KR20100041189A - Controlled release formulation for oral administration of metformin and method - Google Patents

Abstract

PURPOSE: A sustained release formulation for oral administration of metformin and a method for manufacturing the same are provided to control release rate of metformin and maintain uniform concentration of the matformin in blood. CONSTITUTION: A sustained release formulation for oral administration of metformin contains a metformin as an active ingredient or its pharmaceutically acceptable salt, 2-9 weight parts of hydrophobic polyvinyl acetate or ethylcellulose as a sustained release carrier, and 10-30 weight parts of polyethyleneoxide as a swelling polymer. The sustained release formulation additionally contains pharmaceutically acceptable additive of diluents, binder, disintegrating agent, or lubricating agent.

Description

Controlled release formulation for oral administration of metformin and method for oral administration of metformin

The present invention relates to a sustained release formulation for oral administration of metformin and a preparation method thereof.

Metformin, an insulin-independent diabetes treatment, is a drug that can control glucose production in the gastrointestinal tract, increase glucose utilization in muscles, lower blood sugar levels, improve lipid metabolism, and prevent and treat diabetes complications and exacerbations. Biguanide-based drugs. This metformin is very soluble in water, which can cause excessive blood sugar drop due to rapid release in the case of regular tablets, and can cause gastrointestinal disorders.

In addition, since a high dose of 500 to 850 mg fast-release tablets is usually taken 2-3 times a day at a maximum of 2550 mg per day, rapid changes in blood levels due to rapid release may cause side effects and resistance to the drug. Can be further deepened. Therefore, once-daily dosing is considered to be a preferred regimen not only for the convenience of patients but also for the therapeutic effect.

On the other hand, metformin has high water solubility, very poor permeability in the lower gastrointestinal tract, and most of the drug is absorbed in the upper gastrointestinal tract, so the narrow absorption window that is a characteristic of the drug should be considered when designing a sustained release formulation.

Conventional sustained-release preparations of metformin include International Patent Publication No. 98/055107, which discloses a matrix formulation consisting of a hydrophilic polymer which is expanded to a size that can prolong the residence time in the stomach after oral administration to control the release of the drug. However, such a formulation has a disadvantage in that food intake affects the residence time in the stomach, and according to the above state, if the formulation does not stay in the stomach and exits the pylorus, it may not show a delayed release effect. .

International Publication No. 99/047125 discloses a system using an osmotic membrane, in which a core containing an active ingredient is coated with a semipermeable membrane so that the active ingredient is released from the core after sufficient pressure is generated inside the membrane. However, in the case of the above technique, it can be seen that the technique does not consider the limited absorption window of metformin, and a precise process of evenly coating the semipermeable membrane for the controlled release over the tablet surface is essential, and it is difficult to ensure homogeneity of the coating membrane in this process. In addition to the disadvantages, there is a disadvantage that the drug may not be released until the proper osmotic pressure is reached.

In addition, WO 99/47128 discloses a two-phase sustained release system in which an inner solid particulate phase comprising a high water-soluble drug and a sustained release material is dispersed in a solid continuous phase. The patent shows a fast release to the formulation of a once daily regimen in which the release of the active ingredient in the formulation is almost complete within 8 hours.

International Patent Publication No. 2002/36100 discloses a method of manufacturing tablets by granulating using a top-spray fluidized bed granulator, performing a sustained release coating thereof, and then drilling using a laser to control the release of the drug. . However, the present invention requires expensive equipment such as laser drilling and skilled techniques that can make the position and size of the hole where the drug is discharged uniformly. none. In addition, osmotic pressure is a system suitable for drugs absorbed throughout the gastrointestinal tract, and thus can be considered a technology that does not consider the limited absorption window of metformin.

International Patent Publication No. 2003/028704 discloses a sustained release formulation in which the water content in the formulation is adjusted to 3.2 to 10 wt%. However, it is technically difficult to arbitrarily assign a certain level of moisture to the formulation, and the production time is limited due to the limitation of the equipment for the condition of the water, and the process time is required because the water exposure and drying must be repeated for the condition of the water. Over-exposure and drying may be a risk for drug stability.

In addition, Korean Patent Registration No. 772980 discloses a sustained-release preparation using a combination of polyethylene oxide and cheongum gum as a sustained release carrier, but increased viscosity due to hydration of the polymer in the step of granulating a polymer having a high viscosity through an aqueous solution It is difficult to work with furnaces, and once hydrated polymers cannot be expected to control as long as desired in the final product stage.

Korean Patent No. 791844 discloses a sustained-release tablet preparation prepared using hydroxypropylmethylcellulose, coated with the water-insoluble polymer, and then compressed using polyethylene oxide. In the case of the invention is represented by three stages of granulation step, granule coating step, tableting step, in the case of granule coating step, not only takes a very long process time, but also a skilled technique to uniformly coat the granules so as not to agglomerate with each other It is a difficult process that requires.

In addition, the sustained release formulations disclosed in International Publication No. 99/47128, Republic of Korea Patent No. 772980, and Republic of Korea Patent No. 791844 achieved uniform controlled release using techniques that are widely used in pharmacy. However, since the amount of sustained release carrier for controlled release is required at least 0.4 part by weight to 1 part by weight relative to 1 part by weight of metformin in proportion to the amount of metformin which is the active ingredient, It is already inconvenient to take the medication, and the compliance with the medication can be lowered.In the case of actual manufacturing, various pharmaceutical additives are added in consideration of productivity and the properties of the tablet, and the tablet becomes larger, which is inconvenient to take. have.

Therefore, developing a controlled release system that can control the release of drug components using minimal polymers is very important for the convenience and therapeutic purposes of patients who need to take excessive doses of drugs for a long time due to disease. .

Since metformin has a relatively high unit dose, the volume of tablets or capsules must be very large, and because of its high solubility, it is inevitable to use a relatively large amount of polymer. For this reason, even when oral sustained-release tablets are manufactured, the formulations are large enough to be difficult to take, and it is necessary to reduce the size of metformin sustained-release tablets for patient compliance.

However, if the amount of the sustained-release tablet is reduced by miniaturizing the sustained-release tablet of metformin having a high unit dose and high solubility, the sustained-release tablet may easily collapse and thus may not sufficiently exhibit a controlled release effect.

Therefore, the present inventors add a sustained release carrier in a small amount in order to make a dosage form that is difficult to take when a sufficient amount of sustained release carrier is used to exhibit a desired controlled release. As a result of the research efforts to improve the conflicting problem that the controlled release effect can be reduced, it is possible to commercialize the smallest possible formulation while being able to continuously control and release for 24 hours using the optimal amount of two or more sustained release carriers. The present invention has been completed by developing a sustained release formulation for oral metformin administration.

Accordingly, the present invention includes metformin or a pharmaceutically acceptable salt thereof, ethylcellulose or polyvinylacetate and polyethylene oxide having a certain viscosity or more as a sustained release carrier, and a pharmaceutically acceptable additive. It is an object of the present invention to provide a sustained release formulation for oral administration of metformin, which is small in convenience of taking.

The present invention provides a sustained-release preparation for oral administration of metformin or a pharmaceutically acceptable salt thereof, polyvinylacetate or ethylcellulose having a viscosity of 40 cps or more, and metformin containing polyethylene oxide as a swellable polymer as an active ingredient. It is characterized by.

Hereinafter, the present invention will be described in more detail.

The present invention is to prepare a sustained-release tablet using metformin, selected hydrophobic sustained-release carrier and swellable polymer to control the rate of drug release by blocking the water expansion caused by the hydration of the swellable polymer and the water penetration due to the hydrophobic polymer, effective Sustained-release formulation for oral administration of metformin, which is small in size but has a small size while effectively controlling the release rate of metformin even though a small amount of polymer is used compared to the amount of metformin or a salt thereof, It relates to a manufacturing method thereof.

The hydrophobic sustained release carriers referred to in the present invention, ethylcellulose and polyvinylacetate not only serve to form granules with metformin and salts thereof as main components, but also form a film in water after a certain time. That is, ethyl cellulose and polyvinylacetate show a constant release pattern regardless of pH, and play a role of enabling sustained release even after long time in water. Such ethylcellulose is an excipient that is widely used so often mentioned in the examples of the preceding invention. However, the present invention has focused on the need to be able to support more tightly and firmly between granules in order to enable sustained release even with a smaller amount. Accordingly, in the present invention, the ethylenic cellulose having a predetermined viscosity or more is selected according to the degree of substitution of the ethoxy group among the ethyl cellulose used as the hydrophobic sustained release carrier, thereby making the film formed in the water harder, thereby reducing the amount of the hydrophobic sustained release carrier. Even with the use of water, it was possible to effectively control the rate at which water-soluble substances such as metformin emerge. Polyvinylacetate (Colicoat SR30D, BASF, Germany), another hydrophobic sustained release carrier of the present invention, may be used in a suspended state in water, but may be used with other pharmaceutically acceptable substances to obtain a certain viscosity or more. It is desirable to.

Another sustained release carrier mentioned in the present invention, a swellable polymer compound, polyethylene oxide (Polyox, DOW Chemical, USA) is a material having the ability to form a hydrogel in contact with moisture. When taken in the stomach, the tablets are in contact with water and melt to prevent their size. This is to increase the absorption rate of metformin with a narrow absorption window by using the gastrointestinal digestion mechanism, which is smaller than the size of the pylori and is sent to the intestine through the stomach, and larger than the pylorus is reversed and stays in the stomach again. Polyethylene oxide forms a hydrogel in contact with moisture, which allows the tablet to remain in the stomach for a long time without passing through the pylorus. This prolonged release of the drug occurs in the stomach rather than the intestine, which is essential for the absorption of drugs with narrow absorption windows, such as metformin. The polyethylene oxide used in the present invention is preferably used that has a certain viscosity or more so that the matrix does not break for a certain time, and can expand. Moreover, you may mix and use 2 or more types of polyethylene oxide which have a different viscosity according to the design purpose of a formulation.

In addition, in the sustained-release preparation of the present invention, as an optional ingredient for further controlling the elution of the active ingredient, a sustained-release carrier may optionally be used to selectively add a polymer that plays an auxiliary role in order to more reliably exhibit the gel properties in vivo. Examples thereof include wax, polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, and the like.

Hereinafter, the components of the metformin sustained release preparation of the present invention will be described.

(1) Active Ingredient

The active ingredient of the sustained-release preparation according to the present invention is metformin or a pharmaceutically acceptable salt thereof as a therapeutic agent for diabetes, such as succinate, fumarate, malonate, glutarate, adipine, pimerate, male, in addition to hydrochloride. Pharmaceutically acceptable salts such as acid salts, malate salts, tartarate salts, acetate salts, nicotinate salts and the like may be used in the present invention, but the present invention is not limited thereto.

(2) hydrophobic sustained release carrier

(i) ethylcellulose

In the present invention, ethyl cellulose is used as the hydrophobic sustained release carrier. Of these, the cellulose may be used having an ethoxyl substitution rate of 49.5% or less, and more preferably at least 40 cps. Ethyl cellulose may be used in an amount of 2 to 9 parts by weight, more preferably 4 to 8 parts by weight, based on 100 parts by weight of the active ingredient.

(ii) polyvinylacetate

Another hydrophobic sustained release carrier, polyvinylacetate, can be used as a suspension in an aqueous solution diluted with other granulating materials. Representative is Kollicoat SR 30D (Kollicoat SR 30D, BASF, Germany), a mixture of polyvinylacetate, polyvinylpyrrolidone and sodium lauryl sulfate suspended in water, which contains 30% solids. have. In addition, all other types of materials containing at least 30% polyvinylacetate can be used as a source of polyvinylacetate. Polyvinylacetate may be used in an amount of 2 to 9 parts by weight, more preferably 4 to 8 parts by weight, based on 100 parts by weight of the active ingredient.

The hydrophobic sustained release carriers may be used alone or in combination, and vinylpyrrolidones such as polyvinylpyrrolidone and cellulose derivatives such as hydroxyethyl cellulose, hydride, which are pharmaceutically acceptable binders as necessary. It may be used together with oxymethyl cellulose.

(3) swellable polymer

(i) polyethylene oxide

Polyethylene oxide may be selected from those having an average molecular weight of 600,000 to 7,000,000 having an appropriate molecular weight according to the desired dissolution rate, it is more preferable to use an average molecular weight of 5,000,000 or more. In addition, two or more polyethylene oxides having different molecular weights may be mixed to adjust the dissolution rate. Polyethylene oxide may be used in 10 to 30 parts by weight with respect to 100 parts by weight of the active ingredient, more preferably 10 to 20 parts by weight.

(3) pharmaceutically acceptable additives

Ingredients additionally added to the sustained-release preparation of the present invention may include diluents, binders and glidants as pharmaceutical additives acceptable for oral solid preparations.

Starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth as pharmaceutically acceptable diluents within the range that does not impair the effects of the present invention in the sustained-release preparations other than the active ingredient and the sustained release carrier described above. One or more selected from metal salts, clays, polyethylene glycols, dicalcium phosphates, silicic anhydrides, and aluminum magnesium siliconic acid may be physically mixed, or a mixture obtained by dissolving and dispersing, followed by spray drying may be used. As the binder, vinylpyrrolidone, for example, polyvinylpyrrolidone and the like, cellulose derivatives such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, and the like, and natural gums such as xanthan gum Sugars such as alginate, gum arabic, for example, starch, pregelatinized starch, sucrose and the like can be used.

Starch or modified starch, such as sodium starch, corn starch, potato starch or pregelatinized starch, clays such as bentonite, montmorillonite, veegum, microcrystalline cellulose and hydroxypropyl cellulose as the disintegrating agent. Or celluloses such as carboxymethyl cellulose, alginates such as sodium alginate or alginic acid, cross-linked celluloses such as croscarmellose sodium, gums such as guar gum and xanthan gum, crospovidone, etc. Of crosslinked polymer and boiling agents such as sodium bicarbonate, citric acid and the like can be mixed and used. The glidants include talc, stearic acid, magnesium stearate and calcium stearate of alkaline earth metals, zinc stearate, lauryl sulfate, hydrogenated vegetable oils, sodium benzoate, sodium stearyl fumarate, glycerin fatty acid derivatives, glyceryl monostearate, glyceryl behe Nate and glyceryl palmitostearate, polyethylene glycol 4000, and the like, in addition to those that are commonly used as lubricants in the pharmaceutical field.

In addition, a pharmaceutically acceptable additive may be selected and used as various additives selected from colorants and fragrances.

The additives described above may contain a conventional range of doses as selected by those skilled in the art.

The formulation may form a film-like coating layer on the outer surface of the tablet, if necessary.

The method of forming the coating layer may be appropriately selected by a person skilled in the art from the method of forming a film-like coating layer on the surface of the tablet layer using the above-described components, and may be applied to methods such as a fluidized bed coating method and a fan coating method. Can be. It is preferable to use a pan coating method.

The coating layer may be a coating agent, a coating aid or a mixture thereof. Specifically, the coating layer may be used as a coating agent, cellulose derivatives, sugar derivatives, polyvinyl derivatives, waxes, fats and gelatin, and polyethylene glycol as coating aids. Or a mixture of one or more selected from ethyl cellulose, glycerides, titanium oxide, diethyl phthalate and the like can be used.

In the present invention, the sustained-release preparation obtained by the above production method may use 20 to 40 parts by weight of the additives other than metformin or a salt thereof, based on 100 parts by weight of metformin or salts thereof. This is due to the total weight of the tablets, given that the weight of sustained-release tablets containing 500 mg of glucophage XR tablets (Glucophage XR tablet, metformin hydrochloride, 500 mg, BMS) is currently close to or greater than 1 g. It has a big advantage in size.

The present invention can be formulated in a simple manner so as to be suitable for production on a commercial scale, and by using two or more kinds of polymers in an optimal ratio, a metformin sustained-release tablet capable of sufficiently controlled controlled release of the drug even with a small amount of sustained-release carrier It provides a technique for manufacturing. These small size metformin sustained-release tablets provide an improved metformin sustained-release tablet that is easy to take due to a decrease in volume and can be released slowly in the body to maintain a constant blood level for 24 hours with metformin once daily. Can be.

Hereinafter, the present invention will be described in detail with reference to Examples. However, these examples are illustrative of the present invention, and the contents of the present invention are not limited to the following examples.

Preparation Example 1 Preparation of Metformin Acetate (1: 1)

Metformin hydrochloride and sodium hydroxide in a ratio of 1: 1 equivalent ratio in methanol for 2 hours at room temperature, the resulting inorganic salt was filtered and the filtrate was concentrated under reduced pressure. Acetone was added to the resulting solids, and the insolubles were filtered off. The filtrate was concentrated under reduced pressure to obtain a metformin free base. After the metformin free base was dissolved in acetone, glacial acetic acid was added and stirred at room temperature. The resulting crystals were filtered off, washed with acetone and hot-air dried at 70 ° C. to obtain metformin acetate. The metformin acetate thus prepared is used to prepare the metformin extended release formulation.

Preparation Example 2 Preparation of Metformin Nicotinate

The metformin free base obtained in Preparation Example 1 was used.

Metformin free base and nicotinic acid in a 1: 1 equivalent ratio were warmed in methanol anhydrous to completely dissolve, and the solvents were dried in a reduced pressure evaporator. The resulting crystals were triturated, acetone was added and stirred overnight. The resulting crystals were filtered off and washed with acetone. The resulting crystals were filtered and hot-air dried to obtain metformin nicotinate. Metformin nicotinate thus prepared is used to prepare metformin sustained release formulations.

Preparation Example 3 Preparation of Metformin Malonate (2: 1)

The metformin free base obtained in Preparation Example 1 was used.

Metformin free base and malonic acid were dissolved in methanol in an equivalent ratio of 1: 1, and completely dissolved. The solvents were dried by a vacuum evaporator. The resulting crystals were triturated, acetone was added and stirred overnight. The resulting crystals were filtered off and washed with acetone. The resulting crystals were filtered and hot-air dried to obtain metformin malonate. Metformin malonate thus prepared is used to prepare a metformin sustained release formulation.

Preparation Example 4 Preparation of Metformin Maleate (2: 1)

The metformin free base obtained in Preparation Example 1 was used.

Metformin free base and malic acid were dissolved in acetone in a 4: 1 equivalent ratio to complete dissolution, and the solvents were dried by a vacuum evaporator. The resulting crystals were triturated, acetone was added and stirred overnight. The resulting crystals were filtered off and washed with acetone. The resulting crystals were filtered and hot-air dried to obtain metformin malate. Metformin maleate thus prepared is used to prepare the metformin sustained release formulation.

Preparation Example 5 Preparation of Metformin Adipinate (2: 1)

The metformin free base obtained in Preparation Example 1 was used.

Metformin free base and adipic acid were heated in acetone in a 4: 1 equivalent ratio to complete dissolution, and the solvents were dried by a vacuum evaporator. The resulting crystals were triturated, acetone was added and stirred overnight. The resulting crystals were filtered off and washed with acetone. The resulting crystals were filtered and hot air dried to obtain metformin adipic acid salt. The metformin adipic acid salt thus prepared is used to prepare the metformin sustained release formulation.

Preparation Example 6 Preparation of Metformin Glutarate (2: 1)

The metformin free base obtained in Preparation Example 1 was used.

Metformin free base and glutaric acid were heated to acetone in a 4: 1 equivalent ratio to complete dissolution, and the solvents were dried by evaporation under reduced pressure. The resulting crystals were triturated, acetone was added and stirred overnight. The resulting crystals were filtered off and washed with acetone. The resulting crystals were filtered and hot-air dried to obtain metformin glutarate. Metformin glutarate thus prepared is used to prepare a metformin sustained release preparation.

Example 1

500 g of metformin hydrochloride and 20 g of aluminum magnesium silicon acid (Neusilin UFL2, Fuji) were sieved through a No. 35 sieve and then mixed with a high speed mixer and mixed for 10 minutes. Separately, 25 g of ethyl cellulose (Ethylcellulose Type N-100, Aqualon) was dissolved in 200 g of 95% ethanol to prepare a binding solution, and the binding solution was slowly added to a high speed mixer to produce granules (mixer 100 rpm, chopper 1000 rpm). . The resulting granules were dried in a 60 ° C. hot water dryer, sieved through a No. 20 sieve, and granulated. The granules were mixed with 99 g of polyethylene oxide (Polyox WSR aggregate, Dow Chemical) and mixed for 30 minutes. Finally, 6 g of magnesium stearate was added thereto, mixed for 3 minutes, and tableted to contain 500 mg of hydrochloride metformin in 655 mg per tablet.

Example 2

Metformin sustained-release tablets were prepared according to Example 1, except that metformin acetate prepared in Preparation Example 1 was used instead of metformin hydrochloride. However, the amount of metformin acetate added in one tablet was calculated to have the same amount (571 mg) as metformin hydrochloride 500 mg and metformin, and the amount of the added additive was converted into the amount of Example 1 by weight parts of metformin hydrochloride in 1 part by weight. When calculated, it was calculated to have the same parts by weight based on 1 part by weight of metformin acetate.

Example 3

500 g of hydrochloride metformin and 15 g of aluminum magnesium siliconic acid (Neusilin UFL2, Fuji) were sieved through a No. 35 sieve and placed in a fluidized bed granulator (SFC-50, Freund) and mixed at a temperature of 50 ° C. in the fluidized bed. Separately, 25 g of ethyl cellulose (Ethylcellulose Type N-100, Aqualon) was dissolved in 200 g of 95% ethanol to prepare a binding solution, and the binding solution was slowly sprayed through a fluidized bed granulator to produce granules. The resulting granules were stopped spraying the binder solution, dried in a 60 ° C. fluid bed dryer, sieved and sieved with No. 20 sieve, and 85 g of this formulation and polyethylene oxide (Polyox WSR aggregate, Dow Chemical) and 19 g of hydroxypropyl cellulose were added thereto. Mix for 30 minutes. Finally, 6 g of magnesium stearate was added thereto, mixed for 3 minutes, and tableted to prepare 500 mg of hydrochloride metformin in 650 mg per tablet.

Example 4

Metformin sustained-release tablets were prepared according to Example 3, except that metformin nicotinate prepared in Preparation Example 2 was used instead of metformin hydrochloride. However, the amount of metformin nicotinate added in one tablet was calculated to have the same amount (761.6 mg) as metformin hydrochloride 500 mg and metformin, and the amount of the added additive was converted into the weight part relative to 1 part by weight of metformin hydrochloride. When calculated to have the same parts by weight based on 1 part by weight of metformin nicotinate was added.

Example 5

500 g of metformin hydrochloride, 20 g of colloidal silicon dioxide (Aerosil200, Degussa) and 99 g of polyethylene oxide (Polyox 303, Dow Chemical) were sieved through a No. 35 sieve and placed in a fluidized bed granulator (SFC-50, Freund). The temperature was adjusted to 50 ° C. and mixed. Separately, 30 g of ethyl cellulose (Ethylcellulose Type N-50, Aqualon) was dissolved in 200 g of 95% ethanol to prepare a binding solution, and the binding solution was slowly sprayed through a fluidized bed granulator to produce granules. The resulting granules were stopped spraying the binder solution, dried in a 60 DEG C fluid bed dryer, sieved and sieved through a No. 20 sieve, and 6 g of magnesium stearate was mixed for 3 minutes and mixed with 500 mg of hydrochloride metformin in 655 mg of tablets. Tableting was made by compression.

Example 6

Metformin sustained-release tablets were prepared according to Example 5, except that metformin malonate prepared in Preparation Example 3 was used instead of metformin hydrochloride. However, the amount of metformin malonate added in one tablet was calculated to have the same amount (547 mg) as metformin hydrochloride 500 mg and metformin, and the amount of the added additive was converted into the weight part relative to 1 part by weight of metformin hydrochloride. When calculated to have the same parts by weight based on 1 part by weight of metformin malonate was added.

Example 7

500 g of metformin hydrochloride, 15 g of colloidal silicon dioxide (Aerosil200, Degussa), and 85 g of polyethylene oxide (Polyox WSR agglomerates) were put into a fluidized bed granulator, and the temperature of the fluidized bed was mixed at 50 ° C. A binder solution of 14 g of polyvinyl birrolidone dissolved in 100 g of a polyvinyl acetate 30% suspension (Kollicoat SR30D, BASF) was slowly sprayed to produce granules and dried in a fluidized bed. The resulting granules were sieved through No. 20 sieve, and the granules were mixed with 6 g of magnesium stearate, mixed for 3 minutes, and tableted to contain 500 mg of hydrochloride metformin in 650 mg per tablet.

Example 8

Metformin sustained-release tablets were prepared according to Example 7 except that the metformin maleate prepared in Preparation Example 4 was used instead of metformin hydrochloride. However, the amount of metformin malate added in one tablet was calculated to have the same amount (592.3 mg) as metformin hydrochloride 500 mg and metformin, and the amount of the added additive was converted into the weight part relative to 1 part by weight of metformin hydrochloride. When calculated, it was calculated to have the same parts by weight based on 1 part by weight of metformin malate.

Example 9

Metformin sustained-release tablets were prepared according to Example 7 except that metformin adipic acid salt prepared in Preparation Example 5 was used instead of metformin hydrochloride. However, the amount of metformin adipate added in one tablet was calculated to have the same amount (610.5 mg) as metformin hydrochloride 500 mg and metformin, and the amount of the added additives was added in parts by weight based on 1 part by weight of metformin hydrochloride. When calculated, it was calculated to have the same parts by weight based on 1 part by weight of metformin adipic acid salt.

Example 10

Metformin sustained-release tablets were prepared according to Example 7 except that the metformin glutarate prepared in Preparation Example 6 was used instead of metformin hydrochloride. However, the amount of metformin glutarate added in one tablet was calculated to have the same amount (589.3 mg) as metformin hydrochloride 500 mg and metformin, and the amount of the added additive was the weight part relative to 1 part by weight of metformin hydrochloride. When calculated, it was calculated to have the same parts by weight based on 1 part by weight of metformin glutarate.

Comparative Examples 1 to 3 and Example 11

Metformin acetate prepared in Preparation Example 1 was prepared in a sustained-release form metformin according to Example 4, the amount of ethyl cellulose used as a binder was fixed and ethyl cellulose having a different type of viscosity as shown in Table 1 below A total of four sustained release formulations were prepared.

TABLE 1

 division Comparative Example 1 Comparative Example 2 Comparative Example 3 Example 11 Acetate metformin 500 mg of hydrochloride metformin and the equivalent amount as metformin (571 mg) Aluminum Magnesium Silicone Acid 17mg 17mg 17mg 17mg Ethyl Cellulose (Type N-10) 29mg - - - Ethyl Cellulose (Type N-14)  - 29mg  - - Ethyl Cellulose (Type N-22)  - - 29mg  - Ethyl Cellulose (Type N-50)  -  - - 29mg Polyethylene oxide 95 mg 95 mg 95 mg 95 mg Hydroxypropyl cellulose 22mg 22mg 22mg 22mg Magnesium Stearate 6mg 6mg 6mg 6mg Total amount 740 mg 740 mg 740 mg 740 mg

Comparative Example 4

500 g of metformin hydrochloride, 15 g of aluminum magnesium silicon acid (Nuesilin UFL2), and 25 g of polyethylene oxide (Polyox WSR agglomerates) were mixed and placed in a fluidized bed granulator, followed by mixing the temperature of the fluidized bed to 50 ° C. As in Example 1, 200 g of 95% ethanol was slowly sprayed to form granules, and then dried in a fluidized bed. The resulting granules were sieved through No. 20 sieve, and the mixture was mixed with 85 g of polyethylene oxide (Polyox WSR aggregate) and 19 g of hydroxypropyl cellulose and mixed for 30 minutes. Finally, 6 g of magnesium stearate was added thereto, mixed for 3 minutes, and then compressed into tablets.

Comparative Example 5

500 g of metformin hydrochloride and 15 g of aluminum magnesium silicon acid (Nuesilin UFL2) were mixed and placed in a fluidized bed granulator, followed by mixing at a temperature of 50 ° C. in the fluidized bed. A binding solution of 25 g of ethylcellulose (Nthylcellulose Type N-50) dissolved in 200 g of 95% ethanol was slowly sprayed to form granules, and then dried in a fluidized bed. The resulting granules were sieved through a No. 20 sieve, and the mixtures were mixed with 85 g of ethyl cellulose (Ethylcellulose Type N-50) and 19 g of hydroxypropyl cellulose for 30 minutes. Finally, 6 g of magnesium stearate was added thereto, mixed for 3 minutes, and then compressed into tablets.

Experimental Example 1

The dissolution properties of the sustained-release tablets prepared in Examples 1, 3, 5, and 7 and the commercially available products (glucophage Glucophage XL, BMS) were measured by the paddle method in the dissolution test section of the Korean Pharmacopoeia. .

Dissolution Test Equipment: ERWEKA, DT-700

Eluent temperature: 37 ℃

Eluent: pH 6.8 Phosphate Buffer

Eluent amount: 1000 ml

Rotational Speed: 100 rpm

Sampling time (hours): 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24

Analytical Method: Ultraviolet Absorbance Spectrophotometer (Perkin-Elmer, Lambda25)

Wavelength: 232 nm

As shown in Figs. 1 and 3, each of the examples was not only suitable for the dissolution item of metformin sustained-release tablet of USP31, but also showed the same dissolution rate, which showed a difference within 10% at each measurement point compared to the dissolution rate of a commercially available product. It was. It can be seen that by using polyethylene oxide and ethyl cellulose or polyvinylacetate together as a sustained release carrier, a tablet having excellent dissolution control effect can be produced by reducing the total amount of the sustained release carrier and reducing the size of the tablet.

Experimental Example 2

Five sustained-release tablets prepared in Examples 3 and 11 and Comparative Examples 1 to 3 were eluted in the same manner as in Experimental Example 1.

As shown in Figure 2, despite the same prescription, according to the viscosity of the ethyl cellulose in Comparative Examples 1 to 3 was faster than the release rate of metformin sustained-release tablet USP31 due to the rapid release rate. In contrast, when the viscosity of the ethyl cellulose is 40 cps or more, Example 3 and Example 11 were suitable for the elution criteria. In this experiment, when the viscosity of the ethyl cellulose is not more than 40 cps it was confirmed that a large amount should be used because it cannot have the desired dissolution control effect.

Experimental Example 3

The sustained-release tablets prepared in Examples 4, 6, and 8 were eluted in the same manner as in Experimental Example 1.

As shown in Figure 4, the sustained-release tablet manufacturing method of the present invention shows that it has an excellent release control effect showing the same dissolution pattern regardless of the salt of metformin is changed.

Experimental Example 4

The sustained-release tablets prepared in Example 3, Comparative Example 4, and Comparative Example 5 were eluted in the same manner as in Experimental Example 2.

As shown in FIG. 5, in the case of Comparative Example 4 and Comparative Example 5 using ethyl cellulose or polyethylene oxide alone as the sustained release carrier, it was confirmed that the drug was rapidly released at the beginning.

The present invention relates to a controlled release agent of metformin or a pharmaceutically acceptable salt thereof, which may be formulated in a simple preparation method suitable for commercial production, and which allows sustained controlled release of the drug with a minimum amount of sustained release carrier. To provide.

In addition, the use of a minimal amount of sustained release carrier provides a more improved method for preparing metformin sustained-release tablets that allows for a slow release of metformin in the body while reducing the volume of the tablet.

1 is a graph showing the dissolution test results of the sustained-release tablet and the control agent (glucophage XR) prepared in Example 1, Example 3 of the present invention,

Figure 2 is a graph showing the dissolution test results of the sustained-release tablets prepared in Examples 3, 11, Comparative Examples 1, 2, 3 of the present invention,

3 is a graph showing the dissolution test results of the sustained-release tablet and the control agent (glucophage XL) prepared in Examples 5 and 7 of the present invention,

Figure 4 is a graph showing the sustained-release tablet and the control agent (glucophage XR) dissolution test results prepared in Examples 4, 6 and 8 of the present invention,

5 is a dissolution test result of the sustained-release tablet prepared in Example 3, Comparative Example 4 and Comparative Example 5 to compare the present invention.

Claims (11)

Sustained release for oral administration of metformin comprising metformin or a pharmaceutically acceptable salt thereof, polyvinylacetate or ethylcellulose having a viscosity of 40 cps or more, and polyethylene oxide as a swellable polymer as an active ingredient. Formulation. The sustained-release preparation according to claim 1, comprising 2 to 9 parts by weight of hydrophobic sustained release carrier and 10 to 30 parts by weight of swellable polymer with respect to 100 parts by weight of the active ingredient. The salt of claim 1, wherein the pharmaceutically acceptable salt is hydrochloride, succinate, fumarate, malonate, glutarate, adipine, pimerin, maleate, malate, tartarate, acetate, nicotinate Or sustained release preparations in the form of their addition salts. The sustained-release preparation according to claim 1, wherein the polyethylene oxide has an average molecular weight of 600,000 to 7,000,000. The sustained release preparation of claim 1, further comprising one or more pharmaceutically acceptable additives selected from diluents, binders, disintegrants, and glidants. The method of claim 5, wherein the diluent is at least one selected from starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salt, clay, polyethylene glycol, dicalcium phosphate, silicic anhydride and aluminum magnesium silicon acid. Sustained release formulation characterized in that. The sustained-release preparation according to claim 5, wherein the binder is at least one selected from polyvinylpyrrolidone, cellulose derivatives, natural gums and sugars. 6. The disintegrant according to claim 5, wherein the disintegrant is at least one selected from sodium starch glycolate, starch or modified starch, clays, celluloses, algins, crosslinked celluloses, gums, crosslinked polymers and boiling agents. Sustained release preparations. 6. The lubricant according to claim 5, wherein the lubricant is talc, stearic acid, magnesium stearate, alkaline earth metal stearate, zinc stearate, lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate, glycerol. Sustained release formulation, characterized in that at least one selected from reel behenate, glyceryl palmitostearate and polyethylene glycol 4000. As active ingredients metformin or a pharmaceutically acceptable salt thereof Granulating polyvinylacetate or ethylcellulose having a viscosity of at least 40 cps with a hydrophobic sustained release carrier; And Mixing tableting to contain polyethylene oxide as a swellable polymer; Method for producing a sustained release formulation characterized in that. The method according to claim 10, wherein the polyethylene oxide has an average molecular weight of 600,000 to 7,000,000.

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