skilled in the art can make various modifications and changes to the present invention without departing from the spirit and scope of the present invention. Such improvements are considered to be included within the scope of the claims appended to this application. Examples are a further description of the contents of the present invention to illustrate the innovation of the present invention.

Example 1 Vicagrel Capsule

(6) TABLE-US-00002 Raw material Amount mg/capsule vicagrel 20 pregaletinized starch 100 microcrystalline cellulose 79.5 glyceryl behenate 0.5 total 200

(7) Vicagrel was pulverized by a hammer mill (Frewitt) with a 0.20 mm sieve, at 6000 rpm, and a 1 kg/min feed rate, and it was determined that D90=43 μm. The pulverized vicagrel was mixed with microcrystalline cellulose and lactose in a three-dimensional mixer for 15 min, hydrogenated castor oil was added and mixed, and the resulting particles were filled in size 3 capsules.

Example 2 Vicagrel Capsule

(8) TABLE-US-00003 Raw material Amount mg/capsule vicagrel 5.5 microcrystalline cellulose 100 lactose 80 sodium carboxymethyl starch 20 hydroxypropyl methylcellulose 6.5 water q.s magnesium stearate 0.5 total 212.5

(9) The raw materials were pulverized using a QL-100 jet mill at a pressure 0.8 MPa, a working temperature of 15° C., and a pulverization time of 10 min, and it was determined that D90=9 μm. The pulverized vicagrel hydrochloride was mixed with microcrystalline cellulose, lactose, sodium carboxymethyl starch, and hydroxyl propyl methylcellulose in a three-dimensional mixer at 35 rpm for 10 min, the mixture was removed and placed in a high-shear wet granulator, stirred at 500 rpm, and granulated at a shearing rate of 1,000 rpm with added water. Particles were then sized by passing through a 16-mesh sieve, and dried in an air dry oven at 60° C., removed, and sized by passing through a 24-mesh sieve, and magnesium stearate was added and mixed. The drug-containing granules were filled in size 3 capsules to obtain vikagrel instant release capsules.

Example 3 Vicagrel Capsule

(10) TABLE-US-00004 Raw material Amount mg/capsule vicagrel 15 pregaletinized starch 49.5 lactose 140 sodium carboxymethyl starch 20 hydroxypropyl methylcellulose 5 water q.s sodium stearyl fumarate 0.5 total 230

(11) The pulverized vicagrel salt was placed with pregelatinized starch, lactose, and sodium carboxymethyl starch in a fluidized bed, fluidized mixing is started for 10 min, and 5% hydroxypropyl methylcellulose is prepared as a binder. At an air inlet temperature of 80° C., the binder was sprayed while maintaining a bed temperature at 40-50° C. The formed particles were dried for 30 min while the bed temperature was maintained at 50-60° C., and were discharged. Sodium stearyl fumarate was added and mixed for 5 min, and the particles were filled into capsules.

Example 4

(12) Vicagrel was pulverized into powders with different particle sizes, and drug-containing particles were prepared and filled in capsules. The dissolution rate was measured at 50 rpm using a pH 4.0 acetate buffer containing 0.2% SDS as a medium, according to the USPII method. The results are shown in the following table and FIG. 1.

(13) In treatments 1, 2, and 3, when the particle size of API was below 50 μm, the release rate at 30 min of >85% could be satisfied. In particular, when the particle size was <30 μm, the release rate at 15 min was >85%. In treatment 4 and treatment 5, the particle size of API was >50 μm, and the in vitro release rate was slow, and the dissolution rate at 45 min was less than 85%.

(14) TABLE-US-00005 Time Treatment 1 Treatment 2 Treatment 3 Treatment 4 Treatment 5 (min) D90 = 9 um D90 = 23 um D90 = 49 um D90 = 86 μm D90 = 103 um 15 87.36 86.98 76.36 50.9 61.51 30 94.85 94.35 88.07 62.6 75.64 45 95.88 96.28 92.57 71.6 83.67 60 96.67 98.91 95.95 77.8 88.83 90 / 100.59 97.62 94.9 93.06 120 / / 99.69 / 96.09 180 / / 100.11 / 98.92

(15) Following the method in Example 2, vicagrel capsules were prepared with the raw materials of different particle sizes, and the blood drug concentration and pharmacokinetic parameters of active metabolites were measured after administration to Beagle dogs, specifically as follows:

(16) 8 healthy beagle dogs, male, age 7-8 months, weight 8-10 kg, cross-over. The dogs were fasted for 12 h before the test and provided with food 4 h after the administration, and water was not forbidden throughout the test. The wash-out period between cycles was 7 days. The administration was done with 40 ml water. 1 ml of venous blood was taken from limb veins at the following set time points: before administration (0 h) and 10 min, 20 min, 40 min, 1.0 h, 1.5 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h, 12 h and 24 h after administration, and the samples were processed according to relevant standard operating procedures, and then cryopreserved in a refrigerator at −70° C. for test. The concentrations of a metabolite M9-2 and active metabolites M15-1 and M15-2 of vicagrel in plasma were determined using LC-MS/MS method. The main pharmacokinetic parameters of a metabolite M9-2 and active metabolites M15-1 and M15-2 of vicagrel after administration to beagle dogs were calculated using a non-compartmental approach with PhoenixWinNonlin6.4 software. The results are shown in the table below (n=8).

(17) TABLE-US-00006 Main Particle size (μm) metabolite PK parameter 9 23 49 86 active metabolite C.sub.max(ng/mL) 95.4*  .sup. 60.5 .sup..star-solid.  62.3 .sup..star-solid. 46.7 M9-2 AUC.sub.0-1(ng .Math. h/mL) 244  242 .sup..star-solid.  249 .sup..star-solid. 190 active metabolite C.sub.max(ng/mL) 195.8* 87.9 90.1 80.0 M15-1 AUC.sub.0-1(ng .Math. h/mL) 121.6* 83.9 88.6 86.7 active metabolite C.sub.max(ng/mL) 76.4* 40.1 40.3 32.3 M15-2 AUC.sub.0-1(ng .Math. h/mL) 53.6* 37.3 38.3 33.8 *indicates P < 0.05 compared with a particle size group of 23, 49, or 86 μm. .sup..star-solid. indicates P < 0.05 compared with a particle size group of 86 μm.

(18) The structural formula of M9-2 is:

(19) ##STR00001##

(20) The structural formula of M15-1 is:

(21) ##STR00002##

(22) The structural formula of M15-2 is:

(23) ##STR00003##

(24) Blood drug concentration curves of M9-2, M15-1 and M15-2 in dogs after administration of a vicagrel preparation prepared with different particle sizes are shown in FIG. 2, FIG. 3 and FIG. 4, respectively.

(25) When the particle size of the raw material is less than 50 μm, it can be seen that the AUC of the drug is significantly higher than that of the particle size group of 86 km. In particular, when the particle size of the drug is less than 15 μm, it is observed that the area under blood drug concentration-time curve of active metabolites A, B, and C, and the C.sub.max of active metabolites B and C are significantly higher than those of other groups with a particle size>15 μm. This is very beneficial for the anticoagulant drugs to exert their effects.

Example 5 Vicagrel Tablet

(26) TABLE-US-00007 Raw material Amount mg/tablet vicagrel 5 pregaletinized starch 57.5 mannitol 22.5 low-substituted 10 hydroxypropyl cellulose hydroxypropyl methylcellulose 4 water q.s sodium stearyl fumarate 1 total 200

(27) The pulverized vicagrel was subjected to stirred mixing with pregelatinized starch, mannitol, low-substituted hydroxypropyl cellulose, and hydroxypropyl methyl cellulose in a high-shear granulator for 5 min, stirred at a linear speed of 4 m/s, and sheared with a shearer at 800 rpm, and granulated with added water, the particles were deagglomerated through a 10-mesh sieve, and dried in a fluidized bed while maintaining the bed temperature below 60° C. during drying. The particles were removed, and sized through a 24-mesh sieve, and sodium stearyl fumarate was added and mixed, and tableting was performed on a 10-punch rotary tablet press (ZP-10A, Sinopharm Longli), with a 8 mm shallow concave punch.

Example 6 Vicagrel Tablet

(28) TABLE-US-00008 Raw material Amount mg/tablet vicagrel 10 pregaletinized starch 40 microcrystalline cellulose 102 croscarmellose sodium 20 polyvinylpyrrolidone 7 water q.s magnesium stearate 1 total 180

(29) The pulverized vicagrel was mixed with pregelatinized starch, microcrystalline cellulose, polyvinylpyrrolidone, and half of the amount of croscarmellose sodium and half of the amount of magnesium stearate in a V-type mixer for 10 min. The material was put into a dry granulator (LGJ-300) where granulation was operated at parameters of a feed rate of 20 Hz, roller speed of 15 rpm, extrusion force of 6 bar, screen of 20 mesh, and shearing speed of 300 rpm. The particles were mixed with the rest of the disintegration and the lubricant for 5 min to obtain drug-containing particles, which were subjected to further tableting operation.

Example 7 Vicagrel Tablet

(30) TABLE-US-00009 Raw material Amount mg/tablet vicagrel 10 pregaletinized starch 35 lactose 108 low-substituted 11 hydroxypropyl cellulose hydroxypropyl methylcellulose 4 water q.s sodium stearyl fumarate 1 glyceryl behenate 1 total 170

(31) The pulverized vicagrel was subjected to stirred mixing with pregelatinized starch, lactose, low-substituted hydroxypropyl cellulose, and hydroxypropyl methyl cellulose in a wet granulator, and granulated with added water. The particles were sized through a 16-mesh sieve and dried in an air dry oven at 55° C., removed, and ground and sized through a conical mill. Sodium stearyl fumarate was added and mixed for 3 min, and the stabilizer glyceryl behenate was added and mixed for 3 min. The particles were removed, and tableted with a 7.5 mm shallow concave punch, having a hardness>6 kgf.

Example 8 Vicagrel Tablet

(32) TABLE-US-00010 Raw material Amount mg/tablet vicagrel 10 pregaletinized starch 42 mannitol 106 low-substituted 12 hydroxypropyl cellulose hydroxypropyl methylcellulose 8 water q.s sodium stearyl fumarate 1 fumaric acid 1 total 170

(33) The pulverized vicagrel was subjected to stirred mixing with pregelatinized starch, mannitol, low-substituted hydroxypropyl cellulose, and hydroxypropyl methyl cellulose in a wet granulator, and granulated with added water. The particles were sized through a 16-mesh sieve and dried in an air dry oven at 55° C., removed, and ground and sized through a conical mill. Sodium stearyl fumarate was added and mixed for 3 min, and the stabilizer glyceryl behenate was added and mixed for 3 min. The particles were removed, and tableted with a 7.5 mm shallow concave punch, having a hardness>6 kgf.

Example 9 Coated Vicagrel Tablet

(34) The tablet core prepared in Example 8 was coated with a BG-10 type coating machine using Opadry II coating powder, with the coating powder being free of polyethylene glycol and talc. The tablet core was 600 g, the air inlet temperature was 50° C., the coating flow rate was 4 g/min, the air inlet volume was 60 m.sup.3/h, and the bed temperature was 35-45° C. Vicagrel coating tablets were obtained.

Example 10 Effect Comparison of Stabilizers

(35) Vicagrel tablets were prepared following Example 7 and Example 8, except that no stabilizers were added after drug-containing particles were obtained. The resulting tablets were sealed in HDPE bottles and placed at 60° C. for 10 days, and the related substances and the dissolution were determined.

(36) TABLE-US-00011 Maximum single impurity and total impurity after placing in 60° C. HDPE bottles for 10 days Example 7 Example 8 (without (without Impurity Example 7 stabilizer) Example 8 stabilizer) maximum single impurity 0.88 2.04 0.79 1.76 total impurity 1.09 2.78 0.97 2.21 dissolution 0 day 95.1% 94.6% 92.8% 93.1% (45 min) 10 days 94.3%   83%   93%   85%

(37) It can be seen that, when the drug-containing particles are mixed with the stabilizer and tableted, the increase in related substances is reduced, and the dissolution is not significantly reduced.

Example 11 Stability Comparison of Coated Tablets

(38) Vicagrel tablet was prepared following Example 8, and coated in accordance with the parameters in Example 9, except that the coating solution contains a common plasticizer polyethylene glycol and anti-sticking agent talc.

(39) TABLE-US-00012 Maximum single impurity and total impurity after placing in 60° C. HDPE bottles for 10 days Example 9 Example 9 (without (with Example 9 polyethylene polyethylene (with glycol glycol polyethylene Example 9 and talc in and talc in glycol in (with talc in Impurity coating powder) coating powder) coating powder) coating powder) maximum single impurity 0.88 3.04 1.89 2.69 total impurity 1.11 4.06 2.62 3.67 dissolution 0 day 94.6% 95.1% 96.9% 93.0% (45 min) 10 days 93.8% 81.4% 85.8% 87.3%

(40) It is surprisingly found that when the coating component does not contain polyethylene glycol and talc, the vicagrel tablet can still provide a good coating membrane and is easy to prepare, and its stability is significantly increased compared to coated tablets with the above ingredients added.