CN111714458A

CN111714458A - Sustained-release particles of prasugrel hydrochloride, preparation containing same and preparation method thereof

Info

Publication number: CN111714458A
Application number: CN201910203338.XA
Authority: CN
Inventors: 刘学军; 董文敏; 牛国琴
Original assignee: Shanghai Fosun Xingtai Pharma Technology Co ltd
Current assignee: Shanghai Fosun Xingtai Pharma Technology Co ltd
Priority date: 2019-03-18
Filing date: 2019-03-18
Publication date: 2020-09-29

Abstract

The invention discloses a sustained-release granule containing prasugrel hydrochloride, which comprises 2-15% of prasugrel hydrochloride, 0.1-1% of fat-soluble antioxidant, 25-80% of diluent, 20-40% of waxy framework material, 2-20% of pore-forming agent and 0.5-1% of lubricant, wherein the% is weight percentage, and the preparation method of the sustained-release granule containing prasugrel hydrochloride is as follows. The invention also discloses an oral enteric sustained-release preparation containing the sustained-release granules, a preparation method thereof and application of the sustained-release granules containing prasugrel hydrochloride. The sustained-release particles reduce the degradation risk of the raw material medicines, effectively slow down the medicine release speed, and reduce the stimulation of the medicines to gastric mucosa and the adverse reactions of the digestive tract such as hemorrhage, abdominal pain and the like caused by the stimulation of the medicines to the gastric mucosa.

Description

Sustained-release particles of prasugrel hydrochloride, preparation containing same and preparation method thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a sustained-release granule of prasugrel hydrochloride, a preparation containing the sustained-release granule and a preparation method of the sustained-release granule.

Background

Acute Coronary Syndrome (ACS) refers to the clinical type of coronary heart disease, including ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, unstable angina and sudden cardiac death, and the main pathophysiological basis is complete or incomplete coronary blockage caused by secondary platelet aggregation and thrombosis after coronary intimal injury or vulnerable plaque rupture. ACS is a common cardiovascular disease in clinic, and has the advantages of emergent onset, rapid change and high fatality rate. Platelet activation plays an important role in the development of ACS. Therefore, the antiplatelet therapy is the core, has a positive effect on the natural course of ACS, and can effectively reduce the fatality rate and reduce the recurrence. Antiplatelet drugs are mainly classified into aspirin and thiophene pyridine drugs.

Prasugrel hydrochloride is a platelet aggregation inhibitor suitable for patients with recent stroke, myocardial infarction and diagnosed peripheral artery disease, and can reduce the occurrence of atherosclerotic events such as myocardial infarction, stroke and vascular death. One of the adverse reactions of prasugrel is easy to cause gastrointestinal hemorrhage, and other adverse reactions such as abdominal pain, dyspepsia, gastritis and the like.

The prasugrel hydrochloride raw material medicine is white to off-white solid, is dissolved in a solution with the pH value of 2, is slightly dissolved in a solution with the pH value of 3.0-4.0, and is hardly dissolved in a solution with the pH value of 6.0-7.5. Prasugrel hydrochloride is sensitive to humidity and heat, and particularly under the aerobic condition, prasugrel hydrochloride can be degraded by free radical conversion, so that the quality of the medicine is influenced. Currently, there are many studies aimed at improving the dissolution rate and stability of prasugrel hydrochloride preparations.

CN101804042A discloses a preparation method of prasugrel tablets, wherein in order to ensure the stability of prasugrel, a method of preparing tablet cores by tabletting first and coating the tablet cores with gastric soluble protective layers containing antioxidants is adopted. Although the method solves the problem of stability of the prasugrel to a certain extent, adverse reactions of the prasugrel still exist. CN107661320A discloses a prasugrel pharmaceutical composition and a preparation method thereof, the invention adopts the method of firstly preparing a prasugrel sustained-release tablet core, then coating an isolation layer, coating powder and coating sugar to reduce the side effect of prasugrel, the coating process is very complicated, the operation is complicated, and the commercial production is not facilitated.

Disclosure of Invention

The invention aims to solve the technical problems that the prasugrel hydrochloride preparation in the prior art has poor antioxidant effect and the stimulation to the digestive tract is too large due to too fast medicine release, and provides sustained-release particles containing prasugrel hydrochloride, a preparation containing the sustained-release particles and a preparation method of the sustained-release particles.

Antioxidants are not resistant to high temperatures and can be classified into three categories, fat-soluble, water-soluble and compatible according to solubility. In the prior art, in the preparation process of prasugrel hydrochloride preparation, an antioxidant is usually added after a tablet core is prepared, so as to avoid the decomposition of the antioxidant caused by high temperature. The prior art adds antioxidants to the coating solution to coat the core, and water-soluble or compatible antioxidants are often used in order to facilitate compatibility of the antioxidants with other raw and auxiliary materials. In summary, in the prior art, a technology of preparing a tablet core at a high temperature, preparing a coating solution containing a water-soluble or compatible antioxidant and then coating the high-temperature tablet core is adopted to prepare the prasugrel hydrochloride preparation, and technical schemes of preparing the high-temperature tablet core, adding the antioxidant, coating the high-temperature tablet core with the coating solution and the like are mutually in ring-to-ring buckling and lack of one, so that no precedent of preparing the prasugrel hydrochloride preparation by adopting hot-melt granulation exists. The preparation subjected to hot melt granulation can bring the effect of delaying release, which cannot be reached by the traditional high-temperature preparation method. The invention conception of the invention is as follows: the antioxidant is added in the process of preparing the tablet core, so that the antioxidant can protect the active ingredients of the medicine as soon as possible. In order to avoid the destructive effect of high temperature on the antioxidant in the traditional process of preparing the tablet core, the invention adopts a hot melting granulation method and uses a wax skeleton with hot melting property; furthermore, in order to be matched with the sustained release tablet of the invention containing a waxy framework, the invention also adopts a fat-soluble antioxidant. The waxy matrix melts upon reaching its melting point and thus cooperates with the enteric antioxidant. Since the temperature of the hot-melt granulation in the present invention is controlled at 60 to 70 ℃, preferably 65 ℃, under such conditions, the temperature does not have a destructive effect on the antioxidant; and the antioxidant is added in the preparation step of the tablet core, so that the active medicine components can be better protected and prevented from being oxidized. The preparation method is initiated by the technical scheme that the tablet core is prepared by hot-melt granulation, and the fat-soluble antioxidant is added when the tablet core is prepared, and although the technical scheme is simple, the inertial thinking of the traditional prasugrel hydrochloride preparation is broken through, and better antioxidant effect and release delaying effect are unexpectedly generated.

In order to solve the technical problem, one of the technical schemes of the invention is as follows: a sustained release granule containing prasugrel hydrochloride comprises 2% -15% of prasugrel hydrochloride, 0.1% -1% of fat-soluble antioxidant, 25% -80% of diluent, 20% -40% of waxy framework material, 2% -20% of pore-forming agent and 0.5% -1% of lubricant, wherein the% is weight percentage, and the preparation method of the sustained release granule comprises the following steps:

(1) sieving prasugrel hydrochloride;

(2) melting the waxy framework material by a hot water bath, and adding the pore-foaming agent, the diluent, the fat-soluble antioxidant and the prasugrel hydrochloride obtained in the step (1) while stirring;

(3) and continuously stirring to cool, and sieving the solidified body to obtain the prasugrel hydrochloride-containing sustained-release granules. The key point of the technical scheme is that the sustained-release granules containing the fat-soluble antioxidant are prepared in the hot melting granulation process, and the sustained-release granules obtained by the preparation method can slow down the oxidation and release speed of the medicine, so that the stimulation to the gastrointestinal tract is reduced.

In a preferred embodiment, in the step (1), prasugrel hydrochloride is sieved by a sieve with 80 meshes; in the step (2), the temperature of the hot water bath is 60-70 ℃, preferably 65 ℃; and/or, sieving the solidified body by a sieve with 15-20 meshes to prepare the sustained-release granules, preferably a sieve with 18 meshes. The product prepared under the condition has better effect and phase.

In a preferred embodiment, the prasugrel hydrochloride is 10 to 12 wt%, the antioxidant is 0.2 to 0.5 wt%, the diluent is 40 to 50 wt%, the waxy skeleton material is 25 to 35 wt%, the pore-forming agent is 10 to 15 wt%, and the lubricant is 0.6 to 0.9 wt%.

Preferably, the weight percentage of the prasugrel hydrochloride is 10.98%, the weight percentage of the antioxidant is 0.25%, the weight percentage of the diluent is 46.25%, the weight percentage of the waxy framework material is 29.84%, the weight percentage of the pore-forming agent is 11.93%, and the weight percentage of the lubricant is 0.75%.

In a preferred embodiment, the fat-soluble antioxidant comprises one or more of vitamin C, propyl gallate, butylated hydroxyanisole and vitamin E. The diluent comprises one or more of lactose, mannitol, sorbitol, xylitol, starch, microcrystalline cellulose, glyceryl monostearate, palmitate, hydrogenated or unhydrogenated vegetable oil, wax, mono-, di-or tri-substituted glyceride. The waxy framework material comprises one or more of hydrogenated vegetable oil, stearic acid (stearic acid), stearyl alcohol (stearyl alcohol), and glyceryl stearic acid. The pore-forming agent comprises one or more of polyvinylpyrrolidone, microcrystalline cellulose and polyethylene glycol-1500, 4000 and 6000. The lubricant is one or more of magnesium stearate, sodium stearyl fumarate, talcum powder and colloidal silicon dioxide. The above provides various choices of fat-soluble antioxidant, diluent, waxy framework material and pore-forming agent, so that the technical scheme of the invention is more abundant and diversified.

In a most preferred embodiment, the fat-soluble antioxidant is butylated hydroxyanisole, the diluent is microcrystalline cellulose, the waxy framework material is glycerol stearic acid, the pore-forming agent is polyvinylpyrrolidone, and the lubricant is magnesium stearate.

In order to solve the technical problem, one of the technical schemes of the invention is as follows: an oral enteric sustained-release preparation of the sustained-release granules is provided, wherein the oral enteric sustained-release preparation is an enteric sustained-release tablet, an enteric sustained-release capsule or an enteric sustained-release pellet capsule.

In a preferred embodiment, the oral Enteric sustained release formulation further comprises a coating, the raw materials of the coating comprising one or more of an aqueous acrylic Enteric coating system-Acry-EZE, a fully formulated organic solvent coating system-Opadry Enteric (Opadry Enteric), cellulose acetate titanate (CAP), hydroxypropylmethylcellulose titanate (HPMCP), hydroxypropylmethylcellulose succinate (HPMCAS), shellac, zein, acrylics (including Eudragit L100 and Eudragit S100).

In order to solve the technical problem, one of the technical schemes of the invention is as follows: a method of preparing an oral enteric sustained release formulation as described above, comprising the steps of:

(1) sieving prasugrel hydrochloride;

(2) melting the waxy framework material in a hot water bath, and adding the pore-foaming agent, the diluent, the antioxidant and the prasugrel hydrochloride obtained in the step (1) while stirring;

(3) continuously stirring to cool the mixture into solidified bodies, and sieving the solidified bodies by a sieve to prepare the sustained-release particles;

(4) and (4) uniformly mixing the sustained-release granules obtained in the step (3) with a lubricant, and subpackaging into enteric hollow capsules.

In order to solve the technical problem, one of the technical schemes of the invention is as follows: a method for preparing an oral enteric sustained release formulation as described above, wherein the oral enteric sustained release formulation comprises a coating, the preparation of the oral enteric sustained release formulation comprising the steps of:

(1) sieving prasugrel hydrochloride;

(2) melting the waxy framework material on a hot water bath, and slowly adding the pore-foaming agent, the diluent, the antioxidant and the prasugrel hydrochloride obtained in the step (1) while stirring;

(3) continuously stirring to cool the mixture into a solidified body, and sieving the solidified body to prepare the sustained-release granules;

(4) uniformly mixing the sustained-release granules obtained in the step (3) with a lubricant, and pressing on a tablet press to prepare a sustained-release tablet core, wherein the wetting agent is preferably water or 50% alcohol solution;

(5) preparing a coating solution, and coating the sustained-release tablet core obtained in the step (4);

the coating is an enteric coating. Wherein, the coating liquid contains 20 percent of acrylic resin, 1 percent of PEG6000, 1.8 percent of talcum powder and the balance of water, and the percent is weight percentage.

(1) sieving prasugrel hydrochloride;

(2) melting the waxy framework material on a water bath, and adding the pore-foaming agent, the diluent, the antioxidant and the prasugrel hydrochloride obtained in the step (1) while stirring;

(4) adding a wetting agent into the sustained-release granules obtained in the step (3) to prepare a soft material, putting the soft material into a sugar coating machine, and rolling to prepare a sustained-release pellet core, wherein the wetting agent is preferably water or a diluted alcohol solution;

(5) preparing coating liquid from the coating material, and coating the pellet core to obtain pellet;

(6) subpackaging the above pellets into hollow capsules;

wherein the coating solution contains 16.7 percent of water-based acrylic resin enteric coating system Acryl-EZE, the balance of water, and the percent is weight percentage. The hollow capsule can be an enteric hollow capsule and can also be a common hollow capsule.

In order to solve the technical problem, one of the technical schemes of the invention is as follows: application of the sustained-release granules in preparing a medicament for treating acute coronary syndrome.

On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the antioxidant is directly wrapped in the sustained-release granules by a hot-melt granulation method, so that the degradation risk of the raw material medicine is reduced, the medicine release speed is effectively slowed down, the medicine effect is stabilized, and the medicine taking times are reduced. And the prasugrel hydrochloride is difficult to disintegrate in the stomach, so that the stimulation of the medicine to the gastric mucosa and the adverse reaction of the digestive tract caused by the stimulation of the medicine to the gastric mucosa, such as bleeding, abdominal pain and the like can be reduced.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The manufacturers of the main auxiliary materials of the prasugrel hydrochloride sustained-release capsules and the tablets are listed in table 1, and the information of the main production equipment is listed in table 2. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

TABLE 1 prasugrel hydrochloride sustained-release capsules and tablets manufacturer of main adjuvants

Butylated Hydroxyanisole (BHA)	Duport Danisco A/S,Grindsted
		Glycerol stearate	BASF
Polyvinylpyrrolidone	BASF
		Microcrystalline cellulose	JRS
Magnesium stearate	Anhui mountain river
		Acrylic resin Eudragit L	BASF
PEG6000	Guangzhou City of chemical technology Co Ltd
		Talcum powder	German Gusai
Ethanol	Sigma-Aldrich
		Acryl-EZE	Kalekang medicine

TABLE 2 prasugrel hydrochloride sustained-release capsule and tablet major production equipment conditions

Production equipment	Model number	Manufacturer of the product
			Constant temperature water bath kettle	HH-S1	Shanghai Bingsheng Shikou Shikuai development Co Ltd
Mechanical stirrer	DLJ type	New Strong tin-free stirring Equipment Co Ltd
			Three-dimensional motion mixer	SYH-20	Changzhou star drying equipment Co Ltd
Tablet press	Compacting 102i	FETTE COMPACTING GmbH
			High-efficiency coating machine	BGB-5F	ZHEJIANG XIAOLUN PHARMACEUTICAL MACHINERY Co.,Ltd.
Sugar-coating machine	BY800	ZIBO SHAOHAI IDLER BOILER Co.,Ltd.

Example 1: prasugrel hydrochloride enteric sustained-release capsule

The formulation of prasugrel hydrochloride enteric sustained-release capsules is shown in table 3.

TABLE 3 formulation of prasugrel hydrochloride enteric sustained-release capsule

Composition (I)	Content (wt.)
		Prasugrel hydrochloride	10.98mg
Butylated Hydroxyanisole (BHA)	0.25mg
		Glycerol stearate	29.84mg
Polyvinylpyrrolidone	11.93mg
		Microcrystalline cellulose	46.25mg
Magnesium stearate	0.75mg
		Total up to	100mg

The preparation process comprises the following steps:

(A) preparing sustained-release granules containing an antioxidant: sieving prasugrel hydrochloride with a 80-mesh sieve, melting glycerol stearic acid in a hot water bath at 65 ℃, adding a mixture of prasugrel hydrochloride, polyvinylpyrrolidone, microcrystalline cellulose and BHA while stirring, continuously stirring for cooling, sieving the solidified body with a 18-mesh sieve, and granulating.

(B) Preparing enteric sustained-release capsules: mixing the above delayed release granule and magnesium stearate, and packaging into enteric hollow capsule.

Example 2: prasugrel hydrochloride enteric-coated sustained-release tablet

2.1 preparation of the extended Release tablet core

The formulation of prasugrel hydrochloride enteric sustained release tablets is shown in table 4.

TABLE 4 formulation of prasugrel hydrochloride enteric sustained-release tablets

Prasugrel hydrochloride	10.98mg
		BHA	0.25mg
Glycerol stearate	29.84mg
		Polyvinylpyrrolidone	11.93mg
Microcrystalline cellulose	46.25mg
		Magnesium stearate	0.75mg
Total up to	100mg

The preparation process comprises the following steps:

(A) preparing sustained-release granules containing an antioxidant: sieving prasugrel hydrochloride with a 80-mesh sieve, melting glycerol stearic acid in a hot water bath at 65 ℃, slowly adding a mixture of prasugrel hydrochloride, polyvinylpyrrolidone, microcrystalline cellulose and BHA while stirring, continuously stirring to slowly cool the mixture, sieving the solidified body with a 18-mesh sieve, and granulating.

(B) Compressing the sustained-release tablet core: mixing the sustained release granules and magnesium stearate, and tabletting.

2.2 preparation of enteric sustained-release tablets

The formulation of the enteric sustained release tablet is shown in table 5.

TABLE 5 enteric coating formulation (per 100g)

Acrylic resin Eudragit L100	20g
		PEG6000	1g
Talcum powder	1.8g
		Purified water	77.3g

The preparation process comprises the following steps:

(A) preparing a coating solution: adding acrylic resin Eudragit L100 into purified water, and stirring; homogenizing in a homogenizer for 45 minutes in the rest purified water containing PEG6000 and pulvis Talci; slowly pouring the talcum powder suspension into acrylic resin Eudragit L100 aqueous dispersion, and slowly stirring for 30 minutes; filtering the prepared coating solution by a 80-mesh screen;

(B) coating enteric coating: adding the sustained-release tablet core into a coating pan, adjusting the air inlet temperature to 80 ℃, the tablet bed temperature to 30-35 ℃, the atomization pressure to 1.5bar, the rotation speed of the coating pan to 15-25 r/min, the sample injection flow rate to 4-6 g/min, and stopping coating when the weight gain of the coating is about 3%.

Example 3: prasugrel hydrochloride enteric sustained-release pellet capsule

3.1 preparation of core of sustained-Release pellet

The formulation of the core of the sustained release pellet is shown in table 6.

TABLE 6 formulation of core of sustained-release pellet

Prasugrel hydrochloride	10.98mg
		BHA	0.25mg
Glycerol stearate	29.84mg
		Polyvinylpyrrolidone	11.93mg
Microcrystalline cellulose	46.25mg
		Magnesium stearate	0.75mg
Total up to	100mg
		50% ethanol	Proper amount of

The preparation process comprises the following steps:

(B) Preparing a slow-release pellet core: mixing the above delayed release granules and magnesium stearate, adding appropriate amount of 50% ethanol solution into 1/3 mixed powder, making into soft mass, sieving with 30 mesh sieve, and granulating. Putting the wet granules into a sugar coating machine, starting the equipment, adjusting various parameters after the pellets are rounded to ensure that the pellets are in the optimal fluidization state, starting a spray gun, spraying 50% ethanol solution serving as a bonding agent, uniformly adding the rest mixed powder into the sugar coating machine after the pellets are wetted, adjusting the liquid spraying amount and the powder adding amount according to the state of the pellets, preparing the pellets, taking out, drying and screening.

3.2 preparation of enteric sustained-release pellet capsules

The formulation of the enteric coating is shown in table 7.

TABLE 7 enteric coating formulation (per 100g)

Acryl-EZE	16.7g
		Purified water	83.3g

The preparation process comprises the following steps:

(A) preparing a coating solution: adding Acryl-EZE into purified water, and stirring uniformly; homogenizing for 45 minutes in a homogenizer; filtering the prepared coating solution by a 80-mesh screen;

(B) coating enteric coating: adding the core of the sustained-release pellet into a coating pan, adjusting the air inlet temperature to 80 ℃, the temperature of a tablet bed to 30-35 ℃, the atomization pressure to 1.5bar, the rotation speed of the coating pan to 15-25 r/min, the sample injection flow rate to 4-6 g/min, and stopping when the feeding of the coating solution is finished.

(C) And (3) filling capsules: and (3) filling the prepared enteric sustained-release pellets into a common hollow capsule.

Comparative example 1 preparation of pramipexole dihydrochloride sustained-release tablet in the prior art

Tablets were prepared according to the method disclosed in CN101804042a using the formulation in example 2, the preparation method of which is briefly as follows:

(1) preparing a tablet core: taking prasugrel hydrochloride and other auxiliary materials except the antioxidant, uniformly mixing, and pressing on a tablet press;

(2) coating an enteric protective layer containing an antioxidant: coating the enteric coating solution with the coating material, antioxidant and medicinal adjuvants to obtain the antioxidant layer.

Effect example 1 stability study of active ingredient in oral enteric sustained-release preparation

The product of the invention and the product of comparative example 1 were left to stand under simulated gastric acid conditions (0.1M hydrochloric acid) for 24 hours, and sampled and tested at 0, 2, 4, 8, 16 and 24 hours, respectively, and the test methods and test results are shown in Table 8.

Table 8 stability study of active ingredients in oral enteric sustained release formulations

	Example 1	Example 2	Example 3	Comparative example 1
					0 hour	10.98mg	10.98mg	10.98mg	10.98mg
1 hour	3.0	3.2	3.0	2.0
					2 hours	5.0	5.2	5.0	4.9
4 hours	5.0	5.1	5.2	5.0
					8 hours	5.3	5.3	5.3	5.3
16 hours	6.0	6.2	6.0	5.7
					24 hours	6.1	6.3	6.1	6.1

The prepared enteric type samples hardly released under gastric acid conditions, and were stable under gastric acid conditions because examples 1, 2, 3 and comparative example 1 were enteric type formulations, which contained an enteric layer.

In addition, in comparative example 1, the antioxidant is coated together with the coating material, and since the coating material is a water-soluble dispersion and the antioxidant is fat-soluble, the distribution of the antioxidant may be non-uniform in the process, so that examples 1 to 3 have a significant process advantage over comparative example 1.

Effect example 2 comparison of release rates of examples and comparative examples

And (3) measuring the release degree: taking the sample of the embodiment, according to a method for measuring a release rate (XD first method in the appendix of the second part of the 2010 edition of Chinese pharmacopoeia), adopting a device for measuring a release rate (XC first method in the appendix of the second part of the 2010 edition of Chinese pharmacopoeia), taking 700mL of 0.1moL/L hydrochloric acid solution as a release medium, rotating at a speed of 75 revolutions per minute, carrying out the operation according to the method, immediately adding 300mL of 0.6moL/L tris (hydroxymethyl) aminomethane solution preheated to (37 +/-0.5) DEG C into a dissolution cup after 1 hour, uniformly mixing, adjusting the pH to 8.0 by using 2moL/L hydrochloric acid or sodium hydroxide solution, continuing the operation according to the method, taking a proper amount of the solution after 1 hour, 2 hours, 3 hours, 4 hours, 8 hours and 10 hours, filtering, precisely taking 3mL of the filtrate, immediately adding 1mL of 0.5moL/L sodium hydroxide solution, and uniformly mixing. Another 10mg of the standard substance is precisely weighed and placed in a 100mL measuring flask, 1mL of 0.5moL/L sodium hydroxide solution is added for dissolution, and the solution is diluted to the scale and shaken up. Precisely measuring 1mL, placing in a 100mL measuring flask, adding 0.6moL/L trihydroxymethylaminomethane solution to the scale, and shaking up. Precisely measuring 3mL, adding 1mL of 0.5moL/L sodium hydroxide solution, and uniformly mixing to obtain the product. 10 mul of each of the release sample and the control solution was taken and injected into a liquid chromatograph, and the release amount of each tablet was calculated by an external standard method. The release of the products of the different examples was calculated and the degree of release is shown in table 9.

TABLE 9 comparison of the release rates of the respective products

By comparing the release rates of examples 1-3 and comparative example 1, it was found that the release rate of the samples prepared by the hot-melt granulation method (examples 1-3) was slower than that of the product prepared by the direct mixing and tabletting process of comparative example 1 (especially evident within 1-4 hours), thereby reducing the irritation of the drug to the digestive tract, prolonging the action time of the drug, reducing the frequency of administration, and facilitating the administration of the drug by the patient.

It should be understood that various changes and modifications can be made by those skilled in the art after reading the above disclosure, and equivalents also fall within the scope of the invention as defined by the appended claims.

Claims

1. The sustained-release particles containing prasugrel hydrochloride are characterized by comprising 2% -15% of prasugrel hydrochloride, 0.1% -1% of fat-soluble antioxidant, 25% -80% of diluent, 20% -40% of waxy framework material, 2% -20% of pore-forming agent and 0.5% -1% of lubricant, wherein the% are weight percentage, and the preparation method of the sustained-release particles containing prasugrel hydrochloride comprises the following steps:

(1) sieving prasugrel hydrochloride;

(3) stirring continuously to cool, and sieving the solidified body to obtain the product.

2. The sustained-release granule according to claim 1, wherein in the step (1), prasugrel hydrochloride is passed through a 80-mesh sieve; in the step (2), the temperature of the hot water bath is 60-70 ℃, preferably 65 ℃; and/or, sieving the solidified body by a sieve with 15-20 meshes to prepare the sustained-release granules, preferably a sieve with 18 meshes.

3. The sustained-release granule according to claim 1 or 2, wherein the prasugrel hydrochloride is 10 to 12 wt%, the fat-soluble antioxidant is 0.2 to 0.5 wt%, the diluent is 40 to 50 wt%, the waxy framework material is 25 to 35 wt%, the pore-forming agent is 10 to 15 wt%, and the lubricant is 0.6 to 0.9 wt%;

preferably, the weight percentage of the prasugrel hydrochloride is 10.98%, the weight percentage of the antioxidant is 0.25%, the weight percentage of the diluent is 46.25%, the weight percentage of the framework material is 29.84%, the weight percentage of the pore-forming agent is 11.93%, and the weight percentage of the lubricant is 0.75%.

4. The sustained-release granule according to any one of claims 1 to 3, wherein the fat-soluble antioxidant comprises one or more of vitamin C, propyl gallate, butylated hydroxyanisole and vitamin E; the diluent comprises one or more of lactose, mannitol, sorbitol, xylitol, starch, microcrystalline cellulose, glyceryl monostearate, palmitate, hydrogenated or unhydrogenated vegetable oil, wax, mono-, di-or tri-substituted glyceride; the waxy framework material comprises one or more of hydrogenated vegetable oil, stearic acid, stearyl alcohol and glycerol stearic acid; the pore-forming agent comprises one or more of polyvinylpyrrolidone, microcrystalline cellulose and polyethylene glycol-1500, 4000 and 6000; and/or, the lubricant comprises one or more of magnesium stearate, sodium stearyl fumarate, talc, colloidal silicon dioxide;

preferably, the fat-soluble antioxidant is butylated hydroxyanisole, the diluent is microcrystalline cellulose, the waxy framework material is glycerol stearic acid, the pore-forming agent is polyvinylpyrrolidone, and the lubricant is magnesium stearate.

5. An oral enteric-coated sustained-release preparation comprising the sustained-release granule according to any one of claims 1 to 4, wherein the oral enteric-coated sustained-release preparation is an enteric-coated sustained-release tablet, an enteric-coated sustained-release capsule, or an enteric-coated sustained-release pellet capsule.

6. The oral Enteric sustained-release formulation of claim 5, further comprising a coating, wherein the raw material of the coating comprises one or more of an aqueous acrylic resin Enteric coating system Acry-EZE, a full-formulation organic solvent coating system Opadry Enteric, cellulose acetate titanate, hydroxypropylmethylcellulose succinate, shellac, zein, and acrylics.

7. A process for preparing an oral enteric sustained release formulation according to claim 5 or 6, characterized in that it comprises the steps of:

(1) sieving prasugrel hydrochloride;

(2) melting the waxy framework material in a hot water bath, and adding the pore-foaming agent, the diluent, the fat-soluble antioxidant and the prasugrel hydrochloride obtained in the step (1) while stirring;

(4) and (3) mixing the lubricant and the sustained-release granules obtained in the step (a), and subpackaging into enteric hollow capsules.

8. The method for preparing an oral enteric sustained-release formulation according to claim 5 or 6, wherein the oral enteric sustained-release formulation comprises a coating, and the preparation comprises the steps of:

(1) sieving prasugrel hydrochloride;

(2) melting the waxy framework material on a hot water bath, and slowly adding the pore-foaming agent, the diluent, the fat-soluble antioxidant and the prasugrel hydrochloride obtained in the step (1) while stirring;

(4) uniformly mixing a lubricant and the sustained-release granules obtained in the step (3), and pressing on a tablet press to prepare a sustained-release tablet core, wherein the wetting agent is preferably water or 50% alcohol solution;

wherein, the coating liquid contains 20 percent of acrylic resin, 1 percent of PEG6000, 1.8 percent of talcum powder and the balance of water, and the percent is weight percentage.

9. A process for preparing an oral enteric sustained release formulation according to claim 5 or 6, characterized by comprising the steps of:

(1) sieving prasugrel hydrochloride;

(2) melting the waxy framework material in a water bath, and adding the pore-foaming agent, the diluent, the fat-soluble antioxidant and the prasugrel hydrochloride obtained in the step (1) while stirring;

(6) subpackaging the above pellets into hollow capsules;

wherein the coating solution contains 16.7 percent of water-based acrylic resin enteric coating system Acryl-EZE, the balance of water, and the percent is weight percentage.

10. Use of sustained release granules according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment of acute coronary syndrome.