KR100774774B1 - A sustained release preparation of metformin and manufacturing method thereof - Google Patents

Abstract

A sustained release preparation of metformin is provided to release water-soluble metformin slowly without initial burst by coating it with hydrophobic and hydrophilic glyceryl distearate, thereby continuously maintaining a certain level in blood for a long period of time and treating non-insulin dependent diabetes mellitus. A method for manufacturing a sustained release preparation of metformin comprises the steps of: heating and dissolving metformin or its pharmaceutically acceptable salt as a pharmaceutically active ingredient and glyceryl distearate as a sustained release reagent; cooling the dissolved solution and pulverizing the cooled product; and adding pharmaceutically acceptable additives into the pulverized product, wherein the amount of glyceryl distearate is 15-40 wt.% based on the total weight of the preparation; and the pharmaceutically acceptable salt is selected from hydrochloric acid salt, succinic acid salt, fumaric acid salt, methanesulfonic acid salt, benzenesulfonic acid salt and toluenesulfonic acid salt.

Description

A sustained release preparation of metformin and manufacturing method

1 is a dissolution rate analysis graph of a metformin sustained release preparation (Examples 1 to 4) and a control preparation according to the present invention.

Figure 2 is a dissolution rate analysis graph of the metformin sustained release preparation (Examples 4 to 6) and the control according to the present invention.

3 is a dissolution rate analysis graph immediately after 3 hours and 5 hours according to the amount of glyceryl distearate used according to the present invention.

The present invention relates to a sustained release preparation of metformin or a pharmaceutically acceptable salt thereof and a preparation method thereof.

Metformin is a big oral antihyperglycemic agent used to treat insulin-independent diabetes mellitus (type II, NIDDM).

Metformin increases sensitivity to insulin in peripheral tissues, inhibits the absorption of sugar in the gastrointestinal tract, and reduces blood sugar production in the liver. Metformin does not promote the secretion of insulin, reduces the amount of insulin in the blood, and also protects blood vessels. In addition, since it reduces fat in the body and does not cause hypoglycemia, it is a drug suitable for patients with obesity, hyperlipidemia or food control that is not ideal for blood sugar control.

Sixty percent of Type 2 diabetics who receive oral treatment must take pills several times a day to treat the condition. Controlled release formulations allow these patients to more easily control blood glucose following daily therapy.

Sustained release preparations of metformin conventionally used include those using a hydrophilic polymer to control release and those using release control according to osmotic pressure.

WO 99/47128 discloses a method for prolonging the gastrointestinal retention time for hydrophilic drugs using polymers such as ethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, and the like. 10-2004-0022527 is a sustained release of metformin using a hydrophilic polymer polyethylene oxide and natural gums, US Patent No. 3,952,741 is a semi-permeable membrane coating the core containing the active ingredient using an osmotic membrane generated inside the membrane Disclosed is a system for controlling the release of the active ingredient using the established pressure. In addition, PCT patent application IB2002 / 004647 seeks to control the release of metformin by using anionic polymers and nonionic polymers in combination with hydrophilic polymers.

In the case of using a hydrophilic polymer, since the release of the drug is set according to the molecular weight of the polymer used, it is very difficult to manage the excipient. In addition, the release control using osmosis requires high cost because the laser drilling equipment must be used in the production process. And management has a big disadvantage.

Therefore, the present inventors use a fatty acid ester derivative, precirol as a sustained release carrier, to control the release of metformin over a long period of time for 10 hours or more, to maintain a sustained effect, and to facilitate the preparation and storage of metformin. The present invention has been completed by establishing a manufacturing method.

The present invention seeks to provide a sustained release formulation of metformin and a method for preparing the same, which results in stable and sustained release.

The present invention provides a sustained release preparation of metformin and a method for preparing the same.

Pharmaceutically acceptable acids of metformin used in the present invention means salts selected from hydrochloride, succinate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate.

The sustained-release preparation of the present invention is a formulation containing glyceryl fatty acid ester as metformin and base. Glyceryl fatty acid esters used in the present invention control the release of the drug by coating a hydrophobic and highly hydrophilic active ingredient. As the glyceryl fatty acid ester used as the sustained release base of the present invention, glyceryl distearate was specifically used, and the trade name was Fresirol ATO5 (Precirol® ATO5, Gatteffose, France).

The sustained release formulation of the present invention contains a sustained release base at 10 to 40% of the total weight. If the amount of the sustained release agent is 10% or less, the amount of drug release is increased so that the effect of the sustained release is not exerted. If the content is more than 40%, the release of the drug is very low due to the increased action of the sustained release agent.

Ingredients additionally added to the sustained-release preparation of the present invention may include excipients, binders, glidants and the like as acceptable pharmaceutical additives for solid dosage forms for oral administration.

Excipients may be lactose, starch, cellulose, dextrin, microcrystalline cellulose, potassium dihydrogen phosphate, calcium carbonate, saccharides, etc. In addition, all commonly used in the pharmaceutical field for the formulation of oral solid preparations. Can be used.

The binder may be polyvinylpyrrolidone derivatives such as povidone, copovidone, methylcellulose, cellulose derivatives such as ethylcellulose, carboxymethylcellulose sodium, starch, gelatin, and the like, in addition to the formulation of oral solid preparations. Anything commonly used in the pharmaceutical field in chemistry can be used.

As the lubricant, magnesium salt of stearic acid, zinc salt, magnesium aluminum silicate, talc, and the like may be used. In addition, any of those generally used in the pharmaceutical field may be used in formulating oral solid preparations.

It is preferable that the formulation of the sustained release preparation of the present invention is a tablet or capsule.

The present invention also provides a method for producing the sustained release formulation.

The present invention provides a method for preparing a sustained-release preparation 1) mixing the metformin hydrochloride with glyceryl fatty acid esters to prepare a sustained-release mixture, 2) pulverizing the sustained-release mixture, 3) the crushed sustained-release mixture Is mixed with pharmaceutical additives to form a sustained release formulation.

In the first step, metformin and glyceryl distearate (trade name: Freshroll) are mixed and heated and melted before and after the melting point of the Freshroll. After melting, cool to room temperature.

In step 2), the sustained-release mixture cooled in step 1) is pulverized using a No. 30 sieve.

In step 3), the sustained-release mixture prepared in step 2) is usually added with the necessary additives according to the method for preparing tablets or capsules, and then general tablets, such as dry granulation, or direct blow or wet granulation, are used. Tablets and capsules are prepared according to conventional methods such as the preparation method or the conventional method for filling capsules.

Example

Preparation of sustained-release tablets of metformin

Example 1

The metformin sustained release preparation was prepared by the preparation method of the present invention.

The mixing ratio of each component is shown in Table 1.

Metformin hydrochloride and glyceryl distearate, which passed through No. 30, were mixed and placed in a high-speed granulator (FM-VG-05, Powrex corporation), and then maintained at a temperature of 56-60 ° C. under high speed stirring (agitator 200 rpm, chopper 1500rpm) to prepare a uniform mixture. The resulting mixture was cooled to room temperature for 5 hours, then sieved using a No. 30 sieve, and then mixed with cellulose as an excipient and a predetermined amount of copovidone as a binder for 5 minutes. Finally, magnesium stearate was added as a lubricant and mixed for 5 minutes. Then according to the general compressed tablet manufacturing method to prepare a tablet of the configuration of Table 1.

Example 2

The metformin sustained release preparation was prepared by the preparation method of the present invention.

The mixing ratio of each component is shown in Table 1, only the amount of glyceryl distearate used in Example 1 was changed and the rest of the production method was the same.

Example 3

The metformin sustained release preparation was prepared by the preparation method of the present invention.

The mixing ratio of each component is shown in Table 1, only the amount of glyceryl distearate used in Example 1 was changed and the rest of the production method was the same.

Example 4

The metformin sustained release preparation was prepared by the preparation method of the present invention.

The mixing ratio of each component is shown in Table 1, only the amount of glyceryl distearate used in Example 1 was changed and the rest of the production method was the same.

Example 5

The metformin sustained release preparation was prepared by the preparation method of the present invention.

The mixing ratio of each component is shown in Table 1, and in Example 4, only the microcrystalline cellulose was changed to the cell lactose used as the excipient, and the remaining manufacturing method was the same.

Example 6

The metformin sustained release preparation was prepared by the preparation method of the present invention.

The mixing ratio of each component is shown in Table 1, and in Example 5, magnesium stearate used as a lubricant was changed only to magnesium aluminum silicate, and the remaining manufacturing method was the same.

Table 1

Tablet Compositions of Examples 1-6

Test Example 1.

For the physical properties of the metformin sustained-release preparation of the present invention, the angle of repose, Hausner's ratio, hardness and friability were measured. The Hausner's ratio is calculated using the following equation.

The angle of repose was measured using a protractor, the cost was ABD powder characterization instrument (Tsutsui scientific instrument, Japan), and the hardness was C50 tablet hardness tester (HOLLAND, England) and the abrasion degree was FAT-10. A measuring instrument (Fine scientific lab, Korea) was used.

As a result, even if the content of glyceryl distearate increased, it did not significantly affect the tabletting properties and the physical properties of the tablets. However, as in the case of Example 6, it was found that the fluidity was greatly improved as a result of changing to magnesium aluminum silicate with a lubricant. The results are shown in Table 2.

Table 2.

Physical Properties Measurement Profiles of Examples 1-6

Test Example 2.

Confirmation of the dissolution rate of the metformin sustained release preparation of the present invention

The dissolution rate of the metformin sustained release preparation of the present invention was confirmed as follows.

The dissolution rate of the drug was measured by the following dissolution test method for the metformin sustained release tablets prepared in Examples 1 to 6. At this time, as a control agent, glucophage RXR (Merck Co., Ltd.) was used.

Test Method: Method 1 (Rotary Sampling Method) among the general test methods for dissolution of the Korean Pharmacopoeia

Dissolution Test Equipment: VK7020S (Varian Inc. USA)

Eluate: pH 6.8 Phosphate Buffer

Solvent Amount: 1000mL

Eluent temperature: 37 ± 0.5 ℃

Rotational Speed: 100 ± 5 rpm

Sampling time: 0.5 mL, 1, 3, 5 and 10 hours, 3.0 mL of the eluent was taken and filtered through a 0.45 μm membrane filter to make up the same amount of fresh eluate.

Analysis method: The dissolution rate was calculated by measuring the absorbance at 232 nm using an ultraviolet spectrometer using a sample solution filtered and metformin standard solution.

As a result, the elution rate was delayed as the amount of fresh roll increased (Fig. 1). It was found that glyceryl distearate melts and coats a certain portion of metformin, resulting in delayed elution due to the hydrophobicity of the fatty acid structure. In addition, in Examples 1, 2, 3, and 4, Examples 4, 5, and 6, in which excipients and lubricants were changed to improve tableting disorder, were released in a dissolution pattern similar to that of the control. The results are shown in FIG.

In addition, the decrease in quantitative elution with increasing the amount of glyceryl distearate was found, the results are shown in FIG.

Example 7

Metformin hydrochloride and glyceryl distearate, which passed through No. 30, were mixed and placed in a high-speed granulator (FM-VG-05, Powrex corporation), and then maintained at a temperature of 56-60 ° C. under high speed stirring (agitator 200 rpm, chopper 1500rpm) to prepare a uniform mixture. The resulting mixture was cooled to room temperature for 5 hours, then sieved using a No. 30 sieve, and then mixed with an excipient with a predetermined amount of cellulose for 5 minutes. Finally, magnesium stearate was added as a lubricant and mixed for 5 minutes. .

Thus prepared mixture is filled into gelatin light capsules to prepare capsules.

Examples 8-12

Purification of succinate, fumarate, methanesulfonate, benzenesulfonate and toluenesulfonate of metformin was prepared in the same manner as in Example 1.

Examples 13-17

Capsules of succinate, fumarate, methanesulfonate, benzenesulfonate and toluenesulfonate of metformin were prepared in the same manner as in Example 7.

Metoformin or its acid addition salt dissolves very well in water and has a disadvantage that it should be taken frequently because it does not last long.However, when mettoformin or its acid addition salt is coated with hydrophobic and high hydrophilic glyceryl distearate Maintaining it consistently solves the problem of taking it frequently.

Claims (6)

Metformin obtained by heating and melting glyceryl distearate as a pharmacologically active ingredient metformin or a pharmaceutically acceptable salt thereof and a sustained release base, followed by pulverizing and adding a pharmaceutically acceptable additive thereto. And sustained release preparations of the pharmaceutically acceptable salts thereof. The sustained-release preparation according to claim 1, wherein the pharmaceutically acceptable salt is a salt selected from hydrochloride, succinate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate. The sustained release preparation according to claim 1 or 2, wherein the glyceryl distearate is 15 to 40% by weight. Metformin and pharmaceutically acceptable salts thereof and glyceryl distearate as a sustained release base are melted by heating, cooled, ground and added to the pharmaceutically acceptable additives to form metformin and A method for producing a sustained release formulation of the pharmaceutically acceptable salt thereof. The method of claim 4, wherein the pharmaceutically acceptable salt is a salt selected from hydrochloride, succinate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate. The method according to claim 4 or 5, wherein the glyceryl distearate is 15 to 40% by weight.

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