CN111840242A - Metformin hydrochloride controlled release tablet and preparation method thereof - Google Patents

Abstract

The invention discloses a metformin hydrochloride controlled release tablet and a preparation method thereof, the metformin hydrochloride controlled release tablet comprises a tablet core, a coating aqueous dispersion forms a sustained release coating outside the tablet core, and the tablet core comprises the following raw materials in parts by weight: 80-120 parts of metformin hydrochloride, 10-14 parts of tablet core sustained-release material, 2-4 parts of filler and 0.2-1.2 parts of adhesive; the aqueous dispersion comprises the following raw materials in parts by weight: 2-6 parts of coating slow-release material, 1.2-1.6 parts of plasticizer, 1.2-1.6 parts of pore-forming agent, 0.4-0.8 part of anti-sticking agent and 0.1-0.5 part of emulsifier. The controlled release tablet provided by the invention adopts the aqueous dispersion coating, avoids the pollution of organic solvent to the environment and reduces the potential safety hazard. The invention adopts the dual controlled release technology of tablet core sustained release and film controlled coating, the release rate in 2 h is 10-35%, the release rate in 6 h is 40-70% and the release rate in 12 h is more than 80% in the in vitro release rate test, the release rate is constant, the invention is easy to swallow, and the compliance of patients is improved.

Description

Metformin hydrochloride controlled release tablet and preparation method thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a metformin hydrochloride controlled release tablet and a preparation method thereof.

Background

With the development of pharmaceutics, the treatment advantages of the oral sustained and controlled release preparation relative to the common quick release preparation are widely known, the sustained and controlled release preparation has longer release time and more stable drug release, and the fluctuation of the plasma drug concentration in vivo of a patient after the oral sustained and controlled release preparation is taken is very small, thereby reducing the taking times, improving the treatment effect and simultaneously reducing the occurrence of side effects. Therefore, in the development of pharmaceutical preparations, drugs for treating chronic diseases are increasingly designed into sustained-release dosage forms. Metformin hydrochloride has a short half-life, and a conventional preparation needs to be taken 2 or 3 times a day. Therefore, the metformin sustained-release preparation 1 time in 1 day has important significance for clinical treatment of diabetic patients, and has wide demand in related patients.

Currently, most of the metformin hydrochloride sustained-release preparations on the market are skeleton sustained-release mechanisms, and the patient compliance is poor. In order to reduce the tablet weight and improve the sustained-release compliance, osmotic pumps and membrane-controlled release tablets were developed. Most polymers used to develop coatings for controlled release dosage forms are hydrophobic. Since most of these polymers are poorly soluble in water, they are typically applied by dissolving the polymer in an organic solvent and then spraying onto the core and evaporating off the solvent. However, the use of organic solvents is considered problematic for a number of reasons. The most obvious reason is related to the safety hazards associated with the use of organic solvents. Typically, organic solvents are highly flammable and carcinogenic. In addition, organic solvents are expensive, and storage, disposal, and use of organic solvents easily cause environmental problems. The coating liquid prepared from the organic solvent has high viscosity, and sticking is easy to occur during coating. In addition, the coating solution prepared by the organic solvent has low concentration, long coating time and higher production cost.

The invention patent with the patent application number of CN201510416553.X discloses a metformin hydrochloride controlled release tablet and a preparation method and application thereof, wherein the controlled release tablet consists of a tablet core drug-containing layer, a tablet core boosting layer and a coating layer; wherein the medicine-containing layer of the tablet core consists of metformin hydrochloride, a sustained release agent, a bonding agent and a lubricant; the tablet core boosting layer is composed of hydroxypropyl methylcellulose, povidone K30, polyoxyethylene and lubricant; the coating layer consists of cellulose acetate, polyethylene glycol 400 and ethanol; the slow release agent is a montmorillonite compound modified by polyethylene glycol 4000. According to the invention, the montmorillonite compound prepared from the montmorillonite modified by polyethylene glycol 4000 is used as a slow release material, and the aim of slowly releasing metformin hydrochloride is achieved by innovative selection of auxiliary materials and optimized proportion of the auxiliary materials, but the metformin hydrochloride controlled release tablet prepared by the method is easy to stick when coated, the preparation method is complicated, and double slow release cannot be realized.

The patent application No. CN99806434.3 discloses a controlled release pharmaceutical tablet, comprising: (a) a core, comprising: anti-hyperglycemic agents; (ii) an optional binder; and (iii) a selective absorption enhancer; (b) a semipermeable membrane coating surrounding the core; and (c) at least one channel within the semipermeable membrane. The present invention provides a controlled or sustained release pharmaceutical tablet having only a homogeneous osmotic core, wherein the osmotic core component can be prepared by conventional tablet compression techniques, but the dissolution and release thereof are not uniform and there is a problem of burst release.

Disclosure of Invention

In order to overcome the problems in the prior art, the preparation process of the metformin hydrochloride controlled release tablet is optimized, aqueous dispersion coating is adopted, the pollution of organic solvent to the environment is avoided, the potential safety hazard is reduced, an anti-sticking agent is added into the coating aqueous dispersion, the tablet is not easy to stick during coating, a dual controlled release technology of tablet core sustained release and film control coating is adopted, the release rate in 2 hours in an in vitro release rate test is 10-35%, the release rate in 6 hours is 40-70% and the release rate in 12 hours is more than 80%, the tablet is small in weight and easy to swallow, and the compliance of a patient is improved.

The invention provides a metformin hydrochloride controlled release tablet, which comprises a tablet core, wherein a sustained release coating film is formed outside the tablet core by coating aqueous dispersion, the sustained release of the tablet core and the film control coating realize dual controlled release, and the aqueous dispersion comprises the following raw materials in parts by weight: 3-5 parts of coating slow-release material, 1.2-1.6 parts of plasticizer, 1.2-1.6 parts of pore-forming agent, 0.4-0.8 part of anti-sticking agent and 0.1-0.5 part of emulsifier.

Preferably, the tablet core comprises the following raw materials in parts by weight: 80-120 parts of metformin hydrochloride, 10-14 parts of tablet core sustained-release materials, 2-4 parts of filling agents and 0.2-1.2 parts of binding agents.

Preferably in any of the above schemes, the tablet core comprises the following raw materials in parts by weight: 90-110 parts of metformin hydrochloride, 10-14 parts of tablet core sustained-release material, 2-4 parts of filler and 0.2-1.2 parts of adhesive.

Preferably in any of the above schemes, the tablet core comprises the following raw materials in parts by weight: 80 parts of metformin hydrochloride, 10 parts of tablet core sustained-release materials, 2 parts of filling agents and 0.2 part of binding agents.

Preferably in any of the above schemes, the tablet core comprises the following raw materials in parts by weight: 100 parts of metformin hydrochloride, 10-14 parts of tablet core sustained-release materials, 2-4 parts of filling agents and 0.2-1.2 parts of binding agents.

Preferably in any of the above schemes, the tablet core comprises the following raw materials in parts by weight: 100 parts of metformin hydrochloride, 10 parts of tablet core sustained-release materials, 2 parts of filling agents and 0.2 part of binding agents.

Preferably in any of the above schemes, the tablet core comprises the following raw materials in parts by weight: 100 parts of metformin hydrochloride, 12 parts of tablet core sustained-release materials, 3 parts of filling agents and 0.8 part of binding agents.

Preferably in any of the above schemes, the tablet core comprises the following raw materials in parts by weight: 100 parts of metformin hydrochloride, 14 parts of tablet core sustained-release materials, 4 parts of filling agents and 1.2 parts of binding agents.

Preferably in any of the above schemes, the tablet core comprises the following raw materials in parts by weight: 120 parts of metformin hydrochloride, 14 parts of tablet core sustained-release materials, 4 parts of filling agents and 1.2 parts of binding agents.

Preferably, in any of the above embodiments, the aqueous dispersion comprises the following raw materials in parts by weight: 3 parts of coating slow-release material, 1.2 parts of plasticizer, 1.2 parts of pore-forming agent, 0.4 part of anti-sticking agent and 0.1 part of emulsifier.

Preferably, in any of the above embodiments, the aqueous dispersion comprises the following raw materials in parts by weight: 4 parts of coating slow-release material, 1.2-1.6 parts of plasticizer, 1.2-1.6 parts of pore-forming agent, 0.4-0.8 part of anti-sticking agent and 0.1-0.5 part of emulsifier.

Preferably, in any of the above embodiments, the aqueous dispersion comprises the following raw materials in parts by weight: 4 parts of coating slow-release material, 1.2 parts of plasticizer, 1.2 parts of pore-forming agent, 0.4 part of anti-sticking agent and 0.1 part of emulsifier.

Preferably, in any of the above embodiments, the aqueous dispersion comprises the following raw materials in parts by weight: 4 parts of coating slow-release material, 1.4 parts of plasticizer, 1.4 parts of pore-forming agent, 0.6 part of anti-sticking agent and 0.3 part of emulsifier.

Preferably, in any of the above embodiments, the aqueous dispersion comprises the following raw materials in parts by weight: 4 parts of coating slow-release material, 1.6 parts of plasticizer, 1.6 parts of pore-forming agent, 0.8 part of anti-sticking agent and 0.5 part of emulsifier.

Preferably, in any of the above embodiments, the aqueous dispersion comprises the following raw materials in parts by weight: 5 parts of coating slow-release material, 1.6 parts of plasticizer, 1.6 parts of pore-forming agent, 0.8 part of anti-sticking agent and 0.5 part of emulsifier.

Preferably, in any of the above schemes, the core sustained-release material is a mixture of octadecanol and polyoxyethylene, and the dosage ratio of octadecanol to polyoxyethylene is 2-4: 1.

Preferably, in any of the above schemes, the core sustained-release material is a mixture of octadecanol and polyethylene oxide, and the dosage ratio of octadecanol to polyethylene oxide is 2:1.

Preferably, in any of the above schemes, the core sustained-release material is a mixture of octadecanol and polyethylene oxide, and the dosage ratio of octadecanol to polyethylene oxide is 3:1.

In any of the above schemes, preferably, the core sustained release material is a mixture of octadecanol and polyethylene oxide, and the dosage ratio of octadecanol to polyethylene oxide is 4: 1.

Preferably in any of the above embodiments, the polyethylene oxide has a molecular weight of 40 to 90 ten thousand.

In any of the above schemes, preferably, the coating slow-release material is cellulose acetate, and the particle size of the cellulose acetate is 100-400 nm.

In any of the above embodiments, the cellulose acetate preferably has a particle size of 100 nm.

In any of the above embodiments, the cellulose acetate preferably has a particle size of 300 nm.

In any of the above embodiments, the cellulose acetate preferably has a particle size of 400 nm.

In any of the above embodiments, the coating aqueous dispersion preferably has a viscosity of 5 to 15 mPas.

In any of the above embodiments, the coating aqueous dispersion preferably has a viscosity of 5mPa · s.

In any of the above embodiments, the coating aqueous dispersion preferably has a viscosity of 10mPa · s.

In any of the above embodiments, the coating aqueous dispersion preferably has a viscosity of 15mPa · s.

In any of the above embodiments, preferably, the plasticizer is at least one of dibutyl phthalate and diethyl phthalate.

In any of the above embodiments, preferably, the pore-forming agent is at least one of polyethylene glycol 400 and polyethylene glycol 4000.

In any of the above embodiments, preferably, the antisticking agent is at least one of talc and glycerol monostearate.

Preferably, in any of the above embodiments, the emulsifier is sodium lauryl sulfate.

In any of the above schemes, preferably, the binder is a 3% -5% aqueous solution prepared from at least one of hydroxypropyl methylcellulose, povidone K30, and hydroxypropyl cellulose.

In any of the above embodiments, the filler is preferably at least one of starch, lactose, dextrin, microcrystalline cellulose, and pregelatinized starch.

The invention also provides a preparation method of the metformin hydrochloride controlled release tablet, which comprises the following steps:

step 1) crushing and sieving the metformin hydrochloride raw material, the filling agent and the slow-release material, adding an adhesive into the powder and sieve to prepare a soft material, and granulating;

step 2) drying and straightening the wet granules prepared in the step 1;

step 3), mixing uniformly and tabletting;

step 4) adding a coating slow-release material, a plasticizer, a pore-forming agent, an emulsifier and an anti-sticking agent into the purified water to prepare a coating aqueous dispersion, starting a high-speed shearing homogenizer, and shearing at a high speed to prepare a dispersion suspension;

and 5) putting the plain tablets into the dispersion suspension, preheating, adjusting parameters, and discharging after coating under the condition that the plain tablets are not bonded.

In any of the above schemes, preferably, the metformin hydrochloride raw material, the filling agent and the sustained-release material in the step (1) are crushed and sieved by a sieve of 80-100 meshes, the powder and the sieve are added into a wet-process granulator, and after the mixture is uniformly stirred at a low speed, the adhesive is added to prepare a soft material.

In any of the above schemes, the step (1) adopts a swing type granulator with 12 meshes for granulation, and the granulation frequency is 40-50 Hz.

In any of the above embodiments, in the step (2), the wet granules prepared in the step (1) are dried at 50 to 70 ℃, the moisture content is controlled to be 2.5 to 3.5 percent, and the granules are taken out of the swing granulator and sized with 16 meshes, and the sizing frequency is 30 to 40 Hz.

In any of the above embodiments, in the step (2), the wet granules prepared in the step (1) are dried at 50 ℃, the moisture content is controlled to be 2.5%, the granules are taken out from the rocking granulator by a 16-mesh sieve, and the granule-sizing frequency is 30 Hz.

In any of the above embodiments, in the step (2), the wet granules prepared in the step (1) are dried at 60 ℃, the moisture content is controlled to be 3%, and the granules are taken out from the rocking granulator with a 16-mesh size regulation and the granule regulation frequency is 35 Hz.

In any of the above embodiments, in the step (2), the wet granules prepared in the step (1) are dried at 70 ℃, the moisture content is controlled to be 3.5%, and the granules are taken out of the rocking granulator with a 16-mesh size and the granule finishing frequency is 40 Hz.

In any of the above schemes, preferably, the mixing and tabletting in the step (3) are uniform, the tabletting pressure is controlled to be 10-20KN during tabletting, the tabletting speed is 5-10 ten thousand tablets/h, the tablet weight range is +/-5%, and the friability is less than or equal to 1%.

In any of the above embodiments, preferably, in the step (4), the solid content of the coating aqueous dispersion is 15% to 20%, the rotation speed of the high-speed shearing homogenizer is about 20000rpm, and the high-speed shearing is performed for 0.5 to 1 hour to prepare the dispersion suspension.

In any of the above embodiments, it is preferable that the coating aqueous dispersion in the step (4) has a solid content of 15%.

In any of the above embodiments, preferably, the coating aqueous dispersion in the step (4) has a solid content of 18%.

In any of the above embodiments, preferably, the coating aqueous dispersion in the step (4) has a solid content of 20%.

In any of the above schemes, preferably, the preheating in the step (5) is performed for 3-5 minutes, and the adjusting parameters include the distance between the spray gun and the spray gun being 10-15cm, the rotation speed of the liquid feed pump being 20-40rpm, the rotation speed of the pot body being 3-10 rpm, the air inlet temperature being 40-60 ℃, the temperature of the control sheet being 35-45 ℃ and the atomization pressure being 0.25 MPa.

In any of the above schemes, preferably, the preheating in the step (5) is performed for 3 minutes, and the adjusting parameters include a spray gun distance of 10cm, a liquid feed pump rotation speed of 20rpm, a pot body rotation speed of 3rpm, an air inlet temperature of 40 ℃, a control sheet temperature of 35 ℃ and an atomization pressure of 0.25 MPa.

In any of the above schemes, preferably, the preheating in the step (5) is performed for 4 minutes, and the adjusting parameters include a spray gun distance of 12cm, a liquid feed pump rotation speed of 30rpm, a pot body rotation speed of 6rpm, an air inlet temperature of 50 ℃, a control sheet temperature of 40 ℃ and an atomization pressure of 0.25 MPa.

In any of the above schemes, preferably, the preheating in the step (5) is performed for 5 minutes, and the adjusting parameters include a spray gun distance of 15cm, a liquid feed pump rotating speed of 40rpm, a pot rotating speed of 10rpm, an air inlet temperature of 60 ℃, a control piece temperature of 45 ℃ and an atomization pressure of 0.25 MPa.

The invention also provides application of the metformin hydrochloride controlled release tablet in preparation of a medicament for treating diabetes.

Advantageous effects

The invention provides a metformin hydrochloride controlled release tablet and a preparation method thereof, the metformin hydrochloride controlled release tablet comprises a tablet core, and a sustained release coating film is formed outside the tablet core by coating aqueous dispersion, wherein the tablet core comprises the following raw materials in parts by weight: 80-120 parts of metformin hydrochloride, 10-14 parts of tablet core sustained-release material, 2-4 parts of filler and 0.2-1.2 parts of adhesive; the aqueous dispersion comprises the following raw materials in parts by weight: 2-6 parts of coating slow-release material, 1.2-1.6 parts of plasticizer, 1.2-1.6 parts of pore-forming agent, 0.4-0.8 part of anti-sticking agent and 0.1-0.5 part of emulsifier.

The invention mainly adopts a release system formed by combining tablet core slow release and film control coating, thereby achieving the effect of dual controlled release, wherein the release rate is 7-10% per hour, and the constant speed release is nearly 10 hours. The controlled release tablet of the invention has small fluctuation of blood concentration in vivo and low adverse reaction rate, and improves the tolerance of patients.

(1) The controlled release tablet provided by the invention adopts the aqueous dispersion coating, so that the pollution of an organic solvent to the environment is avoided, and the potential safety hazard is reduced;

(2) the invention has higher concentration of coating aqueous dispersion and low viscosity, can shorten the coating time during coating, saves the production cost and improves the production efficiency;

(3) the anti-sticking agent is added into the coating water dispersion, so that the tablet is not easy to stick during coating;

(4) the invention adopts the dual controlled release technology of tablet core slow release and film controlled coating, the 2 nd hour release rate is 10-35%, the 6 th hour release rate is 40-70% and the 12 th hour release rate is more than 80% in the in vitro release rate test, and the slow release is realized;

(5) the metformin hydrochloride controlled release tablet prepared by the invention has the specification of 500mg, is small in tablet weight of 580 mg-590 mg, is easy to swallow, and improves the compliance of patients.

Drawings

Fig. 1 is a graph showing the release profiles corresponding to the controlled-release metformin hydrochloride tablets prepared in examples 1 to 3.

Detailed Description

In order to better understand the technical solutions and advantages of the present invention, the present invention is further described below by way of specific embodiments.

Example 1: the weight parts of the components of the metformin hydrochloride controlled release tablet are shown in the table 1.

Table 1 weight part ratio of each component

The preparation method of the metformin hydrochloride controlled release tablet comprises the following steps:

(1) firstly, grinding the metformin hydrochloride raw material, lactose, octadecanol and polyoxyethylene and sieving the mixture by a 100-mesh sieve; adding the powder sieve into a wet granulating machine, uniformly stirring at low speed, adding 5% polyvidone K30 water solution, making into soft material, granulating with a swing granulator of 12 meshes, and granulating at a frequency of 40-50 Hz;

(2) drying the wet granules at 60 ℃, controlling the moisture to be 2.5-3.5%, taking out the granules of the swing type granulator with 16 meshes, and controlling the granule finishing frequency to be 30-40 Hz;

(3) mixing uniformly and tabletting, wherein the tabletting pressure is controlled to be 10-20KN during tabletting, the tabletting speed is controlled to be 5-10 ten thousand tablets/h, the tablet weight range is +/-5 percent, and the friability is less than or equal to 1 percent;

(4) preparing coating water dispersion with solid content of 20%, adding cellulose acetate with particle diameter of 200nm, dibutyl phthalate, polyethylene glycol 400, sodium dodecyl sulfate and pulvis Talci into purified water, starting high-speed shearing homogenizer (model FM200A) at rotation speed of 20000rpm, and high-speed shearing for 0.5-1h to obtain dispersed suspension with viscosity of 10 mPas.

(5) And (3) preheating the plain tablets prepared in the step (3) for 3-5 minutes, adjusting the distance between spray guns to be 10-15cm, controlling the rotation speed of a liquid feed pump to be 20-40rpm, the rotation speed of a pot body to be 3-10 rpm, the air inlet temperature to be 40-60 ℃, controlling the tablet temperature to be 35-45 ℃ and the atomization pressure to be 0.25MPa, and discharging after coating (increasing the weight by 2% -4%) is finished under the condition that the plain tablets are not bonded.

Example 2:

the weight part ratio of each component of the metformin hydrochloride controlled release tablet is shown in table 2.

Table 2 weight ratio of each component

The preparation method of the metformin hydrochloride controlled release tablet comprises the following steps:

(1) firstly, grinding a metformin hydrochloride raw material, pregelatinized starch, octadecanol and polyoxyethylene and sieving by a 80-mesh sieve; adding the powder sieve into a wet granulating machine, uniformly stirring at a low speed, adding 3% hydroxypropyl methylcellulose water solution to prepare a soft material, granulating by a swing granulator with 12 meshes, wherein the granulating frequency is 40-50 Hz;

(2) drying the wet granules at 60 ℃, controlling the moisture to be 2.5-3.5%, taking out the granules of the swing type granulator with 16 meshes, and controlling the granule finishing frequency to be 30-40 Hz;

(3) mixing uniformly and tabletting, wherein the tabletting pressure is controlled to be 10-20KN during tabletting, the tabletting speed is controlled to be 5-10 ten thousand tablets/h, the tablet weight range is +/-5 percent, and the friability is less than or equal to 1 percent;

(4) preparing coating water dispersion with solid content of 18%, adding cellulose acetate, dibutyl phthalate, polyethylene glycol 400, sodium lauryl sulfate and pulvis Talci into purified water, starting high-speed shearing homogenizer (model FM200A) at 20000rpm, and high-speed shearing for 0.5-1h to obtain dispersed suspension.

(5) Preheating the plain tablets for 3-5 minutes, adjusting the distance between spray guns to 10-15cm, controlling the rotation speed of a liquid feed pump to be 20-40rpm, the rotation speed of a pot body to be 3-10 rpm, the air inlet temperature to be 40-60 ℃, the tablet temperature to be 35-45 ℃ and the atomization pressure to be 0.25MPa, and discharging after coating (increasing the weight by 2% -4%) is finished under the condition that the plain tablets are not bonded.

Example 3:

the weight part ratio of each component of the metformin hydrochloride controlled release tablet is shown in table 3.

TABLE 3 weight ratio of each component

The preparation method of the metformin hydrochloride controlled release tablet comprises the following steps:

(1) the metformin hydrochloride, starch, octadecanol and polyoxyethylene are crushed, mixed and sieved by a 100-mesh sieve; preparing hydroxypropyl methylcellulose aqueous solution with the concentration of 5%, uniformly mixing powder and sieve substances, adding an adhesive to prepare a soft material, and granulating by a swing granulator with a mesh of 12, wherein the granulation frequency is 50 Hz;

(2) drying the wet granules at 60 ℃, controlling the moisture to be 1.5-4.0%, taking out the granules of the swing type granulator with 16 meshes, and controlling the granule finishing frequency to be 35 Hz;

(3) mixing uniformly and tabletting, wherein the tabletting pressure is controlled to be 10-20KN during tabletting, the tabletting speed is controlled to be 5-10 ten thousand tablets/h, the tablet weight range is +/-5 percent, and the friability is less than or equal to 1 percent;

(4) preparing coating water dispersion with solid content of 20%, adding cellulose acetate, dibutyl phthalate, polyethylene glycol 400, sodium dodecyl sulfate and pulvis Talci into purified water, starting high-speed shearing homogenizer (model FM200A) at rotation speed of 20000rpm, and high-speed shearing for 0.5-1h to obtain dispersed suspension;

(5) preheating the plain tablets for 3-5 minutes, adjusting the distance between spray guns to 10-15cm, controlling the rotation speed of a liquid feed pump to be 20-40rpm, the rotation speed of a pot body to be 3-10 rpm, the air inlet temperature to be 40-60 ℃, the tablet temperature to be 35-45 ℃ and the atomization pressure to be 0.25MPa, and discharging after coating (increasing the weight by 2% -4%) is finished under the condition that the plain tablets are not bonded.

The release profile was measured for the metformin hydrochloride controlled-release tablets prepared in examples 1 to 3 and the controlled-release pharmaceutical tablets of patent application No. CN99806434.3 described in the background section as comparative examples: according to a first method of standard operation procedures of a release degree inspection method, 1000ml of phosphate buffer solution with pH6.8 is used as a release medium, the rotation speed is 100 revolutions per minute, 5ml of the solution is respectively taken and filtered after 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours and 20 hours according to the method operation, and 5ml of the phosphate buffer solution with pH6.8 and the same temperature is immediately supplemented in a dissolution cup; accurately weighing 1ml of each of the subsequent filtrates, placing into a 100ml measuring flask, diluting with phosphate buffer solution with pH of 6.8 to scale, and shaking. The results are shown in Table 4.

TABLE 4 Release data for the examples

Since there was a fluctuation of. + -. 5% above and below the compressed tablets, a release of more than 100% was observed for 20 h.

Examples 1 to 3 correspond to release curves as shown in fig. 1, the present invention employs a dual controlled release technology of core sustained release and film controlled coating, in which the release degrees at 2 hours in an in vitro release test are 16.3%, 17.2%, 18.2%, 49.3%, 50.9%, and 51.8% respectively, and the release degrees at 12 hours are more than 80%, 85.9%, 87.5%, and 88.2% respectively, to achieve slow release, constant release, small fluctuation of blood concentration in vivo, low adverse reaction rate, and improved patient tolerance. The Fortamet comparative example is not uniform in release, and burst release occurs in 8-10 hours.

Example 4

A metformin hydrochloride controlled release tablet, similar to example 1, except that the tablet core comprises the following raw materials in parts by weight: 100 parts of metformin hydrochloride, 10 parts of tablet core sustained-release materials, 2 parts of filling agents and 0.2 part of binding agents.

Example 5

A metformin hydrochloride controlled release tablet, similar to example 1, except that the tablet core comprises the following raw materials in parts by weight: 100 parts of metformin hydrochloride, 13 parts of tablet core sustained-release materials, 3 parts of filling agents and 0.5 part of binding agents.

Example 6

A metformin hydrochloride controlled release tablet, similar to example 1, except that the tablet core comprises the following raw materials in parts by weight: 100 parts of metformin hydrochloride, 14 parts of tablet core sustained-release materials, 4 parts of filling agents and 1.2 parts of binding agents.

Example 7

Metformin hydrochloride controlled release tablets, similar to example 1, except that the core sustained release material is a mixture of stearyl alcohol and polyethylene oxide (molecular weight 90 ten thousand), and the dosage ratio of stearyl alcohol and polyethylene oxide is 3:1.

Example 8

A metformin hydrochloride controlled release tablet, similar to example 1, except that the tablet core comprises the following raw materials in parts by weight: the tablet core slow release material is a mixture of octadecanol and polyoxyethylene (with the molecular weight of 90 ten thousand), and the dosage ratio of the octadecanol to the polyoxyethylene is 2:1.

Example 9

A metformin hydrochloride controlled-release tablet, similar to example 1, except that polyethylene oxide has a molecular weight of 40 ten thousand.

Example 10

A metformin hydrochloride controlled-release tablet, similar to example 1, except that polyethylene oxide has a molecular weight of 60 ten thousand.

Example 11

A metformin hydrochloride controlled-release tablet, similar to example 1, except that polyethylene oxide has a molecular weight of 80 ten thousand.

Example 12

A metformin hydrochloride controlled-release tablet, similar to example 1, except that the cellulose acetate particle size was 100 nm.

Example 13

A metformin hydrochloride controlled-release tablet, similar to example 1, except that the cellulose acetate particle size was 300 nm.

Example 14

A metformin hydrochloride controlled-release tablet, similar to example 1, except that the cellulose acetate particle size was 400 nm.

Example 15

A metformin hydrochloride controlled-release tablet, similar to example 1, except that the aqueous coating dispersion comprises the following raw materials in parts by weight: 4 parts of coating slow-release material, 1.2-1.6 parts of plasticizer, 1.2-1.6 parts of pore-forming agent, 0.4-0.8 part of anti-sticking agent and 0.1-0.5 part of emulsifier.

Example 16

A metformin hydrochloride controlled-release tablet, similar to example 1, except that the aqueous coating dispersion comprises the following raw materials in parts by weight: 4 parts of coating slow-release material, 1.2 parts of plasticizer, 1.2 parts of pore-forming agent, 0.4 part of anti-sticking agent and 0.1 part of emulsifier.

Example 17

A metformin hydrochloride controlled-release tablet, similar to example 1, except that the aqueous coating dispersion comprises the following raw materials in parts by weight: 4 parts of coating slow-release material, 1.4 parts of plasticizer, 1.4 parts of pore-forming agent, 0.6 part of anti-sticking agent and 0.4 part of emulsifier.

Example 18

A metformin hydrochloride controlled-release tablet, similar to example 1, except that the aqueous coating dispersion comprises the following raw materials in parts by weight: 4 parts of coating slow-release material, 1.6 parts of plasticizer, 1.6 parts of pore-forming agent, 0.8 part of anti-sticking agent and 0.5 part of emulsifier.

Example 19

A metformin hydrochloride controlled-release tablet, similar to example 1, except that the aqueous coating dispersion comprises the following raw materials in parts by weight: the adhesive is hydroxypropyl methylcellulose or hydroxypropyl cellulose.

Example 20

A metformin hydrochloride controlled-release tablet, similar to example 1, except that the aqueous coating dispersion comprises the following raw materials in parts by weight: the filler is at least one of starch, lactose, dextrin, microcrystalline cellulose and pregelatinized starch

Example 21

Metformin hydrochloride controlled-release tablets, similar to example 1, except that the plasticizer was diethyl phthalate

Example 22

Metformin hydrochloride controlled-release tablets, similar to example 1, except that the pore-forming agent is polyethylene glycol 4000

Example 23

A controlled release metformin hydrochloride tablet, similar to example 1, except that the antiadherent is glyceryl monostearate.

It should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention, and not for limiting the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.

Claims (10)

1. The metformin hydrochloride controlled release tablet is characterized by comprising a tablet core, wherein a sustained release coating film is formed outside the tablet core by coating aqueous dispersion, and dual controlled release is realized by tablet core sustained release and film control coating, wherein the aqueous dispersion comprises the following raw materials in parts by weight: 3-5 parts of coating slow-release material, 1.2-1.6 parts of plasticizer, 1.2-1.6 parts of pore-forming agent, 0.4-0.8 part of anti-sticking agent and 0.1-0.5 part of emulsifier.

2. The controlled release metformin hydrochloride tablet according to claim 1, wherein said core comprises the following raw materials in parts by weight: 80-120 parts of metformin hydrochloride, 10-14 parts of tablet core sustained-release materials, 2-4 parts of filling agents and 0.2-1.2 parts of binding agents.

3. The metformin hydrochloride controlled-release tablet according to claim 2, wherein the core sustained-release material is a mixture of stearyl alcohol and polyethylene oxide, and the dosage ratio of stearyl alcohol to polyethylene oxide is 2-4: 1.

4. The controlled release metformin hydrochloride tablet according to claim 1, wherein said plasticizer is at least one of dibutyl phthalate and diethyl phthalate.

5. The controlled release metformin hydrochloride tablet according to claim 1, wherein said antisticking agent is at least one of talc and glyceryl monostearate.

6. The controlled release metformin hydrochloride tablet according to claim 1, wherein said emulsifier is sodium lauryl sulfate.

7. The controlled release metformin hydrochloride tablet according to claim 2, wherein said binder is a 3% to 5% aqueous solution prepared from at least one of hydroxypropylmethylcellulose, povidone K30, hydroxypropylcellulose.

8. The controlled release metformin hydrochloride tablet according to claim 1, wherein said filler is at least one selected from the group consisting of starch, lactose, dextrin, microcrystalline cellulose and pregelatinized starch.

9. The method for preparing a controlled release tablet of metformin hydrochloride according to any one of claims 1 to 8, comprising the steps of:

step 1) crushing and sieving the metformin hydrochloride raw material, the filling agent and the slow-release material, adding an adhesive into the powder and sieve to prepare a soft material, and granulating;

step 2) drying and straightening the wet granules prepared in the step 1;

step 3), mixing uniformly and tabletting;

step 4) adding a coating slow-release material, a plasticizer, a pore-forming agent, an emulsifier and an anti-sticking agent into the purified water to prepare a coating aqueous dispersion, starting a high-speed shearing homogenizer, and shearing at a high speed to prepare a dispersion suspension;

and 5) putting the plain tablets into the dispersion suspension, preheating, adjusting parameters, and discharging after coating under the condition that the plain tablets are not bonded.

10. Use of a metformin hydrochloride controlled-release tablet according to any one of claims 1 to 8 in the preparation of a medicament for the treatment of diabetes.

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