WO2011026312A1

WO2011026312A1 - Novel matrix slow release tablet containing metoprolol succinate

Info

Publication number: WO2011026312A1
Application number: PCT/CN2010/001294
Authority: WO
Inventors: 赵志全
Original assignee: 鲁南制药集团股份有限公司
Priority date: 2009-09-04
Filing date: 2010-08-26
Publication date: 2011-03-10
Also published as: CN102008456A; CN102008456B

Abstract

A bilayer matrix slow release tablet which comprises slow release layer containing metoprolol succinate and an auxiliary layer assisting in regulating drug release rate is disclosed.

Description

Novel skeleton sustained-release tablet containing metoprolol succinate

The present invention relates to a novel sustained-release tablet comprising metoprolol succinate, in particular to a metoprolol succinate double-layer sustained-release tablet having an auxiliary layer capable of regulating drug release rate. It belongs to the field of pharmaceutical preparations. Background technique

Metoprolol, chemical name 1-[4-(2-methylethyl)phenoxy]-3-isopropylaminopropanol, is a selective βΐ-receptor blocker It is mainly used for the treatment of mild to moderate hypertension, stable angina and arrhythmia. Its oral absorption is rapid and complete, the absorption rate is greater than 90%, but the liver metabolic rate is 95%, the first pass effect is 25%~60%, so the bioavailability (F) is only 40%~75%. The peak time of oral blood plasma concentration is generally 1.5 hours, and the maximum action time is 1 to 2 hours. The half-life (tl/2) of fast metabolizers is 3 to 4 hours; the half-life (tl/2) of slow metabolizers can reach 7.55 hours, and the individual difference in plasma peak concentration can reach 20 times, leading to plasma drug concentration in patients. The fluctuations are large, and adverse reactions such as slow heart rate, lower blood pressure, fatigue and dizziness, depression, nausea, stomach pain, shortness of breath, joint pain, etc. are obvious. The products currently on the market are mainly R, S-Metoprolol tartrate and succinate and S-Metoprolol succinate.

AstraZeneca's Metoprolol Tartrate Tablet (trade name: Betaloc) is the first Metoprolol to be marketed. However, because of its short elimination half-life, about 3~4h, it takes 2~4 times a day to take the drug, which causes the patient's plasma drug concentration to fluctuate greatly, which makes the plasma drug concentration unable to maintain an effective therapeutic concentration and brings about more side effects. In order to overcome these shortcomings, several metoprolol controlled release preparations appeared on the market, and AstraZeneca used a multi-microcapsule technology which can be used as an independent constant-speed release unit, and used a relatively small solubility of amber. The acid salt replaces the tartrate, and the metoprolol succinate sustained release tablet (trade name: Betaloc ZOK, Betaloc sustained release tablets) is introduced, which significantly delays the dissolution rate of the drug and overcomes the previous metoprolol. The lack of pharmacokinetics of the tablet not only reduces the side effects of the drug, but also greatly improves the therapeutic efficacy and tolerance of the drug. However, AstraZeneca's marketed products use pelletizing technology, and its preparation process mainly includes preparation of pellet core, slow release coating, pelleting and film coating. The preparation process has many steps, and each step is more Complex, especially in the pelleting process, because the density and particle size of the pellets are relatively large, it is not easy to mix well with the tableting materials or particles, and the pellet film has a certain pressure resistance, which makes the production process very difficult. control.

In April 2005, Emcure India launched S-Metoprolol Succinate Sustained Release Tablets in India under the trade name METPURE-XL. The specifications are 12.5 mg, 25 mg, 50 mg of Metoprolol S-tartarate. (S. Metoprolol succinate is 11.875 mg, 23.75 mg, 47.5 mg), and the technique is a traditional skeleton sustained-release tablet. However, since the solubility of S-Metoprolol succinate in water is significantly greater than that of racemic metoprolol succinate, the traditional slow release technique is used. The initial release rate is too fast, and the amount of drug released in the late stage is insufficient. Eventually, the effective therapeutic concentration cannot be maintained for 24 hours, and the terminal residue is large, and the blood drug concentration has obvious peak-to-valley phenomenon.

The current standards for the release of commercially available metoprolol sustained-release preparations are as follows - Table 1 Comparison of the release standards of commercially available metoprolol sustained-release preparations

Among them, the traditional skeleton sustained-release tablets of metoprolol tartrate produced according to the Chinese Pharmacopoeia CP2005 standard, the release limit of 8h: >75%, obviously faster, not suitable for long-acting preparations of 24-hour sustained release. The release profile of metoprolol succinate released by AstraZeneca has an ideal release curve. The standard has been included in the USP version of USP30. As a reference for research.

Guangzhou Tianxin Pharmaceutical Co., Ltd. uses a controlled release film coating technology to prepare metoprolol tartrate controlled release tablets.

24h long-acting preparation, but the sampling time point of the standard release limit is lh, 5h, 10h and 20h instead of the 24h long-acting preparation usually used for lh, 4h, 8h and 20h. When using the USP30 method, the sampling time was measured at lh, 4h, 8h and 20h. The release data showed that the 4h and 8h release exceeded the reasonable release limit, indicating that the technology used in the preparation could not Effectively control drug release.

U.S. Patent No. 4,792,452 discloses a controlled release pharmaceutical composition which provides a pH-independent release of a basic drug such as metoprolol. The formulation includes a pH dependent polymer that is an alginate, a pH independent hydrocolloid gelling agent, and a binder. U.S. Patent 5,081,154 relates to an oral pharmaceutical composition of metoprolol succinate coated with an anionic polymer dissolved at a pH above 5.5 and a water-insoluble acrylic polymer. However, the metoprolol controlled release tablets prepared by the above two patents have a shorter controlled release time and cannot achieve 24-hour release.

Huang Guihua et al. In the study of factors affecting the release of metoprolol succinate HPMC matrix tablets (Journal of Biomedical Engineering, 2006, 03), reported hydroxypropyl methylcellulose (HPMC) as the backbone material, ethyl Cellulose (EC) is a retarder. The metoprolol succinate hydrophilic gel matrix tablets were prepared by wet granulation tableting method. The amount of HPMC, HPMC viscosity, EC dosage, preparation method, tableting pressure, release medium were investigated. And the effect of rotational speed on the in vitro release of metoprolol succinate (MS) matrix tablets. The experimental results of this literature show that the release of MS matrix tablets in vitro accords with the Higuchi equation. The drug release mechanism is the combined effect of matrix dissolution and drug diffusion. The pH and rotation speed of the release medium have no significant effect on the release rate, but the amount of HPMC is The viscosity, the amount of retarder, the preparation method, and the tableting pressure have significant effects on the release rate. Therefore, the influencing factors are too many, and it is difficult to operate, and it is difficult to industrialize mass production.

Therefore, the development of a long-acting sustained-release tablet of metoprolol with ideal sustained release effect and simple preparation process and suitable for production and development has important application value. Summary of the invention

In order to overcome the deficiencies of the prior art, the present invention provides a metoprolol succinate double layer skeleton sustained release tablet having an auxiliary layer which can assist in adjusting the release rate. The novel skeleton sustained-release tablet technology of the invention successfully prepares a long-acting sustained-release preparation of metoprolol succinate by adding an auxiliary layer which assists in adjusting the release rate on the basis of the conventional matrix sheet. The release rate of metoprolol succinate sustained-release tablets surprisingly shows good linearity and is fully compliant with the USP30 standard. Compared to AstraZeneca's marketed products, its in vitro release behavior is very close, and preparation The process is simple and the production cost is low.

The present invention provides a double-layered skeleton sustained-release tablet containing metoprolol succinate, characterized in that the core has an inclusion A sustained release layer of metoprolol succinate and an auxiliary layer capable of regulating the release rate. The sustained release layer is composed of metoprolol succinate, skeleton sustained release material and other pharmaceutically acceptable excipients; the auxiliary layer is composed of a skeleton sustained release material and other pharmaceutically acceptable excipients. The type and amount of pharmaceutically acceptable excipients in the sustained release layer and the auxiliary layer can be selected according to the requirements of a general skeleton sustained release tablet, and the metoprolol succinate in the sustained release layer is R, S-metoprolol succinate. Or S-metoprolol succinate, preferably S-Metoprolol succinate.

In the above double-layer skeleton sustained-release tablet containing metoprolol succinate, the sustained release layer accounts for 51-80% by weight of the entire core, and the auxiliary layer accounts for 20-49% by weight of the entire core.

In the above bilayer skeleton sustained-release tablet containing metoprolol succinate, the skeleton sustained-release material may be selected from the group consisting of an insoluble skeleton sustained-release material, a wax skeleton slow-release material, a hydrophilic gel skeleton sustained-release material, and a mixed material skeleton. Sustained release material.

Commonly used insoluble skeleton sustained-release materials are ethyl cellulose, polyethylene, polypropylene, polysiloxane, and polyoxyethylene. In order to adjust the release rate, electrolytes (such as sodium chloride, potassium chloride or sodium sulfate), sugars (such as lactose, fructose, sucrose or mannitol) or hydrophilic gels (such as hydroxypropyl) may be added to the prescription. Methyl cellulose, sodium carboxymethyl cellulose or scutellaria gum, etc.). Commonly used waxy skeleton materials are beeswax, hydrogenated vegetable oil, synthetic wax, butyl stearate, stearic acid, carnauba wax, glyceryl stearate, propylene glycol monostearate and stearyl alcohol, etc. Commonly used backbone porogens for use at the same time are polyvinylpyrrolidone, polyethylene glycol 1500, 1400, a 600 and water soluble surfactants. The hydrophilic gel skeleton sustained-release material can be classified into four types of 1 cellulose derivatives (methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose). , hydroxymethyl cellulose and sodium carboxymethyl cellulose, etc. 2 non-cellulosic polysaccharides (such as glucose, chitin, chitosan and galactomannan) 3 natural rubber (pectin, sodium alginate, Mixtures such as potassium alginate, agar, horn, etc., locust bean gum, claw gum and gelatin, etc.) 4 vinyl polymer or acrylic polymer (such as polyvinyl alcohol and polyhydroxyethylene 934, etc.) The skeleton sustained-release material sheet is obtained by mixing the above two or more insoluble skeleton sustained-release materials, a wax skeleton slow-release material or a hydrophilic gel skeleton material with each other.

In the above bilayer skeleton sustained-release tablet containing metoprolol succinate, the other pharmaceutically acceptable excipients include a binder, a lubricant, a filler, and a porogen. The other auxiliary materials in the sustained release layer include a binder, a lubricant, and a filler; and the porogen may be optionally added as needed. Other pharmaceutical excipients in the auxiliary layer include binders, lubricants, fillers, porogens.

The filler may be selected from the group consisting of micronized silica gel, starch, lactose, pregelatinized starch, microcrystalline cellulose, calcium hydrogen phosphate, mannitol, starch lactose mixture, mannitol starch or a combination thereof; when the skeleton sustained release material is a hydrophilic gel In the case of a skeleton material, fine powder silica gel is preferred as a filler.

The binder may be selected from one or more of polyvinylpyrrolidone (also known as povidone, PVP), methylcellulose, hydroxypropylmethylcellulose; preferably an aqueous ethanol solution of PVP K30, most preferably 10 % PVP K30 85% ethanol solution, It can simultaneously act as a wetting agent.

The lubricant comprises one or more of magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, PEG, talc, preferably magnesium stearate.

The porogen comprises one or more of sucrose, sorbitol, mannitol, glucose, lactose, fructose, sodium chloride, potassium chloride, magnesium sulfate, potassium sulfate, sodium sulfate, preferably lactose.

In the metoprolol succinate skeleton sustained-release tablet of the present invention, the components of the sustained-release layer account for the weight percentage of the sustained-release layer:

Metoprolol succinate 4-25%

Skeletal sustained release material 40-75%

Other pharmaceutically acceptable excipients

The weight percentage of the auxiliary layer component of the auxiliary layer is - skeleton sustained release material 40-80%

Other pharmaceutically acceptable excipients.

As a preferred technical solution of the present invention, the skeleton sustained-release material is a mixture of hydroxypropylmethylcellulose and stearic acid of different molecular weights, wherein the sustained-release material of the sustained-release layer is preferably hydroxypropylmethylcellulose K4M. And a mixture of K15M and stearic acid, the skeleton sustained-release material of the auxiliary layer is preferably a mixture of hydroxypropyl methylcellulose K4M and K100 and stearic acid; the filler is a micro-silica gel, and at the same time, has a certain retarding effect; The lubricant is magnesium stearate; the binder is an aqueous alcohol solution of PVP K30, such as 10% PVP K30 85% aqueous ethanol solution, which simultaneously acts as a wetting agent; the porogen is lactose. These materials not only ensure the excellent effects of the present invention, but also are commonly used auxiliary materials, which are abundant in domestic supply, reasonable in price, stable in performance, reliable in quality, and suitable for industrialized mass production.

The preparation method of the metoprolol succinate skeleton sustained-release tablet of the invention comprises the following steps -

1) Preparation of sustained-release layer: Put metoprolol succinate and other components of the sustained-release layer (except lubricant) into a wet granulator, mix well, add a prescribed amount of binder, mix well, prepare Soft material, sifted, made into wet granules, dried, whole granules, added with a prescription amount of lubricant, mixed and hooked, and pressed together with the auxiliary layer granules;

2) Preparation of auxiliary layer: Put each component (except lubricant) into a wet granulator and mix it evenly, add a prescribed amount of binder, mix well, prepare soft material, sift, make wet granules, and dry , whole grain, adding a prescribed amount of lubricant, mixing evenly, and pressing together with the prepared sustained release layer particles into a double layer sheet, that is, obtained.

Optional steps -

3) Film coating: The pressed core is placed in a coating pan and coated with a coating liquid prepared with a common coating powder, and the coating weight gain is about 1 to 3%. The metoprolol succinate double-layer sustained-release tablet of the invention has the advantages of effectively overcoming the defects of the early release of the conventional slow-release tablet and the large residual at the end, and the sustained-release curve is close to the Aspen. The sustained-release curve of metoprolol succinate sustained-release tablets produced by Likang, and the sustained-release tablets of the present invention only require ordinary double-layered tablet technology, and the process only includes conventional The granulation, pressure double-layer sheet and film-coated garment have simpler process, lower production process control difficulty and lower cost, so it is more suitable for industrial large-scale production and can achieve greater economic benefits. detailed description:

The following examples are intended to illustrate the specific embodiments of the present invention, but do not limit the scope of the present invention in any way. Comparative Example 1 Determination of the release rate of commercially available metoprolol tartrate controlled release tablets

Manufacturer: Guangzhou Baiyunshan Tianxin Pharmaceutical Co., Ltd.

Specifications: 50mg

Batch number: 081101 (production date: 2008.11.19)

Determination of release: According to the Chinese National Drug Standard WS1-(X-017)-2005Z, the results are shown in Table 2 below: Table 2 Results of the release of metoprolol controlled release tablets of tartrate (GB-1) -2005Z method)

Refer to USP30 USP30 for the detection of metoprolol succinate sustained-release tablets (two methods, 50 rpm, release medium: pH 6.8 phosphate buffer 500 ml, HPLC: -280 nm, sampling time: 1, 4, 8, 20 h) The sampling time was changed and the measurement results are shown in Table 3.

Sampling time (h) USP30 limit (%) Release measurement result (%)

1 <25 19.2 4 20~40 42.7

8 40~60 62.1

20 >80 91.0

The results showed that the release data of commercially available metoprolol tartrate controlled release tablets met the requirements of the quality standard at 1, 5, 10, 20 hours of sampling time, but the sampling time was set to 1. 5, 10, 20 hours is very unreasonable. Refer to the USP30 USP30 standard for metoprolol sulphate sustained-release tablets. After the sampling time is changed to 1, 4, 8 and 20 hours, the release results show that 1- The 8-hour release rate is still faster than the release limit of the metoprolol succinate sustained-release tablet in USP30. That is, the release rate of metoprolol tartrate controlled release tablets from Guangzhou Tianxin Pharmaceutical Co., Ltd. is in line with China National Drug Standard WS1-(X-017)-2005Z, but it does not meet the USP30 standard. Comparative Example 2 AstraZeneca's release test results of metoprolol succinate sustained-release tablets

Manufacturer: AstraZeneca Pharmaceutical Co., Ltd.

Specifications: 47.5mg

Batch number: KB3861 (production date: 2008.2)

Release test: Take 6 samples of the same batch, according to USP30 USP30 Metoprolol succinate sustained release tablets, the results are shown in Table 4:

Table 4 Aspirin succinic acid metoprolol sustained release tablets release test results

The results showed that the release behavior of AstraZeneca's metoprolol succinate sustained release tablets was ideal, the release was reasonable in the early stage, and the residual in the final stage was small. Comparative Example 3 Release of S-Metoprolol Succinate Sustained Release Tablets from Emcure, India

Manufacturer: India Emcure

Specifications: 12.5 mg, 25 mg, 50 mg (based on S-metolaol tartrate, if S-Metoprolol amber The acid salts are 11.875, 23.75, 47.5 mg)

Batch number: 12.5mg: LAA07009 (production date: 2007.3), 25mg: LAB07018 (production date: 2007.8), 50mg: LAC07009 (production date: 2007.4)

Release test: Take 6 samples of the same batch, according to USP30 USP30 Metoprolol succinate sustained-release tablets. The results are shown in Table 5 below:

Table 5 India Emcure company S-Metoprolol succinate sustained release tablets release test results

The above results indicate that the pre-release (lh, 4h, 8h) of S-Metoprolol succinate sustained-release tablets of Emcnre Company of India is acceptable, but its release rate is significantly lower at 20h, and release of 25mg and 50mg for 20h. The degree is even lower than 80%, and the residue is obvious. Comparative Example 4 S-Metoprolol succinate monolayer sustained release tablet prepared by the inventors

Table 6 The results of prescription and release test of S-Metoprolol succinate monolayer sustained release tablets prepared by the present inventors

Preparation: (1) Metoprolol S-succinate, hydroxypropylmethylcellulose K4M, hydroxypropylmethylcellulose K15M or K100, and stearic acid respectively passed through a 60 mesh sieve;

(2) Weigh the prescribed amount of metoprolol S-succinate, hydroxypropylmethylcellulose Κ4Μ, hydroxypropylmethylcellulose K15M or Κ100, micronized silica gel, stearic acid, and mix well in a wet granulator ;

(3) Adding an appropriate amount of 10% PVP K30 in 85% ethanol solution to make soft materials;

(4) After 24 mesh sieve granulation, drying at 40 ° C, passing through a 24 mesh sieve;

(5) Adding a prescribed amount of magnesium stearate to be evenly mixed, that is, obtaining a sustained-release layer of particles.

(6) For pellets (DlOmm round stamping sheet.

Release test: Take 6 tablets of the same batch, according to the United States Pharmacopoeia USP30 Metoprolol succinate sustained-release tablets standard test results, S-Metoprolol succinic acid prepared by the traditional single-layer skeleton sustained-release tablet process The salt single-layer sustained-release tablets had a too fast release rate in the early stage, and the results of the release of 4h and 8h significantly exceeded the reasonable limit. Example 1 S-Metoprolol succinate double-layer skeleton sustained-release tablet with auxiliary layer

―, prescription

Core prescription -

Metoprolol S-succinate 11.875g

Hypromellose K4M 70g

Hypromellose K15M 50g

Micro-silica gel 50g

Stearic acid 30g

10% PVP K30 85% ethanol solution

3g

Auxiliary layer:

Hydroxymethyl cellulose K4M 30g

Micro-silica gel 30g

Stearic acid 15g

10% PVP K30 85% ethanol solution Magnesium stearate

Made into 1000 pieces

2, film coating solution prescription

Ordinary stomach-soluble coating powder (purchased from Wenzhou Xiaolun 10g

Coating Technology Co., Ltd.)

Water 100ml

Made into 100 ml

Second, the detailed preparation process

, S-succinic acid metoprolol core preparation process - the core is a two-layer film, one layer is a sustained release layer, and the other layer is an auxiliary layer. The preparation process is as follows - sustained release layer:

(1) Metoprolol S-succinate, hydroxypropylmethylcellulose K4M, hydroxypropylmethylcellulose K15M, stearic acid, respectively, passed through a 60 mesh sieve;

(2) Weighing the prescribed amount of metoprolol S-succinate, hydroxypropylmethylcellulose K4M, hydroxypropylmethylcellulose K15M, micronized silica gel, stearic acid, and uniformly mixed in a wet granulator;

(3) Add 10% PVP K30 in 85% ethanol solution, the amount of which can be made into a suitable soft material;

(5) Add a prescribed amount of magnesium stearate to mix evenly. That is, the sustained release layer particles are obtained.

Auxiliary layer -

(1) hydroxypropylmethylcellulose K4M, stearic acid respectively passed through a 60 mesh sieve;

(2) Weigh the prescribed amount of hydroxypropylmethylcellulose K4M, micronized silica gel, stearic acid, and mix well in a wet granulator;

(3) A soft material made of 10% PVP K30 in 85% ethanol, the amount of which can be made into a suitable soft material;

(5) Add a prescribed amount of magnesium stearate to mix evenly. That is, the auxiliary layer particles are obtained.

The two parts of the granules were punched into a double layer with a 10 mm circle; both layers were shallow concave.

2, film coating preparation process: Weigh the prescribed amount of ordinary stomach-soluble coating powder, add to the full amount of water, stir and hook, that is.

3. Film coating: The pressed core is placed in a coating pan for coating. The spray speed of the coating liquid is l~2ml/min, atomization pressure It is 0.7~0.9bar, the pot speed is 6~10rpm, the bed temperature is 32~35°C, and the inlet air temperature is 50~55°C. A small amount of tablets was weighed regularly to calculate the weight gain of the coating. When the weight gain of the tablet reaches about 1 to 3%, the coating is stopped.

Third, the release test: Take the same batch of 6 samples, according to the United States Pharmacopoeia USP30 Metoprolol succinate sustained release tablets standard release test results, the results are shown in Table 7 below:

Table 7 Results of release test of double-layered skeleton sustained-release tablets prepared according to the formulation and preparation process of Example 1

The experimental results show that the S-Metoprolol succinate double-layer skeleton sustained-release tablets prepared by the method and the preparation process have stable release between the same batch samples, and the release behavior of the sample is ideal, and the release in the early stage is reasonable. The residue is small and meets the USP30 standard. The cumulative release of each sampling time was more reasonable than that of Comparative Example 1, allowing the drug to remain in the body for a longer period of time. Compared with Comparative Example 2, it was close to the cumulative release of the atropicon succinate sustained release tablet at the same time, but the preparation process of this product was relatively simple compared to the slow release microcapsule technology. Compared with Comparative Example 3, the cumulative release was significantly better than that of the sustained release tablets of the same size of Indian Emcure. Compared with the S-Metoprolol succinate monolayer sustained-release tablet prepared by the present inventors, the drug has a smaller cumulative release rate in the early stage, thereby effectively prolonging the maintenance time of the effective concentration of the drug in the body. Example 2 S-Metoprolol succinate double-layer skeleton sustained-release tablets with auxiliary layer

First, the prescription

1. The prescriptions for the sustained release layer and the auxiliary layer are shown in the following table 8

2. The film coating solution is the same as the embodiment 1.

Second, the preparation process

Same as in Example 1, the difference is that the auxiliary layer of hydroxypropylmethylcellulose is K4M and / or 100.

Third, the release test: According to the United States Pharmacopoeia USP30 Metoprolol succinate sustained release tablets standard, the results are as follows: Table 8 The composition of the double-layer skeleton sustained-release tablet core described in Example 2 (1000 pieces, unit: g)

Table 9 Results of release test of double-layered skeleton sustained-release tablets prepared according to the formulation and preparation process described in Example 2

6 16.0 34.8 55.6 88.2

7 17.8 37.3 56.4 91.5 δ 16.3 35.2 54.7 88.9

9 15.1 33.5 52.6 90.3

10 16.0 36.4 56.8 94.9

11 16.5 33.0 53.8 90.2

12 14.7 32.5 54.7 92.9

13 16.9 35.2 56.5 89.0

14 18.1 38.2 56.8 94.7

15 14.7 32.9 53.6 89.3

16 14.2 32.7 50.5 82.9

17 12.1 31.0 49.7 84.6

18 14.0 33.8 54.5 90.4

19 12.5 30.7 53.0 88.2

20 13.0 31.3 51.1 87.6

21 14.9 32.5 53.8 86.0

22 15.1 33.8 52.5 87.2

23 17.2 34.8 54.9 89.3 The above test results show that the auxiliary layer of S-Metoprolol citrate double-layer skeleton sustained release tablets prepared by the prescription and process listed in Table 8 has a cumulative release of lh at 13.0. %-17.0%, cumulative release at 4h is 30.7%-38.2%

• The cumulative release at 8h is between 51.1% and 56.8%, and the cumulative release at 20h is between 83.6 and 92.9. It can be seen that S-Metoprolol of various specifications made by this method and process is used. The release behavior of the succinate double-layer skeleton sustained release tablets is ideal, the release in the early stage is reasonable, and the residual in the final stage is small, which is in accordance with the USP30 standard. The release behavior was significantly more reasonable than that of Comparative Example 1, Comparative Example 3, and Comparative Example 4, and was similar to that of the sustained release sheet of Comparative Example 2. Example 3 Metoprolol succinate double-layer skeleton sustained release tablets with auxiliary layer

First, the prescription

1. The prescriptions for the sustained release layer and the auxiliary layer are shown in the following table.

• 2, film coating solution prescription same as the example 1.

Second, the preparation process

The preparation process of the double-layer skeleton sustained-release tablet of the same embodiment 1 is that the hydroxypropylmethylcellulose of the core auxiliary room is K4M and 100. Third, the release test: according to the United States Pharmacopoeia USP30 Metoprolol succinate sustained-release tablets standard, the results are as follows Table 11: Table 10 Example 3 double-layer skeleton sustained release tablets core prescription composition (1000 tablets, Unit: g)

Table 11 Results of release test of double-layered skeleton sustained-release tablets prepared according to the prescription and preparation process described in Example 3

The metoprolol succinate described in this example is R, S-metoprolol succinate, and the lh sample release rate is Between 14.8% and 16.2%, the release rate of the sample was between 26.2% and 37.2% for 4 hours, and the release rate of the sample for 8 hours was 50.8°/. Between -58.2, the sample release rate is between 84.0-90.5 for 20h, and the sustained release effect is obvious. The above test results show that the R, S-Metoprolol succinate double-layer skeleton sustained-release tablets of various specifications prepared by the above-mentioned process and prescription have reasonable release in the early stage, and the residual residue is small at the end stage, and the release behavior is ideal, which conforms to the USP30 standard of the United States Pharmacopoeia. The results of the release test of the R, S-metoprolol succinate double-layer skeleton sustained-release tablet prepared by the present process and the prescription and the inventor's homemade metoprolol monolayer sustained-release tablet, Emcure of India Compared with the company's S-Metoprolol sustained-release tablets and the commercially available metoprolol tartrate sustained release tablets, the sustained release effect is obvious and the release behavior is more reasonable. The release behavior of metoprolol succinate sustained release tablets produced by AstraZeneca is similar, but the preparation process is simpler than the preparation process of sustained release microcapsules. Example 4 Stability Investigation

The stability of the prescriptions 8, 2, 23 (specifications 11.875mg, 23.75m _g , 47.7mg) in Example 2 was investigated. The specific results are as follows - I. Influencing factors test

1. Sample source: Metoprolol succinate double-layer skeleton sustained-release tablet with auxiliary layer prepared by the invention

Specifications: (1) 11.875mg (Example 2 Prescription 8)

(2) 23.75 mg (Example 2 Prescription 2)

(3) 47.7 mg (Example 2 prescription 23)

2. Investigation items: appearance traits, related substances, isomers, release degree, content, weight loss

Appearance traits: visual inspection

Relevant substances: According to high performance liquid chromatography (Chinese Pharmacopoeia 2005 edition two appendix V D).

Chromatographic conditions and system suitability test using octyl silicon germanium bonded silica as a filler; sodium dodecyl sulfate solution (take 1.3 g of sodium dodecyl sulfate, dissolved in 1000% of 0.1% phosphoric acid solution) - acetonitrile (60 : 40) For the mobile phase, the detection wavelength is 223 nm. The number of theoretical plates should be no less than 2000 according to the S-succinate peak of S-succinic acid.

Accurately weigh the appropriate amount of fine powder under the content determination (about 50 mg of metoprolol S-succinate), place it in a mortar, add a small amount of water to grind it, and transfer it to a 100 ml volumetric flask. Shake the main drug and dilute it to the mark with water. Shake well, centrifuge, remove the supernatant and filter. Take the filtrate as the test solution. Accurately measure lml, place in a 200ml volumetric flask, dilute to the mark with water. Control solution. Precisely measure the control solution 20μ1, inject it into the liquid chromatograph, adjust the sensitivity of the instrument so that the peak height of the main peak is 10~20% of the full scale; then accurately measure the solution and the pair 20 μl of each solution was injected into the liquid chromatograph, and the chromatogram was recorded to twice the retention time of the main peak. If the impurity peak is obtained in the chromatogram of the test solution, the blank impurity peak and the succinic acid peak are subtracted, and the maximum impurity peak area shall not be larger than the main peak area of the control solution (0.5%). The sum of the impurity peak areas shall not be greater than the main peak area of the control solution. Times (1.0%).

Isomers: Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2005 edition two appendix VD).

The chromatographic conditions and system suitability test were carried out using a chiral column (Chiral CD-PH) with a mobile phase of 0.025 mol/L sodium perchlorate-acetonitrile (70:30) at a detection wavelength of 223 nm. Accurately weigh the appropriate amount of metoprolol succinate, add the mobile phase to dissolve and dilute to make 0.2mg solution per 1ml, accurately measure 10μ1, inject into the liquid chromatograph, record the chromatogram, S-succinic acid The separation of the tolol peak from the metoprolol R-succinate should be in accordance with the regulations.

Accurately weigh the appropriate amount of fine powder (about equivalent to 20 mg of metoprolol S-succinate), place it in a 100 ml volumetric flask, add the mobile phase to dissolve and dilute to make 0.2 mg solution per ml, as a test. Product solution; precision measurement lml, placed in a 100ml volumetric flask, add mobile phase diluted to the scale, as a control solution; precision measurement of the control solution 10μ1, injected into the liquid chromatograph, adjust the sensitivity of the instrument so that the peak height of the main peak is 10 ~20%; Then accurately measure 10μ1 of the test solution and the control solution, respectively, and inject them into the liquid chromatograph, and record the chromatogram. The peak area of R-succinic acid metoprolol in the chromatogram of the test solution shall not exceed 1.5 times (1.5%) of the peak area of the main peak of the control solution.

Release:

Release method: According to USP30 USP30 Metoprolol Succinate Sustained Release Tablet Standard

Release limit: The release of each tablet at 1, 4, 8 and 20 hours should be less than 25% of the labeled amount,

20-40%, 40~60% and 80% or more, all should meet the requirements.

Determination of content:

According to high performance liquid chromatography (Chinese Pharmacopoeia 2005 edition two appendix VD).

Chromatographic conditions and system suitability test using octyl silane bonded silica as a filler, sodium dodecyl sulfate solution (take 1.3 g of sodium lauryl sulfate, add 0.1% phosphoric acid solution (W / V) 1000ml dissolved) One acetonitrile (60: 40) is the mobile phase, and the detection wavelength is 223 nm. The number of theoretical plates should be not less than 2000 according to the Metoprolol S-succinic acid.

Take 20 samples of this product, accurately weighed, finely ground, accurately weigh the appropriate amount of fine powder (about equivalent to 25 mg of metoprolol S-succinate), place it in a mortar, add a small amount of pH 6.8 phosphate buffer Grinding and dissolving, transfer to a 100ml volumetric flask in portions, add appropriate amount of pH 6.8 phosphate buffer solution, dissolve and dilute to the mark by ultrasonication, centrifuge, remove the supernatant, filter, and accurately measure 2ml of the filtrate, set 10ml volumetric flask Dilute to the mark with pH 6.8 phosphate buffer, accurately measure 20 ul, inject into the liquid chromatograph, record the chromatogram; take the appropriate amount of S-succinic acid metoprolol, the same method, according to the external standard Method, calculated by peak area, that is.

3. Test methods and results: Take this product and remove the packaging materials that are in direct contact with the drug, respectively, at a light intensity of 4500Lx, The samples were placed at 60 ° C and 40 ° C and relative humidity of 75% and 92.5%, and samples were taken on days 5 and 10, respectively. The results are shown in Tables 12-1, 12-2, and 12-3.

Table 12-1 Results of influencing factors of the double-layered skeleton sustained-release tablet of the present invention 1 (Specification: 11.875 mg, Example 2 Prescription 8)

Table 12-2 Investigation results of influencing factors of the double-layer skeleton sustained-release tablet of the present invention 2 (Specification: 23.75 mg, Example 2, Prescription 2)

(曰) (%) (%) lh 4h 8h 20h body (%)

(%)

White film coat

0 pieces, remove the coating 13.4 31.4 52.8 88.7 Not detected 102.9 -- Out

Rear white

White film coat Undetected Light 5 pieces, remove the coating 12.6 34.7 52.7 87.2 Not detected 103.1 -- Out

Rear white

White film coat

10 tablets, remove the coating 15.5 35.2 53.8 90.9 not detected 103.4 -- out

Rear white

White film coat

5 pieces, remove 3⁄4 clothing 12.3 33.4 53.2 89.4 Not detected 103.4

Out

White after 40 °C

White film coat

10 pieces, remove the coating 14.3 34.9 53.8 86.2 Not detected 102.3 -1.22

Rear white

White film coat

5 pieces, remove the coating 11.3 30.0 50.3 84.8 Not detected 103.0 -1.38

White after 60 °C

White film coat

10 tablets, remove the coating 9.7 27.1 46.7 81.9 not detected 103.8 -1.95

Rear white

White film coat

5 tablets, remove the coating 13.7 34.9 51.9 89.0 Not detected 103.7 1.21 Out

RH75% after white

White film coat

10 pieces, remove the coating 12.8 34.4 53.7 88.9 Not detected 102.6 2.27 t Out

Rear white

White film coat

5 pieces, remove the coating 13.5 33.6 55.3 88.1 not detected 102.2 3.86 out

RH92.5% after white

White film coat

10 pieces, remove the coating 13.4 34.2 54.6 87.8 Not detected 103.5 6.43 Out

Rear white

Table 12-3 Results of influencing factors of the double-layered skeleton sustained-release tablet of the present invention 3 (Specification: 47.5 mg, Example 2, Prescription 23) Time Release (%) Heterogeneous

Related substance content, weight loss, condition, trait

(曰) lh 4h 8h 20h (%) (%) (%)

(%)

White film coat undetected light 0 piece, remove coating 14.4 34.3 54.4 88.2 not detected 102.7 -- out

Rear white White film coat unchecked

5 pieces, remove the coating 15.5 34.6 55.2 86.9 Not detected 102.0 - Out

Rear white

White film coat

10 pieces, remove the coating 14.3 36.5 55.8 88.6 not detected 102.7 -- out

Rear white

White film coat

5 pieces, remove the coating 15.2 35.9 56.2 86.4 not detected 101.8 -0.79 out

White after 40 °C

White film coat

10 tablets, remove the coating 15.0 35.1 56.5 87.9 Not detected 103.2 -1.19 Out

Rear white

White film coat

5 pieces, remove the coating 11.2 29.0 49.1 83.6 not detected 103.4 -1.38

White after 60 °C

White film coat

10 tablets, remove the coating 10.5 28.2 47.0 81.0 not detected 102.9 -2.18 out

Rear white

White film coat

5 pieces, remove the coating 15.8 34.9 53.4 85.5 Not detected 103.5 2.05 Out

RH75% after white

White film coat

10 pieces, remove the coating 15.2 34.5 53.5 86.9 Not detected 102.0 3.03

Rear white

White film coat

5 pieces, remove the coating 13.9 34.6 55.1 87.4 Not detected 103.6 3.91 Out

RH92.5% after white

White film coat

10 pieces, remove the coating 15.4 36.2 56.4 86.1 Not detected 102.3 5.75 Out

Rear white

4. Conclusion: This product has been tested by influencing factors. The results show that the product has a slight weight loss under high temperature conditions, and has certain moisture absorption and weight gain under high humidity conditions; the release rate slightly decreases under 60 °C conditions, and other conditions There is no obvious change in the next indicators. The storage conditions of this product can be set as shading and sealed.

Second, accelerated test

1. Sample source: A metoprolol succinate double-layer skeleton sustained-release tablet having an auxiliary layer prepared by the present invention.

Specifications: (1) 11.875 mg (Three batches of samples prepared according to the prescription 2 of Example 2, numbered 1-1, 1-2, 1-3, respectively)

(2) 23.75 mg (three batches of samples prepared according to the prescription 8 of Example 2, numbered 2-1, 2-2, 2-3, respectively)

(3) 47.7 mg (three batches of samples prepared according to the prescription 23 of Example 2, numbered 3-1, 3-2, 3-3 respectively) 2. Investigation items and methods: The investigation items included appearance traits, related substances, and heterogeneity Body, release, content, investigation Method and method of influencing factors

3. Test methods and results

The three batches of this product were packaged in aluminum plastic and stored at 40 ° C / RH 75% for 6 months, and sampled at 1, 2, 3, 6 months. The results are shown in Tables 13-1, 13-2, and 13-3.

Table 13-1 Accelerated test results of the double-layered skeleton sustained-release tablet of the present invention 1 (Specification: 11.875 mg)

No. lh 4h 8h 20h (%) (%) (%)

0 white film coated tablets, remove the bag

13.4 31.4 52.8 88.7 Not detected Not detected 102.9 Appearance white after clothing

1 White film-coated tablets, remove the package 15.0 33.1 52.4 87.9 Not detected Not detected 103.4

, after the clothing is white

-1 2 White film-coated tablets, remove the package 14.4 33.0 52.6 87.7 Not detected Not detected 102.9 Appearance white after clothing

3 White film-coated tablets, remove the package 12.4 33.5 53.4 88.8 Not detected Not detected 103.7 Appearance white after clothing

6 White film-coated tablets, remove the package 15.0 35.3 53.9 87.9 Not detected Not detected 102.0 Appearance white after clothing

0 white film coated tablets, remove the bag

16.2 34.6 53.8 86.4 Not detected Not detected 103.2 Appearance white after clothing

1 White film-coated tablets, remove the bag 15.7 34.5 54.9 86.6 Not detected Not detected 102.3 Appearance white after clothing

-2 2 White film-coated tablets, remove the package 14.7 32.7 53.9 87.9 Not detected Not detected 103.9 Appearance white after clothing

3 White film-coated tablets, remove the bag 13.4 33.1 54.3 86.7 Not detected Not detected 103.2 Appearance white after clothing

6 White film-coated tablets, remove the package 13.7 34.2 53.0 85.9 Not detected Not detected 103.5 Appearance white after clothing

0 white film coated tablets, remove the bag

14.0 34.2 54.9 88.6 Not detected Not detected 103.4 Appearance white after clothing

1 White film-coated tablets, remove the package 14.8 33.8 53.4 85.6 Not detected Not detected 103.0 Appearance white after clothing

-3 2 White film-coated tablets, remove the bag 14.2 34.3 53.8 88.3 Not detected Not detected 103.2 Appearance white after clothing

3 White film-coated tablets, remove the package 14.7 35.7 54.1 86.5 Not detected Not detected 102.6 Appearance white after clothing

6 White film-coated tablets, remove bag 15.5 33.8 52.8 88.3 Undetected undetected 102.4 Appearance after white Table 13-3 Accelerated test results of double-layer skeleton sustained-release tablets of the present invention 3 (Specification: 47.5mg) Batch release (%) related substance isomer content time (month) trait

No. lh 4h 8h 20h (%) (%) (%) -1 0 White film-coated tablets, remove the bag

14.4 34.3 54.4 88.2 Not detected Not detected 102.7 Appearance white after clothing

1 White film-coated tablets, remove the bag 15.5 34.6 54.4 87.8 Not detected Not detected 102.2 Appearance white after clothing

2 White film-coated tablets, remove the package 13.0 35.1 53.0 86.4 Undetected undetected 102.8 Apparel white 3 white film-coated tablets, remove the bag 15.9 36.8 55.3 88.8 undetected undetected 102.8 after the clothing show white

6 White film-coated tablets, remove the bag 15.3 33.9 53.2 87.6 Not detected Not detected 103.3 Appearance white after clothing

0 white film coated tablets, remove the bag

14.9 33.8 52.9 87.3 Not detected Not detected 102.3 Appearance white after clothing

1 White film-coated tablets, remove the package 13.7 32.4 53.5 88.2 Not detected Not detected 103.7 Appearance white after clothing

3-2 2 White film-coated tablets, remove the bag 14.5 34.5 52.8 85.8 Not detected Not detected 103.0 Appearance white after clothing

3 White film-coated tablets, remove the package 14.7 35.3 54.4 88.0 Not detected Not detected 102.6 Appearance white after clothing

6 White film-coated tablets, remove the package 14.4 34.0 52.3 87.6 Not detected Not detected 103.8 Appearance white after clothing

0 white film coated tablets, remove the bag

15.1 34.5 55.8 84.9 Wo detection not detected 102.9 white after clothing

1 White film-coated tablets, remove the package 13.8 33.5 56.6 85.4 Not detected Not detected 103.7 Appearance white after clothing

3-1 2 White film-coated tablets, remove the bag 15.6 35.6 56.4 87.5 Not detected Not detected 103.3 Appearance white after clothing

3 White film-coated tablets, remove the bag 15.4 35.0 55.2 86.4 Not detected Not detected 103.3 Appearance white after clothing

6 White film-coated tablets, remove the bag 15.6 33.0 52.2 85.9 Not detected Not detected 103.7 Appearance white after clothing

The results show that: three batches of three samples of this product, all the indicators of the accelerated test are in compliance with the regulations. It is indicated that the metoprolol succinate sustained release tablet has good process reproducibility and sample stability.

Claims

Rights request

A double-layered skeleton sustained-release tablet containing metoprolol succinate, characterized in that the core is composed of a sustained-release layer containing metoprolol succinate and an auxiliary layer capable of assisting in regulating drug release rate. , the metoprolol succinate is

R, S-Metoprolol succinate or S-Metoprolol succinate.

The double-layered skeleton sustained-release tablet according to claim 1, wherein the metoprolol succinate is S-Metoprolol succinate.

The double-layered skeleton sustained-release tablet according to claim 1, wherein the sustained-release layer is composed of metoprolol succinate, a skeleton sustained-release material and other pharmaceutically acceptable auxiliary materials, and the auxiliary layer is composed of a skeleton sustained-release material and Other pharmaceutically acceptable excipients.

The double-layered skeleton sustained-release sheet according to claim 1, wherein the sustained release layer accounts for 51-80% by weight of the entire core, and the auxiliary layer accounts for 20-49% by weight of the entire core.

The double-layered skeleton sustained-release tablet according to claim 3, wherein the component of the sustained-release layer accounts for a weight percentage of the total weight of the sustained-release layer - metoprolol succinate 4-25%

Skeletal sustained release material 40-75%

Other pharmaceutically acceptable excipients.

6. The double-layered skeleton sustained-release tablet according to claim 3, wherein the weight percentage of the auxiliary layer component to the total weight of the auxiliary layer is - skeleton sustained-release material 40-80%

Other pharmaceutically acceptable excipients.

The double-layered skeleton sustained-release tablet according to any one of claims 3 to 6, wherein the skeleton sustained-release material is selected from the group consisting of an insoluble skeleton sustained-release material, a waxy skeleton sustained-release material, and a hydrophilic gel. The skeleton sustained-release material and the mixed material skeleton sustained-release material, wherein the mixed material skeleton sustained-release material is any combination of a hydrophilic gel skeleton sustained-release material, an insoluble skeleton sustained-release material, and a wax skeleton slow-release material.

The double-layered skeleton sustained-release sheet according to claim 7, wherein the skeleton sustained-release material is a mixed material skeleton sustained-release material.

The double-layered skeleton sustained-release sheet according to claim 8, wherein the insoluble skeleton sustained-release material or the waxy skeleton sustained-release material in the mixed material skeleton sustained-release material is stearic acid.

The double-layer skeleton sustained-release tablet according to claim 8, wherein the hydrophilic skeleton skeleton material in the mixed skeleton sustained-release material is selected from the group consisting of hydroxypropylcellulose and hydroxypropylmethylcellulose. One or two.

The double-layered skeleton sustained-release tablet according to claim 10, wherein the hydrophilic gel skeleton sustained-release material in the mixed skeleton sustained-release material is hydroxypropylmethylcellulose.

The double-layered skeleton sustained-release tablet according to claim 11, wherein the hydrophilic gel skeleton sustained-release material in the mixed skeleton sustained-release material is a mixture of hydroxypropylmethylcelluloses having different molecular weights.

The double-layered skeleton sustained-release tablet according to claim 12, wherein the hydrophilic gel skeleton sustained-release material in the mixed skeleton sustained-release material of the sustained-release layer is hydroxypropylmethylcellulose K4M and K15M The mixture, the hydrophilic gel skeleton sustained release material of the mixed skeleton sustained release material of the auxiliary layer is a mixture of hydroxypropyl methylcellulose K4M and K100.

The double-layered skeleton sustained-release tablet according to claim 3, wherein the other pharmaceutically acceptable excipients in the sustained-release layer comprise a binder, a lubricant, a filler, and other medicinal substances in the auxiliary layer. Excipients include binders, lubricants, fillers, porogens.

The double-layer skeleton sustained-release tablet according to claim 14, wherein the filler is micronized silica gel, the lubricant is magnesium stearate, and the binder is an aqueous ethanol solution of PVP K30. The porogen is lactose.

The method for preparing a double-layered skeleton sustained-release tablet according to any one of claims 1 to 15, comprising the following steps -

1) Preparation of sustained-release layer: Put the metoprolol succinate and other components of the sustained-release layer except the lubricant into a wet granulator and mix them evenly. Add the prescribed amount of binder and mix well. Sieve, made into wet granules, dried, added with a prescribed amount of lubricant, mixed evenly, and pressed together with the auxiliary layer granules;

2) Preparation of auxiliary layer: Put the components except the lubricant into the wet granulator and mix them evenly, add the prescribed amount of binder, mix well, sieve, make wet granules, dry, add prescription Lubricant, uniformly mixed, and pressed into a two-layer sheet together with the prepared sustained-release layer particles;

3) Optionally film coating.