CN108420798B

CN108420798B - Quick-release medicinal preparation of anticoagulant and preparation method thereof

Info

Publication number: CN108420798B
Application number: CN201710081673.8A
Authority: CN
Inventors: 赵焱磊; 张建军; 刘雪芳; 高缘; 孙宏斌; 龚彦春; 刘永强
Original assignee: Jiangsu Vcare Pharmatech Co Ltd
Current assignee: Jiangsu Vcare Pharmatech Co Ltd
Priority date: 2017-02-15
Filing date: 2017-02-15
Publication date: 2021-03-02
Anticipated expiration: 2037-02-15
Also published as: CN108420798A; CN113116834B; CN113116834A

Abstract

The invention relates to a quick-release medicinal preparation of an anticoagulant and a preparation method thereof, belonging to the technical field of medicines. The immediate release pharmaceutical formulation of an anticoagulant agent comprises a vicagrel compound or a pharmaceutically acceptable form thereof, wherein the formulation is in the form of a tablet, a capsule, the vicagrel or the pharmaceutically acceptable form thereof is provided in a suitable particle size having a D90 < 50 μm. The drug-containing granules obtained by the invention form a drug preparation which shows rapid release characteristics in an in vitro dissolution test and shows considerable advantages in vivo pharmacokinetics, namely larger drug absorption degree (AUC) and speed (C)_max). The invention also provides a preparation method of the rapid-release pharmaceutical preparation of the anticoagulant, and according to the prescription of the drug-containing particles disclosed by the invention, a capsule or tablet rapid-release preparation with excellent stability can be obtained through the combination of optional preparation steps.

Description

Quick-release medicinal preparation of anticoagulant and preparation method thereof

Technical Field

The invention provides a quick-release pharmaceutical preparation, in particular to a quick-release tablet or capsule containing anticoagulant vicagrel and an acceptable salt carrier thereof, and also provides a preparation method of the quick-release pharmaceutical preparation, belonging to the technical field of medicines.

Background

Vicagrel is a novel anti-platelet aggregation drug, and can be used for overcoming the clinical application defects of the existing anti-platelet drugs, such as clopidogrel resistance, high bleeding risk of prasugrel and the like. Vicagrel has entered the clinical research stage, hopefully develop into more safe and effective antiplatelet new medicine.

Patent CN103254211B discloses a preparation method of vicagrel and its derivatives, and patent CN103720700A discloses a composition of vicagrel and aspirin, which is used for preventing or treating diseases caused by thrombus, but at present, there is no report on the prescription process of single active ingredient preparation of vicagrel. As an anticoagulant, it is required to rapidly reach an effective blood concentration in vivo to exert a therapeutic effect, and development of an oral immediate release preparation thereof is particularly necessary.

Disclosure of Invention

The invention aims to provide a quick-release preparation of vicagrel. Based on this, the invention designs an oral pharmaceutical preparation which is used for quick release and can be in the form of capsules or tablets or granules, and comprises the vicagrel or a pharmaceutically acceptable form thereof.

The technical scheme adopted by the invention is as follows:

an immediate release pharmaceutical formulation of an anticoagulant agent comprising a vicagrel compound or a pharmaceutically acceptable form thereof, wherein said formulation is in the form of a tablet, capsule, said vicagrel or a pharmaceutically acceptable salt thereof being provided in a suitable particle size having a D90 < 50 μm.

The pharmaceutically acceptable forms of vicagrel in the invention include, but are not limited to, salts, solvates and other pharmaceutically acceptable carriers of vicagrel, which have the pharmaceutical activity of vicagrel.

The quick-release preparation provided by the invention has the advantages that the raw material medicines are crushed, the particle size is preferably D90 less than 50 mu m, more preferably D90 less than 30 mu m, and most preferably D90 less than 15 mu m.

In one embodiment of the invention, the immediate release pharmaceutical formulation is in the form of drug-containing granules for filling into capsules or forming tablets, comprising:

a) vicagrel active ingredient: vicagrel or a pharmaceutically acceptable form thereof;

b) one or more fillers;

c) one or more disintegrants;

d) one or more binders;

e) one or more glidants/lubricants.

Preferably, the composition ratio thereof is as follows:

a) the vicagrel active ingredient accounts for 0.5 to 30 percent of the weight of the tablet or capsule filler;

b) the filler is present in the range of 1% to 95% by weight of the tablet or capsule fill;

c) the binder is present in the range of 0% to 20% by weight of the tablet or capsule fill;

d) the disintegrant is present in the range of 0% to 20% by weight of the tablet or capsule fill;

e) glidant/lubricants are present in the range of 0% to 5% by weight of the tablet or capsule fill;

f) the stabilizer is present in the range of 0% to 5% wt;

the percentages of all components are 100% in total.

In one embodiment, the drug-containing particles comprise vicagrel and one or more fillers. Suitable fillers include, for example, microcrystalline cellulose, lactose, pregelatinized starch/starch, a combination of one or more of mannitol or other common fillers known in the art. In other embodiments, the drug-containing particles optionally comprise one or more of the following adjuvants: (1) one or more binders; (2) one or more disintegrants; (3) one or more glidant/lubricants. Suitable binders include, for example, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, and others known in the art. Suitable disintegrants include, for example, low substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, crospovidone, and others known in the art. Suitable glidants/lubricants include, for example, silicon dioxide, magnesium stearate, sodium stearyl fumarate and others known in the art.

After the medicine-containing granules are filled into capsules or pressed into tablets, the Vicagrel exists in a form of containing 1-30 mg of Vicagrel per unit preparation, the daily dosage is 1-30 mg, and the medicine-containing granules can be administered in a single dose or multiple doses for 1-4 times a day.

The invention provides an immediate release pharmaceutical preparation, including tablet and capsule preparations, which contains an anticoagulant drug of vicagrel or vicagrel salt, solvate or other pharmaceutically acceptable carriers.

The quick release preparation of the invention can be capsules or tablets, and the quick release preparation is embodied by drug-containing granules filled into capsules or pressed into tablets.

The "drug-containing granules" described herein include, but are not limited to, granules formed by mixing the granules prepared by adding the auxiliary materials to the granules with the auxiliary materials added later by using a method such as high shear granulation, roller granulation, spray drying granulation, lamination granulation, and the like, and mixed powders formed by directly mixing the granules with the API by selecting appropriate excipients.

The immediate release formulations of the present invention may contain pharmaceutical excipients as indicated herein to aid in the formation of granules, powders for filling capsules or tableting.

The proportion of the drug-containing particles of the present invention is equal in measure to the weight percentage of the material before compression or capsule filling without the addition of a stabilizer.

In the medicine-containing particles, the vicagrel or the pharmaceutically acceptable form thereof accounts for 0.5 to 30 percent by weight of the medicine-containing particles, and preferably accounts for 1 to 20 percent.

The filler is present in the drug-containing particles in an amount of 1 to 95 wt%, more preferably 10 to 85 wt%, based on the weight of the drug-containing particles. Such fillers include, but are not limited to, microcrystalline cellulose, lactose, starch, pregelatinized starch, mannitol, sorbitol, and fillers commonly used in the art as are known. Preferably, the medicament comprises microcrystalline cellulose, lactose, pregelatinized starch and mannitol, wherein the lactose is present in the range of 10-75% of the medicament-containing particles, the mannitol is present in the range of 10-75% of the medicament-containing particles, the pregelatinized starch is present in the range of 5-65% of the filler of the medicament-containing particles, and the microcrystalline cellulose is present in the range of 10-60% of the medicament-containing particles;

the binder is present in an amount ranging from 0% to 20% by weight of the drug-containing particles, preferably from 1% to 10% by weight. Suitable binders include, but are not limited to, one or more blends of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, ethylcellulose and other conventional binders. Hydroxypropyl methylcellulose, hydroxypropyl cellulose, is preferred.

The disintegrant is present in an amount in the range of 0% to 20% by weight of the drug-containing particles, preferably in the range of 1% to 10% by weight. Suitable disintegrants include, but are not limited to, low substituted hydroxypropyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, and crospovidone. Sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose are preferred.

The glidant/lubricant is present in an amount in the range of 0% to 5% by weight of the drug-containing particles, preferably in the range of 0.2% to 2%. Suitable glidants/lubricants include hydrogenated vegetable oils, silicon dioxide, magnesium stearate, sodium stearyl fumarate, preferably stearic acid, sodium stearyl fumarate.

According to the present invention, the preferred drug-containing particle formulation is as follows:

the invention further provides a preparation method of the quick-release preparation, which comprises the following steps:

a) providing a micronized powder of the active ingredient of vicagrel with a D90 < 50 μm; the vicagrel active powder refers to a micronized form of vicagrel or a pharmaceutically acceptable form thereof;

b) mixing the Vicagrel active ingredient powder with an auxiliary agent to prepare medicine-containing particles;

c) and (3) filling, tabletting or filling the drug-containing granules to obtain the Vicagrel capsule or tablet.

The micronization of step a) of the process of the present invention is carried out using conventional art comminution techniques including, but not limited to, milling, extrusion, impact, cutting using comminution apparatus including, but not limited to, ball mills, jet mills, hammer mills. More preferably, a jet mill is used.

In step b), the preparation of the drug-containing granules can adopt a dry granulation mode, a wet granulation mode or a direct mixing mode, and specifically can be as follows:

b1) mixing the vicagrel active ingredient with one or more fillers in any desired order; in other embodiments, vicagrel or a pharmaceutically acceptable carrier thereof may be mixed with one or more fillers and optionally one or more of the following compounds in any order: one or more binders; one or more disintegrants; one or more glidant/lubricants; the mixing method employs mixing equipment conventional in the art, including but not limited to three-dimensional mixers, V-shaped mixers, stirring mixing, fluidized mixing.

b2) Optionally, the granulation is carried out by a wet or dry process. Adopting a wet granulation method, enabling the mixed material in b1) to pass through wet granulation equipment, spraying a binding agent to enable the mixed material to be agglomerated into particles, and then drying and finishing the particles; adopting a dry granulation method, adding the mixed material in b1) into a lubricant, rolling the mixture by a dry granulator to form material strips, and crushing and screening the strips to obtain particles. The wet granulation method includes conventional methods such as granulation using high shear mixing, fluidized bed granulation, non-porous pan lamination granulation, and the like. The dry granulation refers to pre-compacting materials, rolling the materials by a horizontal or vertical roller to form material strips, and crushing the material strips to form particles.

b3) Optionally, if a wet granulation method is adopted, the granules need to be dried, and the temperature of the materials in the drying process is controlled below 60 ℃; the drying process uses equipment including but not limited to a blast drying oven, fluidized bed drying.

b4) Mixing the particles obtained in the step b1) b2) or b3) with a glidant/lubricant and/or a disintegrant and a filler which need to be added externally to obtain the drug-containing granules.

In the step c) of the method, one or more stabilizers can be added into the drug-containing granules for filling, tabletting or filling; the weight ratio of the stabilizer to the medicine-containing particles is 0-5: 100, preferably 0.2 to 1:100

The stabilizer is selected from fumaric acid, citric acid, hydrogenated castor oil, hydrogenated soybean oil, glyceryl behenate, methyl silicone oil, and dimethyl silicone oil.

Further, for the tablets obtained in c), a coating step may be taken to obtain a vicagrel coated tablet, said coating component not containing polyethylene glycol and talc. The coating solution can be hydroxypropyl methylcellulose, hydroxypropyl cellulose or polyvinyl alcohol, and can be added with color lake to adjust color, such as ferric oxide, titanium dioxide, etc. For the commercially available coating formulations, the plasticizer polyethylene glycol and the anti-sticking agent talc are usually included, while the present invention does not include polyethylene glycol and talc.

The drug-containing granules obtained according to the present invention form a drug formulation showing a fast release profile in an in vitro dissolution test and a considerable advantage in vivo pharmacokinetics in terms of a greater degree of drug Absorption (AUC) and rate (C)_max)。

According to the drug-containing granule formulation and the preparation method provided by the present invention, an immediate release preparation having high in vivo bioavailability and blood concentration can be provided, and according to the drug-containing granule formulation provided by the present invention, a capsule or tablet immediate release preparation having excellent stability can be obtained by combining optional preparation steps.

Drawings

FIG. 1 is a dissolution profile of Vicagrel formulations at different particle sizes

Fig. 2 is a graph of the blood concentration of M9-2 after dogs were administered vicagramer formulations prepared at different particle sizes. A: d90 ═ 23 μm; b: d90 ═ 86 μm; c: d90 ═ 9 μm; d: d90 ═ 49 μm.

Fig. 3 is a graph of the blood concentration of M15-1 in dogs after administration of vicagramer formulations prepared at different particle sizes. A: d90 ═ 23 μm; b: d90 ═ 86 μm; c: d90 ═ 9 μm; d: d90 ═ 49 μm.

Fig. 4 is a graph of the blood concentration of M15-2 after dogs were administered vicagramer formulations prepared at different particle sizes. A: d90 ═ 23 μm; b: d90 ═ 86 μm; c: d90 ═ 9 μm; d: d90 ═ 49 μm.

Detailed Description

While specific embodiments of the present invention are given below, it is to be understood that the present invention is not limited to these specific embodiments, and that various modifications and changes can be made by those skilled in the art without departing from the spirit and scope of the present invention, but such modifications are to be considered as included within the scope of the appended claims of the present application. The examples are further illustrative of the present disclosure to illustrate the innovative teachings of the invention.

Example 1 Vicagrel capsules

Vicagrel was crushed using a hammer mill (Frewitt)0.20mm screen at 6000rpm at a discharge rate of 1kg/min and D90 was measured to be 43 μm. Mixing pulverized Vicagrel with microcrystalline cellulose and lactose in three-dimensional mixer for 15min, adding hydrogenated castor oil, mixing, and filling the obtained granule into No. 3 capsule.

Example 2 Vicagrel capsules

Raw and auxiliary materials	Dosage is mg/granule
		Vicagrel	5.5
Microcrystalline cellulose	100
		Lactose	80
Sodium carboxymethyl starch	20
		Hydroxypropyl methylcellulose	6.5
Water (W)	q.s
		Magnesium stearate	0.5
Total of	212.5

Crushing the raw materials by a QL-100 type jet mill at the working temperature of 15 ℃ under the pressure of 0.8MPa for 10min, wherein D90 is 9 mu m. Mixing the crushed Vicagrel hydrochloride, microcrystalline cellulose, lactose, sodium carboxymethyl starch and hydroxypropyl methyl cellulose in a three-dimensional mixer at 35rpm for 10min, taking out the mixture and putting the mixture into a high-shear wet granulator, stirring the mixture at 500rpm, cutting the mixture at 1000rpm, adding water for granulation, sieving the granules with a 16-mesh sieve for granulation, drying the granules in a blast drying oven at 60 ℃, taking out the granules, sieving the granules with a 24-mesh sieve, adding magnesium stearate for total mixing. And filling the drug-containing particles into a No. 3 capsule to obtain the Vicagrel quick-release capsule.

Example 3 Vicagrel capsules

Placing the pulverized Vicagrel salt, pregelatinized starch, lactose and sodium carboxymethyl starch in a fluidized bed, starting fluidization and mixing for 10min, and preparing 5% hydroxypropyl methyl cellulose as an adhesive. Spraying an adhesive at the air inlet temperature of 80 ℃ and maintaining the bed layer temperature at 40-50 ℃, maintaining the bed layer temperature at 50-60 ℃ after forming particles, drying for 30min, discharging, adding sodium stearyl fumarate, mixing for 5min, and filling into capsules.

Example 4

Pulverizing Vicagrel into powder with different particle sizes, preparing medicine-containing granules, filling the medicine-containing granules into capsules, measuring the dissolution rate according to USPII method and 50rpm by taking acetate buffer solution with pH4.0 containing 0.2% SDS as a medium, and obtaining the results shown in the following table and figure 1:

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

Vicagrel capsules were prepared according to the method of example 2 using different particle size raw materials, and the plasma concentration and pharmacokinetic parameters of active metabolites were determined after administration to Beagle dogs as follows:

8 healthy beagle dogs, male dogs, age 7-8 months and weight 8-10 kg, and adopt a cross test design. Food was fasted for 12h before the test and 4h after the administration, and water was not prohibited throughout the test. The washing period is 7 days in the week period. The administration was carried out with 40ml of water. Pre-dose (0h) and post-dose 10min, 20min, 40min, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 12 and 24 h; taking 1ml of venous blood from veins of limbs at the set time points, processing the sample according to relevant standard operating procedures, and freezing and storing in a refrigerator at-70 ℃ to be tested. The concentrations of Vicagrel metabolite M9-2, active metabolites M15-1 and M15-2 in plasma were determined by LC-MS/MS method. Results of calculation of major pharmacokinetic parameters of vicagrel metabolite M9-2, active metabolites M15-1 and M15-2 after administration to beagle dogs using the Phoenix WinNonlin 6.4 software non-atrioventricular method are given in the following table (n-8):

denotes P <0.05 compared to the particle size 23, 49, 86 μm group.

It means that P <0.05 is compared with the group with a particle size of 86 μm

M9-2 has the structural formula:

m15-1 has the structural formula:

m15-2 has the structural formula:

the blood concentration curves of M9-2, M15-1 and M15-2 after dogs are administered Vicagrel preparations with different particle sizes are respectively shown in figure 2, figure 3 and figure 4.

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 improved compared with the 86 μm particle size group, particularly, when the particle size of the drug is less than 15 μmThe area under the plasma concentration-time curve of active metabolite A, B, C, and the C of active metabolite B, C were observed_maxCompared with other groups with the grain diameter of more than 15 mu m, the grain diameter is obviously improved. This is very advantageous for the effect of the anticoagulant drug. Example 5 Vicagrel tablet

Mixing the pulverized Vicagrel with pregelatinized starch, mannitol, low-substituted hydroxypropyl cellulose and hydroxypropyl methyl cellulose in a high-shear granulator for 5min, stirring at a linear speed of 4m/s, cutting with a cutter at 800rpm, adding water for granulation, removing cluster of the granules through a 10-mesh screen, drying in a fluidized bed, and keeping the bed temperature below 60 ℃ during drying. Taking out the granules, sieving with 24 mesh sieve, adding sodium stearyl fumarate, mixing, and tabletting with 10-punch rotary tablet press (ZP-10A, LONGLI, Chinese medicine) with 8mm shallow concave punch.

Example 6 Vicagrel sheet

Mixing the crushed vicagrel, pregelatinized starch, microcrystalline cellulose, polyvinylpyrrolidone, half of croscarmellose sodium and half of magnesium stearate in a V-shaped mixer for 10min, putting the materials in a dry granulator (LGJ-300) to perform granulation by using the parameters of feeding of 20Hz, roller rotation speed of 15rpm, extrusion force of 6bar, sieve of 20 meshes and cutting rotation speed of 300rpm, mixing the granules with the rest of disintegrant and lubricant for 5min to obtain medicine-containing granules, and performing further tabletting operation on the medicine-containing granules.

Example 7 Vicagrel sheet

Mixing the crushed Vicagrel with pregelatinized starch, lactose, low-substituted hydroxypropyl cellulose and hydroxypropyl methyl cellulose in a wet granulator under stirring, adding water for granulation, granulating the granules by a 16-mesh sieve, drying at 55 ℃ in a blast drying box, taking out, grinding and granulating by a cone granulator, adding sodium stearyl fumarate, mixing for 3min, adding glyceryl behenate serving as a stabilizer, mixing for 3min, taking out, and taking out a 7.5mm shallow concave punching tablet with the hardness of more than or equal to 6 kgf.

Example 8 Vicagrel tablet

Mixing the crushed Vicagrel with pregelatinized starch, mannitol, low-substituted hydroxypropyl cellulose and hydroxypropyl methyl cellulose in a wet granulator under stirring, adding water for granulation, granulating the granules by a 16-mesh sieve, drying at 55 ℃ in a blast drying box, taking out, grinding and granulating by a cone granulator, adding sodium stearyl fumarate, mixing for 3min, adding glyceryl behenate serving as a stabilizer, mixing for 3min, taking out, and stamping into 7.5mm shallow concave tablets with the hardness of more than or equal to 6 kgf.

Example 9 Vicagrel coated tablets

The tablet cores obtained in example 8 were coated with a BG-10 type coating machine using an opadry II coating powder, wherein the coating powder does not contain polyethylene glycol and talc. The tablet core is 600g, the air inlet temperature is 50 ℃, the coating flow rate is 4g/min, and the air inlet amount is 60m³The temperature of the bed layer is 35-45 ℃. Obtaining the Vicagrel coated tablet

EXAMPLE 10 comparison of the Effect of the stabilizers

Vicagrel tablets were prepared as in examples 7 and 8 except that no stabilizer was added after the drug-containing granules were obtained. The tablets were sealed in HDPE bottles and left at 60 ℃ for 10 days to determine the substances and dissolution rates.

Therefore, the increase degree of related substances is reduced and the dissolution rate is not remarkably reduced when the medicine-containing granules and the stabilizing agent are mixed and then tabletted.

Example 11 comparison of stability of coated tablets

Vicagrel tablets were prepared according to example 8 and coated according to the parameters of example 9, except that the coating solution contained the usual plasticizer polyethylene glycol and anti-tack talc.

Surprisingly, it has been found that Vicagrel tablets provide good films and are easy to manufacture without the polyethylene glycol and talc being included in the coating ingredients, but have significantly increased stability over coated tablets incorporating such ingredients.

Claims

1. An immediate release pharmaceutical formulation of an anticoagulant agent comprising a vicagrel compound or a pharmaceutically acceptable salt form thereof, said vicagrel or pharmaceutically acceptable salt form thereof being a micronized powder of a vicagrel active ingredient provided in a suitable particle size, D90 < 50 μm; the preparation is characterized by being in the form of tablets and capsules and consisting of the following components:

e) glidants and/or lubricants are present in the range of 0% to 5% by weight of the tablet or capsule fill;

f) the weight ratio of the stabilizer to the medicine-containing particles is 0.2-1: 100 is present; the drug-containing granules are prepared by mixing Vicagrel active ingredient powder with a filler, a binder, a disintegrant, a glidant and/or a lubricant;

the total percentage of all the components is 100 percent, the filling agent is selected from microcrystalline cellulose, lactose, starch, pregelatinized starch, mannitol or sorbitol, the adhesive is selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone or ethyl cellulose, the disintegrating agent is selected from low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose or cross-linked polyvinylpyrrolidone, the glidant/lubricant is selected from hydrogenated vegetable oil, silicon dioxide, magnesium stearate or sodium stearyl fumarate, and the stabilizer is selected from fumaric acid or glyceryl behenate.

2. Formulation according to claim 1, characterized in that the particle size D90 < 30 μ ι η.

3. Formulation according to claim 2, characterized in that the particle size D90 < 15 μ ι η.

4. A method of preparing an immediate release pharmaceutical formulation of an anticoagulant agent of claim 1, comprising the steps of:

a) providing a micronized powder of the active ingredient of vicagrel with a D90 < 50 μm; the vicagrel active powder refers to a micronized form of vicagrel or a pharmaceutically acceptable salt thereof;

b) mixing the Vicagrel active ingredient powder with a filler, a binder, a disintegrant, a glidant and/or a lubricant to prepare a drug-containing granule;

c) and adding one or more stabilizing agents into the drug-containing granules, and then filling, tabletting or filling to obtain the Vicagrel capsule or tablet.

5. The preparation method according to claim 4, wherein, for the tablets obtained in c), a further coating step is performed to obtain Vicagrel coated tablets, wherein the coating component is Opadry II coating powder and polyethylene glycol and talc are not contained therein.