KR20130136718A - Sustained release and enteric metformin formulation and method for preparation thereof - Google Patents

Abstract

The present invention relates to a sustained release and enteric metformin formulation which contains the followings: (a) a core part formed of metformin or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable diluent; (b) a sustained release coating layer containing a sustained release agent and a pharmaceutically acceptable diluent and coated on the core unit; and (c) an enteric coating layer containing an enteric agent and a pharmaceutically acceptable diluent and coated on the sustained release coating layer. The present invention also relates to the production method of the sustained release and enteric metformin formulation. The formulation delays the discharging of medicines, sustains and releases the medicines in small intestines, minimizes side effects caused by regular formulations, and has improved intake convenience by having smaller size than conventional sustained release formulations. [Reference numerals] (AA) Accumulated burst rate(%);(BB) Time(minute);(CC) Example 1;(DD) Example 2;(EE) Example 3;(FF) Example 4;(GG) Example 5;(HH) Comparative example 1;(II) Comparative example 2;(JJ) Comparative example 3;(KK) Comparative example 4;(LL) Comparative example 5;(MM) Comparative example 6

Description

Metformin sustained-release enteric preparation and its preparation method {SUSTAINED RELEASE AND ENTERIC METFORMIN FORMULATION AND METHOD FOR PREPARATION THEREOF}

The present invention provides an essential ingredient comprising (a) metformin or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient; (b) a sustained release coating layer coated on the core and comprising a sustained release base and a pharmaceutically acceptable excipient; And (c) a metformin sustained-release enteric preparation coated on the sustained-release coating layer, the enteric coating layer comprising an enteric base and a pharmaceutically acceptable excipient, and a preparation method thereof.

Metformin is a biguanide-based drug used to treat non-insulin dependent diabetes mellitus (NIDDM) and is the drug of choice for many diabetics. to be. Although metformin is a relatively stable drug, it may cause gastrointestinal side effects such as diarrhea, nausea and vomiting, and some patients may stop taking it.

Glucose-regulating mechanisms of metformin work independently of insulin secretion and are known to activate glucose transporters in the liver, for example. Metformin induces weight loss in diabetic patients and shows a decrease in triglycerides and low density lipoproteins in blood and an increase in high density lipoproteins.

Currently, metformin is commercially available in tablet form as its hydrochloride. Commercial metformin tablets contain 250 mg, 500 mg, 850 mg and 1000 mg of metformin hydrochloride, the administration of which does not exceed the maximum required dose of 2550 mg per day in consideration of both efficacy and resistance. In addition, commercially available sustained-release tablets of metformin contain 500 mg and 1000 mg of metformin hydrochloride, with a typical initial dose of 500 mg of sustained-release tablets taken daily as dinner and up to 2000 mg once daily. Can be taken with dinner.

In addition, metoformin is known to be absorbed mainly in the upper intestine when only part of it is slowly absorbed from the gastrointestinal tract, and the blood half-life is known to be 2-6 hours. The solubility of the drug is very high, but the bioavailability on fasting is low, 50-60%.

Side effects associated with the use of metformin are loss of appetite, bloating, nausea and diarrhea in 20 to 30% of patients taking it, and it is advisable to stop taking it if diarrhea or severe bloating persists. Such side effects can be avoided in part by methods using sustained release formulations that can reduce the minimum and / or sustained dose or reduce the number of doses. However, in general, sustained-release tablets have a disadvantage in that the tablet size increases due to the amount of excipients larger than the general tablets, which may cause difficulty in swallowing of the elderly and pediatric patients, which may lead to low medication compliance.

Accordingly, the present inventors have metformin, which delays the release of the drug, slows down the drug in the small intestine, minimizes the side effects that occur in general tablets, and improves the compliance of the medications. The present invention has been completed by finding a sustained release enteric preparation.

Accordingly, it is an object of the present invention to provide a metformin sustained-release enteric preparation which can prevent the direct stimulation of the active ingredient on the stomach and has a low frequency of side effects compared to the general preparation.

Another object of the present invention is to provide a method for preparing the metformin sustained-release preparation.

The present invention to achieve the above object

(a) a core comprising as an active ingredient metformin or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient;

(b) a sustained release coating layer coated on the core and comprising a sustained release base and a pharmaceutically acceptable excipient; And

(c) to provide a sustained-release enteric formulation metformin, which is coated on the sustained-release coating layer, comprising an enteric coating layer comprising an enteric base and a pharmaceutically acceptable excipient.

The present invention to achieve the above object

1) preparing a metformin pellet or tablet comprising metformin or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient;

2) forming a sustained release coating layer by coating a coating material comprising a sustained release base and a pharmaceutically acceptable excipient on the surface of the metformin pellet or tablet; And

3) coating the enteric coating material comprising an enteric base and a pharmaceutically acceptable excipient on the surface of the sustained release coating layer to form an enteric coating layer, to provide a method for producing a sustained-release form metformin.

The metformin sustained-release enteric preparation according to the present invention delays the release of the drug, slows down the drug in the small intestine, minimizes the side effects that occur in general tablets, and at the same time increases the convenience of taking the medication to a smaller size compared to the conventional sustained-release tablets. Can be improved. In addition, unlike conventional tablets and sustained-release tablets, there is no gastrointestinal irritation, and there is an advantage in that the medication can be taken at a more convenient time.

1 is a graph showing the dissolution test results of the tablets prepared in Examples 1 to 5 and Comparative Examples 1 to 6 of the present invention.
Figure 2 is a graph showing the dissolution test results of the tablets prepared in Example 1, and Comparative Examples 1 and 7 to 9 of the present invention.
Figure 3 shows the rat stomach picture in the gastric stimulation test of the animal test.
4 is a graph showing the gastric stimulation test results of the animal test as the sum of the gastric internal injury length (Ulcer index).
Figure 5 compares the size of the tablets of Example 1, Comparative Examples 1 and 9 of the present invention.

The present invention provides an essential ingredient comprising (a) metformin or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient; (b) a sustained release coating layer coated on the core and comprising a sustained release base and a pharmaceutically acceptable excipient; And (c) an enteric coating layer coated on the sustained release coating layer, the enteric coating layer comprising an enteric base and a pharmaceutically acceptable excipient.

The components of the metformin sustained-release preparation are described below.

(a) core

The formulations of the present invention comprise a core comprising as an active ingredient metformin or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In the present invention, the core may be in the form of pellets or tablets, with the form of tablets being preferred.

The active ingredient is metformin, or a pharmaceutically acceptable salt thereof, for treating diabetes, and for example, pharmaceutically acceptable salts such as metformin hydrochloride, metformin succinate or metformin fumarate may be used. The active ingredient is preferably contained in 50 to 95% by weight, preferably 60 to 85% by weight based on the total weight of the formulation.

Pharmaceutically acceptable excipients included in the core may be selected from the group consisting of binders, diluents, glidants and mixtures thereof.

The binder may be selected from the group consisting of hydroxypropyl cellulose, povidone, hypromellose, and mixtures thereof. In addition, all binders are generally used in the pharmaceutical field in formulating oral solid preparations. Can be used. The binder may be contained in 1 to 50% by weight, preferably 3 to 7% by weight based on the total weight of the formulation.

The diluent may be selected from the group consisting of lactose, mannitol, microcrystalline cellulose, and mixtures thereof. In addition, any of those generally used in the pharmaceutical field may be used in formulating oral solid preparations. The diluent may be contained at 1 to 50% by weight, preferably 2 to 20% by weight, based on the total weight of the formulation.

The glidant may be selected from the group consisting of talc, magnesium stearate and mixtures thereof, and in addition, any of those generally used in the pharmaceutical field may be used in formulating oral solid preparations. Glidants may be contained in an amount of 0.1 to 5% by weight, preferably 0.2 to 2% by weight, based on the total weight of the formulation.

(b) sustained release coating layer

In the formulation of the present invention, the sustained release coating layer is coated between the core portion comprising the metformin or a pharmaceutically acceptable salt thereof and the enteric coating layer, ie on the core portion, before the enteric coating, and comprises a sustained release base and a pharmaceutically acceptable excipient. do. In the present invention, the sustained release coating layer serves to slowly release the drug, thereby reducing the side effects that may occur while the drug is rapidly released and the blood concentration in the body is rapidly increased.

The sustained release base may be selected from the group consisting of ethyl cellulose (EC), cellulose acetate (CA), polyvinyl acetate, and mixtures thereof, preferably a water-insoluble sustained release base Ethyl cellulose can be used. The sustained release base may be contained in an amount of 5 to 40% by weight, preferably 10 to 30% by weight, based on the total weight of the formulation.

The sustained release coating layer may use a plasticizer component as a pharmaceutically acceptable excipient. The plasticizer may be selected from the group consisting of triethyl citrate, diethyl phthalate, dibutyl phthalate, propylene glycol, polyethylene glycol, and mixtures thereof, based on the total weight of the formulation, 0.1 to 3% by weight, preferably 0.2 to It may be contained in 2% by weight.

In the sustained release coating layer, the coating solvent may be ethanol, acetone, ethanol aqueous solution, acetone aqueous solution or a mixed solvent of ethanol and acetone.

According to one embodiment of the invention, the sustained release coating layer is formed by coating a sustained release coating material comprising a sustained release base and a pharmaceutically acceptable excipient on the surface of a metformin tablet prepared by tableting the core prepared above. Can be. Specifically, the sustained release coating layer may be formed by spray coating a sustained release coating solution prepared by dissolving a sustained release base and a plasticizer in ethanol, acetone, an ethanol aqueous solution, an acetone aqueous solution, or a mixed solvent of ethanol and acetone on the surface of the metformin tablet. have.

(c) enteric coating layer

In the formulation of the present invention, the enteric coating layer is coated on the sustained release coating layer and includes an enteric base and a pharmaceutically acceptable excipient. In the present invention, the enteric coating layer is not dissolved in the stomach, enteric coating using an enteric base dissolved in the small intestine can also minimize the direct stimulation of the preparation for the stomach to minimize the side effects that can appear when taking a general tablet.

The enteric base may be selected from the group consisting of methacrylic acid copolymer, hypromellose phthalate (HPMCP), hypromellose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP) and mixtures thereof, wherein the total weight of the formulation is determined. 5 to 30% by weight, preferably 10 to 20% by weight may be contained.

In the enteric coating layer, a plasticizer may be used as a pharmaceutically acceptable excipient. The plasticizer may be selected from the group consisting of triethyl citrate, diethyl phthalate, dibutyl phthalate, propylene glycol, polyethylene glycol, and mixtures thereof, based on the total weight of the formulation, 0.1 to 3% by weight, preferably 0.2 to It may be contained in 2% by weight.

In the enteric coating layer, the coating solvent may be ethanol, acetone, ethanol aqueous solution, acetone aqueous solution or a mixed solvent of ethanol and acetone.

According to one embodiment of the present invention, an enteric coating solution prepared by dissolving an enteric base and a plasticizer in ethanol, acetone, an ethanol aqueous solution, an acetone aqueous solution, or a mixed solvent of ethanol and acetone is prepared on the surface of the metformin tablet having the sustained release coating layer. The enteric coating layer can be formed by spray coating.

In addition, the present invention comprises the steps of 1) preparing a metformin pellet or tablet comprising metformin or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient; 2) forming a sustained release coating layer by coating a coating material comprising a sustained release base and a pharmaceutically acceptable excipient on the surface of the metformin pellet or tablet; And 3) forming an enteric coating layer by coating an enteric coating material comprising an enteric base and a pharmaceutically acceptable excipient on the surface of the sustained release coating layer to form an enteric coating layer.

The metformin sustained-release enteric preparation according to the present invention includes an enteric coating layer in the form of a film or a film containing a sustained release coating for slowly releasing a drug, and an enteric base that does not melt in an acidic environment but dissolves in a neutral environment such as the small intestine. Surrounded by an enteric coating, the drug is passed through the stomach without releasing the drug, dissolving the enteric coating in the small intestine and slowly releasing the drug from the small intestine by the sustained release coating. Therefore, the formulation of the present invention can not only lower the release rate of the drug due to the sustained release coating, but also prevent diarrhea, nausea, vomiting, etc., which may occur when taking general tablets by blocking the direct stimulation of the preparation to the stomach due to the enteric coating. Gastrointestinal side effects can be minimized. It is also possible to provide tablets of smaller size as compared to sustained release tablets to improve medication compliance.

[Example]

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example  One

ingredient

    Core part (tablet)

Metformin Hydrochloride 500.0mg

Hydroxypropylcellulose 30.0mg

Colloidal silicon dioxide 2.0mg

Povidone 23.0mg

Magnesium Stearate 5.0mg

    Sustained release coating layer

Ethyl Cellulose 40.0mg

Hypromellose 12.0mg

Diethylphthalate 4.0mg

   Enteric coating layer

Hypromellose Phthalate (HP-50) 56.0 mg

5.6 mg triethyl citrate

Total 677.6 mg

A homogeneously mixed mixture of metformin hydrochloride and povidone was combined with isopropanol (75 mg / T) to prepare granules and dried in a fluid bed drier (GRECT-30, GR-ENG). The dried granules were passed through a 50 mesh sieve and hydroxypropyl cellulose and colloidal silicon dioxide were added thereto, followed by primary mixing for 60 minutes. Methyl stearate was added to the first mixed portion, followed by primary mixing for 5 minutes, followed by tableting to produce metformin tablets.

To prepare a sustained release coating solution, ethyl cellulose (Dow Chemical Co., Ltd.), hypromellose and diethyl phthalate were added to a mixed solution of ethanol and purified water (560 mg / T, 9: 1 (w / w)) and stirred until it became clear. It was. The sustained release coating solution thus prepared was sprayed onto a metformin tablet in a coating machine (SFC-60F, Sejong Pharmatech) and coated.

Subsequently, hypromellose phthalate (HP-50, Shinetsu) and triethyl citrate were added to a mixture of acetone and ethanol (620 mg / T, 2: 1 (w / w)) and stirred until it became clear. The enteric coating solution thus prepared was sprayed onto a metformin tablet coated with a sustained release coating layer in a coater to prepare a metformin sustained-release enteric preparation.

Example  2

ingredient

    Core part (tablet)

Metformin Hydrochloride 500.0mg

Hydroxypropylcellulose 30.0mg

Colloidal silicon dioxide 2.0mg

Povidone 23.0mg

Magnesium Stearate 5.0mg

    Sustained release coating layer

Ethyl Cellulose 40.0mg

Hypromellose 12.0mg

Diethylphthalate 4.0mg

    Enteric layer

Hypromellose Phthalate (HP-55) 56.0 mg

5.6 mg triethyl citrate

Total 677.6 mg

Metformin tablets were prepared in the same manner as in Example 1, using the above ingredients and contents.

Subsequently, ethylcellulose, hypromellose, and diethylphthalate were added to a mixed solution of ethanol and purified water (560 mg / T, 9: 1 (w / w)) and stirred until it was clear, thereby preparing a sustained release coating solution. The sustained release coating solution thus prepared was sprayed onto a metformin tablet in a coating machine (SFC-60F, Sejong Pharmatech) and coated.

Hypromellose phthalate (HP-55, Shinetsu) and triethyl citrate were added to a mixture of acetone and ethanol (620 mg / T, 2: 1 (w / w)) and stirred until it became clear. The enteric coating solution thus prepared was sprayed onto a metformin tablet coated with a sustained release coating layer in a coater to prepare a metformin sustained-release enteric preparation.

Example 3

ingredient

    Core part (tablet)

Metformin Hydrochloride 500.0mg

Hydroxypropylcellulose 30.0mg

Colloidal silicon dioxide 2.0mg

Povidone 23.0mg

Magnesium Stearate 5.0mg

    Sustained release coating layer

Ethyl Cellulose 40.0mg

Hypromellose 12.0mg

Diethylphthalate 4.0mg

    Enteric layer

Hypromellose Acetate Succinate 56.0mg

5.6 mg triethyl citrate

Total 677.6 mg

Metformin tablets were prepared in the same manner as in Example 1, using the above ingredients and contents.

Subsequently, ethylcellulose, hypromellose, and diethylphthalate were added to a mixed solution of ethanol and purified water (560 mg / T, 9: 1 (w / w)) and stirred until it was clear, thereby preparing a sustained release coating solution. The sustained release coating solution thus prepared was sprayed onto a metformin tablet in a coating machine (SFC-60F, Sejong Pharmatech) and coated.

Hypromellose acetate succinate and triethyl citrate were added to a mixture of acetone and ethanol (620 mg / T, 2: 1 (w / w)) and stirred until clear. The enteric coating solution thus prepared was sprayed onto a metformin tablet coated with a sustained release coating layer in a coater to prepare a metformin sustained-release enteric preparation.

Example 4

ingredient

    Core part (tablet)

Metformin Hydrochloride 500.0mg

Hydroxypropylcellulose 30.0mg

Colloidal silicon dioxide 2.0mg

Povidone 23.0mg

Magnesium Stearate 5.0mg

    Sustained release coating layer

Ethyl Cellulose 40.0mg

Hypromellose 12.0mg

Diethylphthalate 4.0mg

    Enteric layer

Cellulose acetate phthalate 56.0mg

5.6 mg triethyl citrate

Total 677.6 mg

Metformin tablets were prepared in the same manner as in Example 1, using the above ingredients and contents.

Subsequently, ethylcellulose, hypromellose, and diethylphthalate were added to a mixed solution of ethanol and purified water (560 mg / T, 9: 1 (w / w)) and stirred until it was clear, thereby preparing a sustained release coating solution. The sustained release coating solution thus prepared was sprayed onto a metformin tablet in a coating machine (SFC-60F, Sejong Pharmatech) and coated.

Cellulose acetate phthalate (Eastman) and triethyl citrate were added to a mixture of acetone and ethanol (620 mg / T, 2: 1 (w / w)) and stirred until it became clear. The enteric coating solution thus prepared was sprayed onto a metformin tablet coated with a sustained release coating layer in a coater to prepare a metformin sustained-release enteric preparation.

Example 5

ingredient

    Core part (tablet)

Metformin Hydrochloride 500.0mg

Hydroxypropylcellulose 30.0mg

Colloidal silicon dioxide 2.0mg

Povidone 23.0mg

Magnesium Stearate 5.0mg

    Sustained release coating layer

Ethyl Cellulose 40.0mg

Hypromellose 12.0mg

Diethylphthalate 4.0mg

    Enteric layer

Methacrylic acid copolymer dispersion (as a solid) 56.0 mg

5.6 mg triethyl citrate

Total 677.6 mg

Metformin tablets were prepared in the same manner as in Example 1, using the above ingredients and contents.

Subsequently, ethylcellulose, hypromellose, and diethylphthalate were added to a mixed solution of ethanol and purified water (560 mg / T, 9: 1 (w / w)) and stirred until it was clear, thereby preparing a sustained release coating solution. The sustained release coating solution thus prepared was sprayed onto a metformin tablet in a coating machine (SFC-60F, Sejong Pharmatech) and coated.

Triethyl citrate was added to a methacrylic acid copolymer dispersion (Evonik) and stirred. The enteric coating solution thus prepared was sprayed onto a metformin tablet coated with a sustained release coating layer in a coater to prepare a metformin sustained-release enteric preparation.

Comparative Example  One

ingredient

    Core part (tablet)

Metformin Hydrochloride 500.0mg

Hydroxypropylcellulose 30.0mg

Colloidal silicon dioxide 2.0mg

Povidone 23.0mg

Magnesium Stearate 5.0mg

Total 560.0 mg

Metformin tablets were prepared in the same manner as in Example 1, using the above ingredients and contents.

Comparative Example 2

ingredient

    Core part (tablet)

Metformin Hydrochloride 500.0mg

Hydroxypropylcellulose 30.0mg

Colloidal silicon dioxide 2.0mg

Povidone 23.0mg

Magnesium Stearate 5.0mg

    Enteric layer

Hypromellose Phthalate (HP-50) 56.0 mg

5.6 mg triethyl citrate

Total 631.6 mg

Metformin tablets were prepared in the same manner as in Example 1, using the above ingredients and contents.

Subsequently, hypromellose phthalate (HP-50) and triethyl citrate were added to a mixed solution of acetone and ethanol (620 mg / T, 2: 1 (w / w)) and stirred until it became clear. The enteric coating solution thus prepared was sprayed onto a metformin tablet in a coater and coated.

Comparative Example 3

ingredient

    Core part (tablet)

Metformin Hydrochloride 500.0mg

Hydroxypropylcellulose 30.0mg

Colloidal silicon dioxide 2.0mg

Povidone 23.0mg

Magnesium Stearate 5.0mg

    Enteric layer

Hypromellose Phthalate (HP-55) 56.0 mg

5.6 mg triethyl citrate

Total 631.6 mg

Metformin tablets were prepared in the same manner as in Example 1, using the above ingredients and contents.

Subsequently, hypromellose phthalate (HP-55) and triethyl citrate were added to a mixed solution of acetone and ethanol (620 mg / T, 2: 1 (w / w)) and stirred until it became clear. The enteric coating solution thus prepared was sprayed onto a metformin tablet in a coater and coated.

Comparative Example 4

ingredient

    Core part (tablet)

Metformin Hydrochloride 500.0mg

Hydroxypropylcellulose 30.0mg

Colloidal silicon dioxide 2.0mg

Povidone 23.0mg

Magnesium Stearate 5.0mg

    Enteric layer

Hypromellose Acetate Succinate 56.0mg

5.6 mg triethyl citrate

Total 631.6 mg

Metformin tablets were prepared in the same manner as in Example 1, using the above ingredients and contents.

Subsequently, hypromellose acetate succinate and triethyl citrate were added to a mixed solution of acetone and ethanol (620 mg / T, 2: 1 (w / w)) and stirred until it became clear. The enteric coating solution thus prepared was sprayed onto a metformin tablet in a coater and coated.

Comparative Example 5

ingredient

    Core part (tablet)

Metformin Hydrochloride 500.0mg

Hydroxypropylcellulose 30.0mg

Colloidal silicon dioxide 2.0mg

Povidone 23.0mg

Magnesium Stearate 5.0mg

    Enteric layer

Cellulose acetate phthalate 56.0mg

5.6 mg triethyl citrate

Total 631.6 mg

Metformin tablets were prepared in the same manner as in Example 1, using the above ingredients and contents.

Subsequently, cellulose acetate phthalate and triethyl citrate were added to a mixed solution of acetone and ethanol (620 mg / T, 2: 1 (w / w)) and stirred until it became clear. The enteric coating solution thus prepared was sprayed onto a metformin tablet in a coater and coated.

Comparative Example 6

ingredient

    Core part (tablet)

Metformin Hydrochloride 500.0mg

Hydroxypropylcellulose 30.0mg

Colloidal silicon dioxide 2.0mg

Povidone 23.0mg

Magnesium Stearate 5.0mg

    Enteric layer

Methacrylic acid copolymer dispersion (as a solid) 56.0 mg

5.6 mg triethyl citrate

Total 631.6 mg

Metformin tablets were prepared in the same manner as in Example 1, using the above ingredients and contents.

Then, triethyl citrate was added to the methacrylic acid copolymer dispersion and stirred. The enteric coating solution thus prepared was sprayed onto a metformin tablet in a coater and coated.

Comparative Example 7

ingredient

    Core part (tablet)

Metformin Hydrochloride 500.0mg

Hydroxypropylcellulose 30.0mg

Colloidal silicon dioxide 2.0mg

Povidone 23.0mg

Magnesium Stearate 5.0mg

    Sustained release coating layer

Ethyl Cellulose 45.0mg

Hypromellose 4.5mg

Diethylphthalate 4.5mg

    Enteric layer

Hypromellose Phthalate (HP-50) 56.0 mg

5.6 mg triethyl citrate

Total 675.6 mg

The metformin sustained-release enteric preparation was prepared in the same manner as in Example 1, except that the content of ethylcellulose, hypromellose, and diethylphthalate in the sustained release layer was used as the content described above.

Comparative Example 8

ingredient

    Core part (tablet)

Metformin Hydrochloride 500.0mg

Hydroxypropylcellulose 30.0mg

Colloidal silicon dioxide 2.0mg

Povidone 23.0mg

Magnesium Stearate 5.0mg

    Sustained release coating layer

Ethyl Cellulose 34.0mg

Hypromellose 17.0mg

Diethylphthalate 3.4mg

    Enteric layer

Hypromellose Phthalate (HP-50) 56.0 mg

5.6 mg triethyl citrate

Total 676.0 mg

The metformin sustained-release enteric preparation was prepared in the same manner as in Example 1, except that the content of ethylcellulose, hypromellose, and diethylphthalate in the sustained release layer was used as the content described above.

Comparative Example 9

ingredient

    Tablet-Granule Formation

Metformin Hydrochloride 500.0mg

Polyethylene Oxide 100.0mg

Povidone 20.0mg

    Tablet-Mix

Xanthan Gum 210.0mg

Locust Bean Gum 150.0mg

Colloidal Silicon Dioxide 10.0mg

Magnesium Stearate 10.0mg

Total 1000.0 mg

Metformin hydrochloride, polyethylene oxide and povidone were mixed in the amounts described above, then a mixture of purified water and isopropyl alcohol (400 mg / T, 1: 1 (w / w)) was added and combined and dried in a fluid bed dryer. The dried granules were passed through a 50 mesh sieve and xanthan gum, locust bean gum and colloidal silicon dioxide were added to the obtained granules and mixed firstly for 60 minutes. Subsequently, magnesium stearate was added, and further mixed for 5 minutes, followed by compression to prepare a sustained-release tablet for metformin.

Test Example 1: Dissolution Test

Using the tablets prepared in Examples 1 to 5 and Comparative Examples 1 to 6, the dissolution test was conducted under the following conditions in order to compare the effect of the sustained release base and the enteric base on the dissolution rate, respectively.

<Condition>

Dissolution test equipment: PHARMA TEST PTWS-1210 (Germany PHARMA TEST)

Eluate: Disintegration test method 2 (Principal factory solution)

Eluent Temperature: 37 ℃ ± 0.5 ℃

Eluent amount: 900 mL

Speed: 100 rpm

For elution test, sample of eluate was taken every 5, 10, 15, 30, 45, 60 and 90 minutes, filtered with 0.45μm membrane filter, and used as a sample solution. gave. The release amount was calculated as a cumulative release amount, and the results are shown in FIG. 1.

As shown in Figure 1, it was confirmed that the elution of the tablet consisting of the sustained release coating and enteric coating is delayed compared to the tablet consisting of only enteric coating.

Test Example 2: Dissolution Test

Dissolution test was carried out in the same manner as in Test Example 1 using the tablets prepared in Example 1 and Comparative Examples 7 to 9 and the results are shown in FIG. 2.

As shown in FIG. 2, it was found that the drug was delayed as the amount of water-insoluble sustained-release agent in the sustained-release coating increased. The sustained-release enteric preparation of the present invention was released more rapidly than the conventional sustained-release tablet formulation, but was found to be sustained release rather than the general tablet.

Test Example 3: Animal Test

Gastric irritation test was performed using the metformin hydrochloride (main ingredient), the formulations of Example 1 and Comparative Example 1 under the following conditions, the rat gastrointestinal photograph is shown in Figure 3, the sum of the gastric internal injury length (Ulcer index) 4 is shown in FIG. The uncontrolled rat was used as a control group, and was opened on the 7th day of fasting.

<Condition>

Test animal: Rat (Sprague-Dauri male rats (weight 280g, 8 weeks old))

Dosage: Three times a day, orally administered at a dose of 500 mg / kg per dose

Confirmation Method: Opening after 2, 4 and 7 days to confirm stomach irritation

As shown in Figures 3 and 4, the formulation of Example 1 did not show any internal damage to the stomach was confirmed that significantly lower gastric irritability.

Test Example  4: tablet size comparison

The size of the tablets of Example 1, Comparative Examples 1 and 9 prepared in the above Example was measured and the results are shown in Table 1 and FIG. 5. As shown in FIG. 5, the tablet of Example 1 was not significantly different from the tablet of Comparative Example 1, but was confirmed to be very small compared to the sustained release tablet of Comparative Example 9.

Comparative Example 1 Example 1 Comparative Example 9 Length - - 19.0 mm width 10.8 mm 11.1 mm 8.2 mm thickness 6.0 mm 6.8 mm 6.9 mm weight 560.0 mg 677.6 mg 1000.0 mg

As can be seen from the results of Test Examples 1 to 4, the sustained-release enteric preparation of the present invention uses a small amount of excipients compared to general sustained-release tablets (Comparative Example 9) to reduce the size of the tablets to improve the drug compliance In addition to improving, as well as showing excellent sustained release compared to the general tablets can also reduce the gastrointestinal side effects due to enteric coating has the advantage that pre-medication is possible.

Claims (14)

(a) a core comprising as an active ingredient metformin or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient;
(b) a sustained release coating layer coated on the core and comprising a sustained release base and a pharmaceutically acceptable excipient; And
(c) a metformin extended release enteric formulation coated on the sustained release coating layer, the enteric coating layer comprising an enteric base and a pharmaceutically acceptable excipient. The method of claim 1,
Metformin sustained-release enteric preparation, characterized in that the metformin or a pharmaceutically acceptable salt thereof is contained in 50 to 95% by weight based on the total weight of the formulation. The method of claim 1,
A pharmaceutically acceptable excipient at the core portion is characterized in that it is selected from the group consisting of binders, diluents, glidants and mixtures thereof. The method of claim 3, wherein
Metformin sustained-release enteric preparation, characterized in that the binder is selected from the group consisting of hydroxypropyl cellulose, povidone, hypromellose, and mixtures thereof. The method of claim 3, wherein
The metformin sustained-release enteric preparation, characterized in that the diluent is selected from the group consisting of lactose, mannitol, microcrystalline cellulose, and mixtures thereof. The method of claim 3, wherein
Metformin sustained-release enteric preparation, characterized in that the lubricant is selected from the group consisting of talc, magnesium stearate and mixtures thereof. The method of claim 1,
The sustained release base is selected from the group consisting of ethyl cellulose (EC), cellulose acetate (CA), polyvinylacetate, and mixtures thereof, metformin sustained-release enteric preparation. The method of claim 1,
Metformin sustained-release enteric preparation, characterized in that the sustained-release base is contained in 5 to 40% by weight based on the total weight of the formulation. The method of claim 1,
Metformin sustained release, characterized in that the enteric base is selected from the group consisting of methacrylic acid copolymer, hypromellose phthalate (HPMCP), hypromellose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP) and mixtures thereof Enteric preparations. The method of claim 1,
Metformin sustained-release enteric preparation, characterized in that the enteric base is contained in 5 to 30% by weight based on the total weight of the formulation. The method of claim 1,
A pharmaceutically acceptable excipient in the sustained release layer and the enteric coating layer is a plasticizer, metformin sustained-release enteric preparation. The method of claim 11,
Metformin sustained-release enteric preparation, characterized in that the plasticizer is selected from the group consisting of triethyl citrate, diethyl phthalate, dibutyl phthalate, propylene glycol, polyethylene glycol and mixtures thereof. The method of claim 1,
In the sustained release coating layer and enteric coating layer, the coating solvent is ethanol, acetone, ethanol aqueous solution, acetone aqueous solution or a mixed solvent of ethanol and acetone, metformin sustained-release enteric preparation. 1) preparing a metformin pellet or tablet comprising metformin or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient;
2) forming a sustained release coating layer by coating a coating material comprising a sustained release base and a pharmaceutically acceptable excipient on the surface of the metformin pellet or tablet; And
3) forming an enteric coating layer by coating an enteric coating material comprising an enteric base and a pharmaceutically acceptable excipient on the surface of the sustained release coating layer;
A method for preparing the metformin extended release enteric preparation according to claim 1.

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