WO2015055130A2 - Long-lasting, sustained-release micropellet and preparation method therefor - Google Patents

Abstract

A long-lasting, sustained-release micropellet and a preparation method therefor are disclosed. A long-lasting trimetazidine hydrochloride sustained-release micropellet comprises, from the inside outward, a drug-containing pellet core, a sustained-release coating layer, and, optionally, an isolation coating layer provided between the core and the sustained-release coating. The mass weight of the isolation coating layer is 0-15% of that of the core, the mass weight of the sustained-release coating layer is 5-30% of that of the core, and the sustained-release coating layer contains a gastrointestinal tract adhesive. The trimetazidine hydrochloride sustained-release micropellet of the present invention is prescription-designed, using sustained-release coating material to encapsulate uniformly a drug-containing core, thus allowing the drug-release effects of the micropellet to be sustained, slow, and uniform. This reduces the release rate of active components and delays the peak time, such that release occurs steadily and continuously over 24 hours and plasma concentration stability is maintained, thereby avoiding the possibility of insufficient plasma concentration during morning ischemia. This also reduces the dosage rate to once per day, which promotes an increase in patient compliance.

Description

Long-acting sustained-release pellet and preparation method thereof Technical field

The invention relates to a sustained release preparation, in particular to a long-acting trimetazidine hydrochloride sustained-release pellet with a sustained release time of up to 24 hours. The invention also relates to a process for the preparation of the formulation.

Background technique

Trimetazidine Dihydrochloride (TMZ), as a new class of drugs for the effective prevention and treatment of angina pectoris, has been widely used in many countries and regions, and has a good effect on the treatment of angina pectoris. Oral tablet of trimetazidine hydrochloride entered China in 2000, and the product has been listed in the National Essential Drugs List.

Trimetazamine Hydrochloride is 1-(2,3,4-trimethylphenyl)piperazine dihydrochloride with a molecular weight of 339.3 and a molecular formula of C ₁₄ H ₂₂ N ₂ O ₃ .2HCl, which is highly soluble in water. Trimetazidine hydrochloride has a fast absorption rate in the body, and the half-life is about 6 hours. Therefore, the plasma concentration reaches a peak in the short time after taking the drug, and the blood drug is taken before the next administration, especially in the early morning when the ischemia is most severe. The concentration is very low.

Oral tablet of trimetazidine hydrochloride, the specification is 20mg/tablet, in order to provide sufficient blood concentration to ensure good therapeutic effect, the patient needs to take the medicine 3 times a day. Trimetazidine hydrochloride sustained-release tablets, the specification is 35mg / tablet, the patient needs to take 2 times a day, reducing the dose once a day than the ordinary tablets, the compliance is higher. However, most of the patients with angina pectoris are middle-aged and elderly. These patients have many forgetfulness characteristics. It is easy to cause busy patients to forget to take medicine on time. The sustained release preparation can provide a constant blood concentration, which not only improves the safety, effectiveness and patient compliance of the medication, but also controls the blood concentration and reduces the number of medications. Therefore, the development of sustained release of trimetazidine hydrochloride has received increasing attention and is becoming more and more popular.

In 2010, Servier (Tianjin) Pharmaceutical Co., Ltd. officially launched the trial release of trimetazidine hydrochloride sustained release tablets in English, the English name Trimetazidine Dihydrochloride Modified Release Tablets, the active ingredient is trimetazidine hydrochloride, the specification is 35mg/tablet, the trade name is 10,000 Supple, take 2 times a day.

CN1124140A discloses an oral orally delayed release of trimetazidine pharmaceutical composition for ensuring controlled release of trimetazidine via a depot system using a system selected from the group consisting of ethyl cellulose, a water insoluble polymer of a polymethacrylic acid polymer. The film formed by the mixture of acetyl tributyl citrate and the wet granulation method are used to granulate the film-coated tablets or pellets. The preparation process of the composition is to prepare a blank pill core by spheroidizing technology, and then spray the drug-containing solution on the blank pill core. The method is easy to cause crystallization of the drug by the method, and the drug content is low.

CN102133195A discloses a sustained-release pellet of trimetazidine hydrochloride and a preparation method thereof, wherein the content of trimetazidine hydrochloride is 4.65% to 51.62%. Trimetazidine Hydrochloride is applied to a blank pellet core, followed by a sustained release coating with ethyl cellulose or acrylic resin, using a plasticizer selected from the group consisting of dibutyl sebacate, triglyceride or triethyl citrate. , prepared trimetazidine hydrochloride sustained-release pellets. The invention patent preparation blank blank core preparation process is long and the process is cumbersome, and the use of the spray liquid medicine form to prepare the drug-containing pellet core, which is also easy to cause drug crystallization, resulting in insufficient content of trimetazidine hydrochloride in the drug-containing pellet core.

CN1994280A discloses a trimetazidine sustained-release pellets with a daily dose of 20 to 40 mg and a preparation method thereof, and a preparation method thereof The weight ratio of the sustained-release coating layer for controlling drug release by the drug-containing pellet core is 20:1 to 5:1, the sustained-release coating material is Kollicoat SR30D, and the content of trimetazidine in the drug-containing core is 10% to 60%. . The preparation method mainly comprises preparing a drug-containing pellet core by an extrusion-spheronization method, and then using a fluidized bed for a sustained-release coating. The pellets of the invention patent contain both immediate release and sustained release pellets, and the immediate release pellets and the sustained release pellets have different bulk density and volume difference due to the inconsistent thickness of the wrapping material and the package, which inevitably leads to The drug content of the pellets is different, which affects the stability of the therapeutic effect.

These sustained-release preparations are convenient for patients to some extent, but due to gastric emptying and normal metabolism of the human body, the time for staying in the body after oral sustained-release preparations is generally less than 10 hours, which also leads to the existing oral sustained-release preparations. At least twice a day, to ensure adequate blood levels.

Summary of the invention

It is an object of the present invention to provide a long-acting sustained-release modified trimetazidine sustained-release pellet and a preparation method thereof.

The technical solution adopted by the present invention is:

Long-acting trimetazidine hydrochloride sustained-release pellets, which are composed of a drug-containing pellet core and a sustained-release coating layer from the inside to the outside, and an optional coating layer between the drug-containing pellet core and the sustained-release coating layer The quality of the isolated coating layer is 0-15% of the drug-containing pellet core, and the quality of the sustained-release coating layer is 5-30% of the drug-containing pellet core, and the sustained-release coating layer contains the gastrointestinal adhesive. Preferably, the quality of the release coating layer is 0 to 10% of the core containing the pellet, and the mass of the sustained release coating layer is 5 to 25% of the core containing the pellet; the quality of the better coating coating layer is the core containing the pellet. 0 to 10%, the quality of the sustained-release coating layer is 10 to 20% of the drug-containing pellet core.

Further, in the above-mentioned trimetazidine hydrochloride sustained-release pellets, the composition of the drug-containing pellet core is as follows:

Preferably, the composition of the medicated pellet core is as follows:

More preferably, the composition of the medicated pellet core is as follows:

Further, in the above-mentioned trimetazidine hydrochloride sustained-release pellets, the composition of the barrier coating layer is as follows:

Isolation coating material 50%～90%

Anti-adhesive agent 1%～50%

Plasticizer 0.1% to 25%,

Wherein, the release coating material is at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol, Opadry, acrylic resin, povidone, and yake.

Preferably, the composition of the barrier coating layer is as follows:

Isolation coating material 60%～85%

Anti-adhesive agent 1%～28%

Plasticizer 0.1% to 18%.

Further, in the above-mentioned trimetazidine hydrochloride sustained-release pellets, the composition of the sustained-release coating layer is as follows:

Preferably, the composition of the sustained release coating layer is as follows:

More preferably, the composition of the sustained release coating layer is as follows:

As a further improvement of the present invention, a long-acting trimetazidine hydrochloride sustained-release pellet, which is composed of a drug-containing pellet core and a sustained-release coating layer from the inside to the outside, is provided between the drug-containing pellet core and the sustained-release coating layer. The optional isolating coating layer has a quality of 0.1 to 15% of the drug-containing pellet core, and the quality of the sustained-release coating layer is 5 to 30% of the drug-containing pellet core, and the sustained-release coating layer contains the stomach and the intestine. A road adhesive, wherein the composition of the drug-containing core is as follows:

The composition of the barrier coating layer is as follows:

Isolation coating material 60%～85%

Anti-adhesive agent 1%～28%

Plasticizer 0.1% to 18%;

The composition of the sustained release coating layer is as follows:

The gastrointestinal adhesive used in any of the above pellets is selected from the group consisting of carbomer, polycarboxyvinyl pentaerythritol ester, hydroxypropyl methylcellulose, high molecular weight (300,000 to 400,000) polyethylene oxide, high molecular weight. (2500 to 4000) at least one of sodium carboxymethylcellulose, liposome, methylcellulose, gelatin, and pectin.

The sustained-release coating material used in any of the above pellets is selected from one or more of ethyl cellulose, acrylic resin, silicone elastomer, shellac, cellulose acetate phthalate, and Sulis. Preferably, the sustained release coating material is an acrylic resin, specifically a low permeability Eudragit series sustained release coating material.

A method for preparing the above-mentioned long-acting trimetazidine hydrochloride sustained-release pellets, comprising preparing a drug-containing pellet core, directly coating the sustained-release coating layer in the medicine-containing pellet core, or coating the separation coating layer in the medicine-containing pellet core, and then The preparation method of the coated sustained-release coating layer containing the pill core comprises the following steps:

1) sieving: sifting the active ingredient, filler, binder, and glidant, and standby;

2) mixing: accurately weigh the sieved active ingredients, fillers, binders, and glidants in a mixer and mix them evenly;

3) Preparation of pellets: the mixture and the wetting agent are extruded-spheronized, and the obtained soft material is dried at 30 ° C to 80 ° C and sieved to obtain a pellet core.

A long-acting sustained-release oral preparation of trimetazidine hydrochloride, the preparation being a dispersible tablet or capsule containing the long-acting trimetazidine hydrochloride sustained-release pellet according to any one of the above, single dose containing hydrochloric acid Mitazine 70mg ~ 90mg, more preferably, a single dose of trimetazidine hydrochloride 75mg ~ 85mg.

The beneficial effects of the invention are:

The trimetazidine hydrochloride sustained-release pellet of the invention is carefully designed and coated, and the drug-containing pellet core is evenly wrapped by the sustained-release coating material to maintain a slow and uniform release property, reduce the release rate of the active ingredient, and delay the peak time. The pellets can be stably released for 24 hours, maintaining stable blood concentration and avoiding insufficient blood concentration in early morning ischemia; the frequency of administration can be reduced to once a day, which helps to improve patient compliance.

The sustained-release pellets prepared by the method of the invention not only have uniform size, high true sphericity, small difference between batches of pellets, good quality stability and good reproducibility of the coating process, and the preparation process is simple and reliable. The production equipment is simple, easy to operate and low in production cost.

DRAWINGS

1 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellet of Example 1 in a medium water;

2 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 2 in a medium of 0.1 mol of HCl;

Figure 3 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellet of Example 3 in a medium of water;

Figure 4 is a comparison diagram of in vitro release of trimetazidine hydrochloride sustained-release pellets of Example 4 and Wanshuangli in 0.1 mol of HCl;

Figure 5 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 5 in a medium at pH 6.8;

Figure 6 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 6 in a medium of water;

Figure 7 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellet of Example 7 in a medium at pH 4.5;

Figure 8 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellet of Example 8 in a medium of 0.1 mol of HCl;

Figure 9 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellet of Example 9 in a medium of water;

Figure 10 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 10 in a medium of pH 6.8;

Figure 11 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 10 in a medium of 0.1 mol of HCl;

Figure 12 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 10 in a medium of 0.1 mol of HCl.

Figure 13 is a graph showing the concentration of trimetazidine hydrochloride in plasma at different times after administration of the trimetazidine hydrochloride sustained-release pellets of Example 4 and the commercially available trimetazidine hydrochloride sustained-release tablets.

detailed description

Long-acting trimetazidine hydrochloride sustained-release pellets, which are composed of a drug-containing pellet core and a sustained-release coating layer from the inside to the outside, and an optional coating layer between the drug-containing pellet core and the sustained-release coating layer The quality of the isolated coating layer is 0-15% of the drug-containing pellet core, and the quality of the sustained-release coating layer is 5-30% of the drug-containing pellet core, and the sustained-release coating layer contains the gastrointestinal adhesive. Preferably, the quality of the release coating layer is 0 to 10% of the core containing the pellet, and the mass of the sustained release coating layer is 5 to 25% of the core containing the pellet; the quality of the better coating coating layer is the core containing the pellet. 0 to 10%, the quality of the sustained-release coating layer is 10 to 20% of the drug-containing pellet core.

Further, in the above-mentioned trimetazidine hydrochloride sustained-release pellets, the composition of the drug-containing pellet core is as follows:

Preferably, the composition of the medicated pellet core is as follows:

More preferably, the composition of the medicated pellet core is as follows:

Further, in the above-mentioned trimetazidine hydrochloride sustained-release pellets, the composition of the barrier coating layer is as follows:

Isolation coating material 50%～90%

Anti-adhesive agent 1%～50%

Plasticizer 0.1% to 25%,

Wherein, the release coating material is at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol, Opadry, acrylic resin, povidone, and yake.

Preferably, the composition of the barrier coating layer is as follows:

Isolation coating material 60%～85%

Anti-adhesive agent 1%～28%

Plasticizer 0.1% to 18%.

Further, in the above-mentioned trimetazidine hydrochloride sustained-release pellets, the composition of the sustained-release coating layer is as follows:

Preferably, the composition of the sustained release coating layer is as follows:

More preferably, the composition of the sustained release coating layer is as follows:

As a further improvement of the present invention, a long-acting trimetazidine hydrochloride sustained-release pellet, which is composed of a drug-containing pellet core and a sustained-release coating layer from the inside to the outside, is provided between the drug-containing pellet core and the sustained-release coating layer. The optional isolating coating layer has a quality of 0.1 to 15% of the drug-containing pellet core, and the quality of the sustained-release coating layer is 5 to 30% of the drug-containing pellet core, and the sustained-release coating layer contains the stomach and the intestine. A road adhesive, wherein the composition of the drug-containing core is as follows:

The composition of the barrier coating layer is as follows:

Isolation coating material 60%～85%

Anti-adhesive agent 1%～28%

Plasticizer 0.1% to 18%;

The composition of the sustained release coating layer is as follows:

The gastrointestinal adhesive used in any of the above pellets is selected from the group consisting of carbomer, polycarboxyvinyl pentaerythritol ester, hydroxypropyl methylcellulose, high molecular weight (300,000 to 400,000) polyethylene oxide, high molecular weight. (2500 to 4000) at least one of sodium carboxymethylcellulose, liposome, methylcellulose, gelatin, and pectin.

The sustained-release coating material used in any of the above pellets is selected from one or more of ethyl cellulose, acrylic resin, silicone elastomer, shellac, cellulose acetate phthalate, and Sulis. Preferably, the sustained release coating material is an acrylic resin, specifically a low permeability Eudragit series sustained release coating material. Acrylic resin is a kind of polymer formed by two or more kinds of monomers. The acrylic resin used as a film coating material is copolymerized by monomers such as methacrylate, acrylate and methacrylic acid in different proportions. A large class of polymers. Acrylic resin is a safe, non-toxic polymer material. The acrylic resin produced by Evonik Industries has good film-forming properties, including E, L, S, RL and RS. E type is gastric soluble, L and S are enteric. RL and RS are insoluble in water, and Eudragit is the trade name.

在水中不溶，但能溶胀，在包衣中形成孔道。尤特奇RL的孔道直径为1～5μm，尤特奇RS为0.1～0.6μm。包衣内侧的药物通过这些孔道释放，调节这两种材料的配比和包覆量就可调整释药速率。

由中性甲基丙烯酸与少量甲基丙烯酸三甲胺乙酯氯化物共聚而成。

的季胺基团与中性酯基团的摩尔比为1：20(相当于50毫克当量/100g)，而

的相应比是l：40(相当干25毫克当量/100g)。因为季胺基团决定薄膜在水中的溶胀性和渗透性，含季胺基团较少的

所形成的薄膜有较低的渗透性，对药物释放的延缓作用较大，适用于水溶性好的药物的缓释包衣。

Insoluble in water, but swellable, forming pores in the coating. The Eutec RL has a pore diameter of 1 to 5 μm and the Eudragit RS has a diameter of 0.1 to 0.6 μm. Drugs on the inside of the coating are released through these channels, and the ratio of the two materials can be adjusted to adjust the release rate.

It is formed by copolymerization of neutral methacrylic acid with a small amount of trimethylammonium methacrylate chloride.

The molar ratio of the quaternary amine group to the neutral ester group is 1:20 (equivalent to 50 meq/100 g), and

The corresponding ratio is 1:40 (equivalent to 25 mg equivalents per 100 g). Because the quaternary amine group determines the swelling and permeability of the film in water, it contains less quaternary amine groups.

The formed film has low permeability and has a long delay effect on drug release, and is suitable for a sustained release coating of a water-soluble drug.

A method for preparing the above-mentioned long-acting trimetazidine hydrochloride sustained-release pellets, comprising preparing a drug-containing pellet core, directly coating the sustained-release coating layer in the medicine-containing pellet core, or coating the separation coating layer in the medicine-containing pellet core, and then The preparation method of the coated sustained-release coating layer containing the pill core comprises the following steps:

1) sieving: sifting the active ingredient, filler, binder, and glidant, and standby;

2) mixing: accurately weigh the sieved active ingredients, fillers, binders, and glidants in a mixer and mix them evenly;

3) Preparation of pellets: the mixture and the wetting agent are extruded-spheronized, and the obtained soft material is dried at 30 ° C to 80 ° C and sieved to obtain a pellet core.

A long-acting sustained-release oral preparation of trimetazidine hydrochloride, the preparation being a dispersible tablet or capsule containing the long-acting trimetazidine hydrochloride sustained-release pellet according to any one of the above, single dose containing hydrochloric acid Mitazine 70mg ~ 90mg, more preferably, a single dose of trimetazidine hydrochloride 75mg ~ 85mg.

The bioadhesive drug delivery system (BDDS) is a new branch of modern drug delivery forms. The bioadhesive preparation is a kind of pharmaceutical preparation which uses a bioadhesive material as a drug carrier and adheres to the mucosa for a long time through bioadhesion. Bioadhesive formulations have the following major advantages over other dosing forms:

1 The carrier is composed of bioadhesive materials, which have different degrees of adhesion to the mucosa, which can prolong the release time and improve the absorption of the drug;

2 The site of action is the tissue mucosa of the human body. The drug directly enters the systemic blood system through mucosal transport, avoiding the first-pass effect of the liver and improving the bioavailability of the drug;

3 has a targeting function, for local diseases, can greatly increase the local drug concentration, to avoid the difficulty of oral drugs in the lesions to achieve effective concentrations.

According to the different effects of the preparation on the human tissue, the biological adhesion preparation can be divided into oral adhesion preparation, nasal adhesion preparation, gastrointestinal oral adhesion preparation, eye adhesion preparation, uterine and vaginal adhesion preparation, rectal adhesion preparation and the like. The current technical methods for prolonging the transit time of drugs in the gastrointestinal tract are mainly intragastric floating drug delivery systems and gastrointestinal mucosal drug delivery systems.

Sources of bioadhesives are available in a variety of synthetic and natural sources. Natural such as: gelatin, pectin, western gum, gum arabic, sodium alginate and so on. Synthetic are: methyl cellulose (MC), sodium carboxymethyl cellulose (CMC ~ Na), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl methacrylic acid Ester, polyvinyl alcohol (PVA), Carbopol, polycarbophil, and the like.

The solid sustained-release and controlled-release dosage forms prepared by the coating technology control and adjust the release rate of the drug in the body and the outside of the dosage form through the coating film, so the selection of the coating material and the composition of the coating film are largely The success or failure of the sustained release and controlled release of this preparation is determined. Commonly used sustained release coating materials are ethyl cellulose (EC), acrylic resin, hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), cellulose acetate phthalate (CAP), polyethylene. Acetaldehyde diethylamine acetate (AEA), polyvinyl acetate (PVAc), cellulose acetate (CA), methacrylic acid copolymer, polyacrylic resin, silicone elastomer, crosslinked alginate, shellac , cellulose acetate phthalate, Eudragit, Su Lisi and so on.

The invention will be further illustrated by the following examples and experiments.

In the following examples, the composition of the raw material is an amount of 1000 unit parts, such as 1000 pieces of sustained release disintegrating tablets, or the amount of contents required for 1000 sustained release capsules.

Example 1

A trimetazidine hydrochloride sustained-release pellet comprising the following components:

Pharmaceutical core:

Sustained release coating:

The method for preparing the above-mentioned trimetazidine hydrochloride sustained-release pellets is as follows:

A. Preparation of drug-containing pellet core:

1) Screening: the active ingredient, filler, binder and glidant pass through a 40 mesh screen, ready for use;

2) mixing: accurately weigh the sieved active ingredients, fillers, binders and glidants in a three-dimensional mixer and mix them evenly;

3) using purified water as a wetting agent to wet the mixture, and then extruding - spheronization, the obtained soft material is dried at 50 ° C, and sieved to obtain a pill core;

B. Sustained release coating:

1) Formulation of sustained-release coating liquid: slow-release coating material, anti-adhesive agent, plasticizer, porogen and gastrointestinal adhesive are added to the purified water under stirring, and stirred to completely dissolve to form a solid content of 10 % of coating liquid;

2) using a fluidized bed to spray the drug-containing pellet core;

3) The obtained trimetazidine hydrochloride sustained-release pellets were aged in an oven at 40 ° C for 24 hours to obtain sustained-release pellets.

Example 2

A trimetazidine hydrochloride sustained-release pellet comprising the following components:

Pharmaceutical core:

Isolation coating:

Polyvinyl alcohol (separating coating material) 13.50g

Talc (anti-adhesive) 6.30g

Dimethyl phthalate (plasticizer) 2.70g

Sustained release coating:

Su Lisi (sustained release coating material) 27.00g

Magnesium stearate (anti-adhesive) 2.25g

Polycarboxyvinyl pentaerythritol ester (gastrointestinal adhesive) 13.50g

The method for preparing the above-mentioned trimetazidine hydrochloride sustained-release pellets is as follows:

A. Preparation of drug-containing pellet core:

1) Screening: the active ingredient, filler, binder and glidant pass through a 40 mesh screen, ready for use;

2) mixing: accurately weigh the sieved active ingredients, fillers, binders and glidants in a three-dimensional mixer and mix them evenly;

3) using a 75% ethanol-water solution as a wetting agent to wet the mixture, and then extruding - spheronization, the obtained soft material is dried at 45 ° C, and sieved to obtain a pill core;

B. Isolation coating:

1) formulating the coating liquid: adding the isolation coating and the plasticizer material to the purified water in the stirring, stirring to completely dissolve;

2) adding the anti-adhesive agent to the purified water for homogenization, and after homogenization, the suspension is added to the A coating liquid, and stirring is continued;

3) using a fluidized bed to spray the drug-containing pellet core, that is, to isolate the pellet;

C. Sustained release coating:

1) Formulating a sustained-release coating liquid: adding a sustained-release coating material, an anti-adhesive agent and a gastrointestinal adhesive to purified water in a stirring, stirring to completely dissolve it, and forming a coating liquid having a solid content of 10%;

2) using a fluidized bed to spray the isolated pellets;

3) The obtained trimetazidine hydrochloride sustained-release pellets were aged in an oven at 40 ° C for 24 hours to obtain sustained-release pellets.

Example 3

A trimetazidine hydrochloride sustained-release pellet comprising the following components:

Pharmaceutical core:

Sustained release coating:

The method for preparing the above-mentioned trimetazidine hydrochloride sustained-release pellets is as follows:

A. Preparation of drug-containing pellet core:

1) Screening: the active ingredient, filler, binder and glidant pass through a 40 mesh screen, ready for use;

2) mixing: accurately weigh the sieved active ingredients, fillers, binders and glidants in a three-dimensional mixer and mix them evenly;

3) using 95% ethanol as a wetting agent to wet the mixture, and then extruding - spheronization, the obtained soft material is dried at 50 ° C, and sieved to obtain a pill core;

B. Sustained release coating:

1) Preparation of sustained-release coating liquid: adding sustained-release coating material, anti-adhesive agent, plasticizer, porogen and gastrointestinal adhesive to 80% ethanol in stirring, stirring to completely dissolve, forming solid 10% of the coating liquid;

2) using a fluidized bed to spray the drug-containing pellet core;

3) The obtained trimetazidine hydrochloride sustained-release pellets were aged in an oven at 40 ° C for 24 hours to obtain sustained-release pellets.

Example 4

A trimetazidine hydrochloride sustained-release pellet comprising the following components:

Pharmaceutical core:

Isolation coating:

Hydroxypropyl cellulose (isolation material) 12.00g

Talc (anti-adhesive) 5.60g

Triacetin (plasticizer) 2.40g

Sustained release coating:

The method for preparing the above-mentioned trimetazidine hydrochloride sustained-release pellets is as follows:

A. Preparation of drug-containing pellet core:

1) sieving: the active ingredient, filler, binder and glidant are passed through a 40 mesh screen for use;

2) mixing: accurately weigh the sieved active ingredients, fillers, binders and glidants in a three-dimensional mixer and mix them evenly;

3) using purified water as a wetting agent to wet the mixture, and then extruding - spheronization, the obtained soft material is dried at 50 ° C, and sieved to obtain a pill core;

B. Isolation coating:

1) formulating the coating liquid: adding the isolation coating, the anti-adhesive agent and the plasticizer material to the purified water in the stirring, stirring and completely dissolving;

2) Using a fluidized bed to spray the drug-containing pellet core, the pellet is isolated.

C. Sustained release coating:

1) Formulating a sustained-release coating liquid: adding a sustained-release coating material, an anti-adhesive agent, a plasticizer, a porogen and a gastrointestinal adhesive to 80% ethanol in a stirring, and stirring to completely dissolve;

2) using a fluidized bed to spray the drug-containing pellet core;

3) The obtained trimetazidine hydrochloride sustained-release pellets were aged in an oven at 40 ° C for 24 hours to obtain sustained-release pellets.

Example 5

A trimetazidine hydrochloride sustained-release pellet comprising the following components:

Pharmaceutical core:

Isolation coating:

Polyvinyl alcohol (separation material) 28.00g

Talc (anti-adhesive) 4.00g

Triethyl citrate (plasticizer) 7.20g

Sustained release coating:

The method for preparing the above-mentioned trimetazidine hydrochloride sustained-release pellets is as follows:

Preparation of drug-containing pellet core:

Screening: the active ingredient, filler, binder and glidant are passed through a 40 mesh screen for use;

Mixing: Accurately weigh the sifted active ingredients, fillers, binders and glidants in a three-dimensional mixer for uniform mixing;

The mixture is wetted with purified water as a wetting agent, and then extruded and spheronized, and the soft material is dried at 50 ° C and sieved to obtain a pill core;

Isolation coating:

Formulating the coating liquid: adding the isolation coating and the plasticizer material to the purified water under stirring, and stirring to completely dissolve;

The anti-adhesive agent is added to the purified water to be homogenized, and after the homogenization is completed, the suspension is added to the coating liquid, and the stirring is continued;

The pellets are sprayed with a fluidized bed to isolate the pellets.

Sustained release coating:

Formulating a sustained-release coating liquid: adding a sustained-release coating material, an anti-adhesive agent, a plasticizer, a porogen and a gastrointestinal adhesive to a stirred 80% acetone-water mixture, and stirring to completely dissolve;

Spraying the drug-containing pellet core with a fluidized bed;

The obtained trimetazidine hydrochloride sustained-release pellets were aged in an oven at 40 ° C for 24 hours to obtain sustained-release pellets.

Example 6

A trimetazidine hydrochloride sustained-release pellet comprising the following components:

Pharmaceutical core:

Isolation coating:

Hydroxypropylmethylcellulose (isolation material) 51.00g

Talc (anti-adhesive) 6.00g

Propylene glycol (plasticizer) 3.00g

Sustained release coating:

Eudragit RSPO (Sustained Release Coating Material) 24.00g

Magnesium stearate (anti-adhesive) 2.00g

Carbomer (gastrointestinal adhesive) 12.00g

The above method for preparing the trimetazidine hydrochloride sustained-release pellets was the same as in Example 2, wherein the sustained-release coating wetting agent was changed to 50% ethanol.

Example 7

A trimetazidine hydrochloride sustained-release pellet comprising the following components:

Pharmaceutical core:

Isolation coating:

Oubaday (isolation material) 34.00g

Talc (anti-adhesive) 4.00g

Triethyl citrate (plasticizer) 2.00g

Sustained release coating:

Eudragit RSPO (Sustained Release Coating Material) 48.00g

Glyceryl monostearate (anti-adherent) 4.00g

Gelatin (gastrointestinal adhesive) 24.00g

The above method for preparing the trimetazidine hydrochloride sustained-release pellets was the same as in Example 2, wherein the sustained-release coating wetting agent was changed to 80% ethanol.

Example 8

A trimetazidine hydrochloride sustained-release pellet comprising the following components:

Pharmaceutical core:

Isolation coating:

Hydroxypropylmethylcellulose (isolated coating material) 36.75g

Talc (anti-adhesive) 5.25g

Triacetin (plasticizer) 9.45g

Sustained release coating:

The method for preparing the above-mentioned trimetazidine hydrochloride sustained-release pellets was the same as in Example 4.

Example 9

A trimetazidine hydrochloride sustained-release pellet comprising the following components:

Pharmaceutical core:

Isolation coating:

Povidone (Isolation Material) 28.00g

Talc (anti-adhesive) 4.00g

Polyethylene glycol (plasticizer) 7.20g

Sustained release coating:

The method for preparing the above-mentioned trimetazidine hydrochloride sustained-release pellets was the same as in Example 4.

Example 10

A trimetazidine hydrochloride sustained-release pellet comprising the following components:

Pharmaceutical core:

Isolation coating:

Povidone (isolation material) 44.63g

Talc (anti-adhesive) 5.25g

Dimethyl phthalate (plasticizer) 2.63g

Sustained release coating:

Eudragit NE30D (sustained release coating material) 63.00g

Magnesium stearate (anti-adhesive) 5.25g

Carbomer (gastrointestinal adhesive) 31.50g

The above method for preparing the trimetazidine hydrochloride sustained-release pellets was the same as in Example 2, wherein the sustained-release coating wetting agent was changed to 80% ethanol.

Example 11

A trimetazidine hydrochloride sustained-release pellet comprising the following components:

Pharmaceutical core:

Sustained release coating:

The method for preparing the above-mentioned trimetazidine hydrochloride sustained-release pellets was the same as in Example 1.

Example 12

A trimetazidine hydrochloride sustained-release pellet comprising the following components:

Pharmaceutical core:

Isolation coating:

Povidone (Isolation Material) 34.00g

Talc (anti-adhesive) 4.00g

Dimethyl phthalate (plasticizer) 2.00g

Sustained release coating:

Eudragit NE30D (sustained release coating material) 48.00g

Magnesium stearate (anti-adhesive) 4.00g

Polyethylene oxide (300,000, gastrointestinal adhesive) 24.00

The above method for preparing the trimetazidine hydrochloride sustained-release pellets was the same as in Example 2, wherein the sustained-release coating wetting agent was changed to 80% ethanol.

In vitro release test of trimetazidine hydrochloride sustained-release pellets:

Determination of in vitro release of trimetazidine hydrochloride sustained-release pellets: in vitro release assay (Chinese Pharmacopoeia 2010 edition two appendix XD first method) and dissolution assay (Chinese Pharmacopoeia 2010 edition two appendix XC The apparatus of one method) measures the trimetazidine hydrochloride sustained-release pellets prepared in Examples 1 to 10 of the present invention and the commercially available trimetazidine hydrochloride sustained-release tablets (named Wan Shuangli, 35 mg/tablet) Drug release characteristics.

1 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellet of Example 1 in a medium water;

2 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 2 in a medium of 0.1 mol of HCl;

Figure 3 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellet of Example 3 in a medium of water;

Figure 4 is a comparison diagram of in vitro release of trimetazidine hydrochloride sustained-release pellets of Example 4 and Wanshuangli in 0.1 mol of HCl;

Figure 5 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 5 in a medium at pH 6.8;

Figure 6 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 6 in a medium of water;

Figure 7 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellet of Example 7 in a medium at pH 4.5;

Figure 8 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellet of Example 8 in a medium of 0.1 mol of HCl;

Figure 9 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellet of Example 9 in a medium of water;

Figure 10 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 10 in a medium at pH 6.8.

Figure 11 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 10 in a medium of 0.1 mol of HCl;

Figure 12 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 10 in a medium of 0.1 mol of HCl.

As can be seen from the figure, the sustained-release pellets of Examples 1 to 12 all have long-acting and sustained-release properties, and the release degree is substantially linear with time, and has a good sustained-release property. Meanwhile, the pellets of the respective examples were in about 24 hours.

The trimetazidine hydrochloride sustained-release pellet of Example 4 has better sustained-release properties than the commercially available trimetazidine hydrochloride sustained-release tablet, and has a longer release time (up to 24 hours) than the commercially available sustained-release tablet. It is about 1 times longer.

Pharmacokinetics experiment of trimetazidine hydrochloride sustained-release tablets

(1) Sample:

Reference preparation: Commercially available trimetazidine hydrochloride sustained-release tablets (named Wan Shuangli, 35mg/tablet), produced by Servier (Tianjin) Pharmaceutical Co., Ltd.;

The trimetazidine hydrochloride sustained-release pellet of Example 4 of the present invention.

(2) Test method:

Experimental animals: 12 healthy beagle dogs, half male and half female, weighing about 10 ± 1 kg, were randomly divided into 2 groups;

Method of administration: Commercially available trimetazidine hydrochloride sustained-release tablets (named Wanshuangli, 35 mg/tablet) were orally administered, one tablet was administered for the first time, and one tablet was administered again 12 hours later; the hydrochloric acid of Example 4 was orally administered once. Trimetazidine sustained-release pellets 80mg (capsules, based on trimetazidine hydrochloride);

Detection method: The concentration of trimetazidine hydrochloride in plasma was measured by high performance liquid chromatography at different times after administration, and the blood concentration-time curve was plotted.

Figure 13 is a graph showing the concentration of trimetazidine hydrochloride in plasma at different times after administration of the trimetazidine hydrochloride sustained-release pellets of Example 4 and the commercially available trimetazidine hydrochloride sustained-release tablets. The results showed that the trimetazidine hydrochloride sustained-release pellet of Example 4 effectively delayed the peak time (Tmax) of the concentration of trimetazidine hydrochloride in vivo, and peaked after about 10 hours of oral administration. At the same time, the use of gastrointestinal mucoadhesive agents prolongs the elimination half-life of trimetazidine hydrochloride in dogs, reaching the requirement of a one-day sustained-release dosage form. In addition, the AUC of the trimetazidine hydrochloride sustained-release pellet of Example 4 was 1398.25 ng·h/mL, which was similar to the control (1437 ng·h/mL) and had good bioequivalence.

Claims (10)

Long-acting trimetazidine hydrochloride sustained-release pellets, which are composed of a drug-containing pellet core and a sustained-release coating layer from the inside to the outside, and an optional coating layer between the drug-containing pellet core and the sustained-release coating layer , characterized in that: the quality of the isolation coating layer is 0-15% of the drug-containing pellet core, the quality of the sustained-release coating layer is 5-30% of the drug-containing pellet core, and the sustained-release coating layer contains gastrointestinal adhesion. Agent. The long-acting trimetazidine hydrochloride sustained-release pellet according to claim 1, wherein the composition of the drug-containing pellet core is as follows:

The long-acting trimetazidine hydrochloride sustained-release pellet according to claim 1, wherein the composition of the drug-containing pellet core is as follows:

The long-acting trimetazidine hydrochloride sustained-release pellet according to any one of claims 1 to 3, wherein the composition of the barrier coating layer is as follows: Isolation coating material 50%～90% Anti-adhesive agent 1%～50% Plasticizer 0.1% to 25%, Wherein, the release coating material is at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol, Opadry, acrylic resin, povidone, and yake. The long-acting trimetazin hydrochloride sustained-release pellet according to any one of claims 1 to 3, wherein the composition of the sustained-release coating layer is as follows:

The long-acting trimetazin hydrochloride sustained-release pellet according to any one of claims 1 to 3, wherein the composition of the sustained-release coating layer is as follows:

The long-acting trimetazidine hydrochloride sustained-release pellet according to any one of claims 1 to 6, wherein the gastrointestinal adhesive is selected from the group consisting of carbomer, polycarboxyvinyl pentaerythritol ester, and hydroxypropyl group At least one of a cellulose, a high molecular weight polyethylene oxide, a high molecular weight sodium carboxymethylcellulose, a liposome, methylcellulose, gelatin, and pectin. The long-acting trimetazidine hydrochloride sustained-release pellet according to claim 5 or 6, wherein the sustained-release coating material is selected from the group consisting of ethyl cellulose, acrylic resin, silicone elastomer, shellac, One or more of cellulose acetate phthalate and Sulis. A method for preparing long-acting trimetazidine hydrochloride sustained-release pellets, comprising preparing a drug-containing pellet core, directly coating the sustained-release coating layer in the drug-containing pellet core, or first coating the coating layer with the drug-containing pellet core, and then packaging The sustained release coating layer is characterized in that the preparation method of the drug-containing pellet core comprises the following steps: Screening: sieving the active ingredient, filler, binder, and glidant for use; Mixing: accurately weigh the sieved active ingredients, fillers, binders, and glidants in a mixer and mix them evenly; Preparation of pellets: the mixture and the wetting agent are extruded - rounded, the obtained soft material is dried at 30 ° C ~ 80 ° C, sieved to obtain a pellet core; The composition of the long-acting trimetazidine hydrochloride sustained-release pellets according to any one of claims 1 to 8. A long-acting sustained-release oral preparation of trimetazidine hydrochloride, the preparation being a dispersible tablet or capsule, characterized in that the preparation contains the sustained-release of long-acting trimetazidine hydrochloride according to any one of claims 1-8. Pellets, a single dose containing trimetazidine hydrochloride 70mg ~ 90mg.

Images