KR20060096728A - Sustained-release formulation and combinative sustained-release tablet with sustained-release pellets - Google Patents

Abstract

The present invention provides a tablet or capsule sustained release formulation comprising a sustained release pellet comprising a drug requiring sustained release and a second drug which does not require sustained release in a tablet comprising the sustained release pellet. It relates to a complex sustained release tablet. Formulations comprising sustained release pellets of the drug requiring the sustained release of the present invention can more precisely control drug release compared to a single-type tablet formulation, and can be administered once a day to increase patient compliance, as well as Since it can be administered with a second drug that does not require immediate release, the dosage method can be simplified to obtain an excellent therapeutic effect. More specifically, the sustained release formulation and the composite sustained release tablet of the present invention can be effectively used for the treatment of the second diabetes.

Pellets, sustained-release tablets, composite sustained-release tablets, metformin hydrochloride, glymepiride

Description

Sustained-release formulation and combinative sustained-release tablet with sustained-release pellets}

Figure 1 is a dissolution test result of the sustained-release tablet of metformin hydrochloride prepared by the method of Example 1 and using Glucophage ^® XR (BMS, USA) commercially available in the United States as a reference.

2 (a) and 2 (b) show the results of a dissolution test performed by preparing a composite sustained-release tablet consisting of metformin hydrochloride and glymepiride, using Glucophage XR and amaryl, which are commercially available in the United States. Among these, (a) is the result of the dissolution test of metformin hydrochloride, and (b) is the result of the dissolution test of glymepiride.

In the figure, CJ500 is a sustained-release tablet containing 500 mg of metformin hydrochloride prepared in Example 3, and CJ502 is a composite sustained-release tablet containing 500 mg of metformin hydrochloride prepared in Example 4 and 2 mg of glymepiride. And B500 refers to Glucophage XR, which is commercially available in the United States, and A is a commercial Amarilla tablet (Aventis, Korea).

Figure 3 is an embodiment with a first one sustained-release tablet of metformin hydrochloride prepared in the Glucophage ^® XR (BMS, USA) that is when plates in the United States as the reference product is conducted with a beagle dogs in animals in order to determine the body absorption .

The present invention relates to a sustained release tablet or capsule formulation consisting of sustained release pellets and a complex sustained release tablet.

More specifically, a sustained-release tablet or capsule comprising a sustained-release pellet consisting of a drug that requires sustained release and a composite sustained-release tablet prepared by coating a second drug that does not require sustained release in the sustained-release tablet It is about.

Certain pharmacological therapies require the administration of drugs in a sequential manner, from which good therapeutic effects can be expected. This can be done by the patient complying with a prescription consisting of a defined time schedule, but often it is difficult to achieve the expected therapeutic effect due to the patient's non-compliance. Therefore, a sustained release formulation capable of continually releasing a drug that must be repeatedly administered several times a day to maintain an effective plasma concentration and combining the sustained release agent and a second drug requiring immediate release in a single dosage form The development of specific formulations is required. Such preparations can simplify treatment and reduce or eliminate the risk of inappropriate administration. Currently, the need for such agents is urgently needed for the treatment of type 2 diabetes.

Diabetes mellitus is a common and serious disease characterized by hyperglycemia. This disease can be divided into two major subclasses. It is divided into insulin-dependent diabetes mellitus (IDDM), also known as type 1 diabetes, and non-insulin-dependent diabetes mellitus (NIDDM), also known as type 2 diabetes.

Among them, type 2 diabetes is one of the most common metabolic diseases with a prevalence rate of about 5% worldwide, and it is expected to increase to 7% in 2010, and the total number of diabetic patients worldwide will be 10 years. It is expected to double by about.

The pathophysiology of type 2 diabetes is characterized by "insulin secretion disorder" and "insulin resistance". Insulin resistance can lead to hyperinsulin secretion from the beta cells of the pancreas, which in turn leads to hyperinsulinemia, which has already existed before being diagnosed with diabetes and acts as an independent risk factor for many other diseases. Eventually, beta cell function decreases, leading to insulin deficiency, resulting in hyperglycemia, which leads to hypoglycemia after meals and to fasting hyperglycemia, and eventually to microvascular complications or cardiovascular events such as retinopathy, neuropathy, and cardiac disease. Many chronic complications can occur, including large vessel complications such as cerebrovascular or peripheral arterial vessels. These chronic complications reduce the quality of life and significantly increase mortality in diabetics. Therefore, the primary need in treating type 2 diabetes is to prevent these chronic diseases, in other words, to delay the onset and progression of these chronic complications. Diabetics who are likely to experience chronic complications in the future should participate in a rigorous diabetes treatment process and have satisfactory metabolic control to maintain normal or at least near normal glycated hemoglobin (HbA1c). Results from the Diabetes Control and Complication Trial and the United Kingdom Prospective Diabetes Study (UKPDS) demonstrate that strict blood sugar control can lower the risk of developing chronic complications from diabetes. have. In practice, however, many Type 2 diabetics fail to control blood glucose below targets set by the American Diabetes Association. In addition, the UKPDS analysis shows that the failure rate of oral hypoglycemic monotherapy increases with time, and therefore, inevitably requires combination therapy with other drugs for better glycemic control.

Metformin hydrochloride, a diabetes treatment, has been widely prescribed to lower blood sugar levels in type 2 diabetes. However, the short-acting drug metformin hydrochloride requires administration such as twice a day or three times a day. In addition, adverse reactions associated with the use of metformin hydrochloride actually occur frequently in the gastrointestinal tract, such as anorexia, nausea, vomiting and, in some cases, diarrhea. Thus, it is meant that extended release formulations of metformin hydrochloride can not only improve the quality of treatment of type 2 diabetes patients, but also provide a safer profile compared to conventional formulations.

In addition, the selection of a suitable drug in combination therapy may vary depending on the individual's circumstances, but it is preferable to use drugs having different mechanisms in consideration of complementary effects. In this respect, the combination of sulfonylurea-based drugs with metformin hydrochloride is an ideal combination therapy that can simultaneously access two stages of type 2 diabetes, "insulin secretion disorder" and "insulin resistance". Indeed, many clinical trials have already demonstrated that the combination of sulfonylurea-based drugs and metformin hydrochloride is effective in terms of blood sugar control compared to individual monotherapy.

However, the combination therapy of two or more hypoglycemic agents is difficult to sustain long-term patients in the actual clinic because the frequency of administration required by each oral hypoglycemic agent is different. This low compliance has, after all, been an important cause of the failure of glycemic control in the vast majority of patients with type 2 diabetes who require combination therapy with oral hypoglycemic agents.

Therefore, the combination of two oral hypoglycemic agents combined in one dosage form is convenient to improve the patient's compliance with the drug, and may be an effective alternative to long-term effective glycemic control. According to a study comparing the compliance of patients according to the mode of administration in the combination therapy of oral hypoglycemic agents, the compliance of the subjects who took the individual alone was 54%, whereas the compliance of the subjects who took the combination drug was 77%. It has been demonstrated that the benefits of these combinations go beyond simple possibilities and can provide practical benefits for many Type 2 diabetics who require long-term combination therapy.

In the prior art, many techniques are used to provide controlled release and extended release formulations to minimize the effect of lost dose of drug caused by a patient's lack of compliance and to maintain the therapeutic concentration of drug in the blood. Has been. The rate of reaching the body fluids of the drug administered in conventional tablet or capsule formulations tended to be very high initially and then rapidly decreased. This pattern leads to transient drug over-blood concentrations in many drugs, followed by therapeutically inadequate drug concentrations. These problems have limited clinical use. This delivery pattern improved with the introduction of various controlled delivery systems in the 1970s. These systems, which provide relatively constant controlled drug delivery, have made it possible to avoid overblood concentrations and inadequate drug maintenance. This technique provides effective medications with reduced side effects and has led to a reduction in the number of doses.

More specifically WO 03/66028 discloses the invention of the preparation of tablets for oral administration with immediate release and sustained release aspects. A technique is described in which a rapid release form drug of 10 microns or less in diameter is applied as a layer on top of a unitary core consisting of a sustained release drug and a sustained release mechanism. Among them, for the treatment of type 2 diabetes, metformin hydrochloride is used as a sustained release drug and glymepiride is used as an immediate release drug. In this invention, the sustained release base used in the unitary core is a swellable hydrophilic polymer material, and in the case of a sustained release drug, it is not secreted in the phase at least 40% or more within 1 hour after administration. WO 1999/47128 provides a two-phase sustained release system for drugs with high water solubility, such as metformin hydrochloride, which is a diabetes treatment, which is a dosage form that extends gastrointestinal retention time, and has high water solubility and sustained release. It describes a formulation in which the particulate material is mixed to form fine particles, and the fine particles and the sustained release material are mixed and compressed into tablets. US 6,099,862, on the other hand, specifies a controlled release or sustained release pharmacological formulation consisting of one or more passages in a membrane by coating the antihyperglycemic drug with at least a semipermeable membrane without applying the expandable polymer.

The present inventors have a form of a multiple unit including a sustained-release pellet in the form of particles, unlike the sustained-release preparation or a composite sustained-release preparation in the form of a single core, and by using a water-insoluble polymer sustained release base, Sustained release formulations or complex sustained release tablets have been developed that can more precisely control drug release. In the preparation of the sustained-release pellet of metformin hydrochloride of the present invention, it is possible to design a more convenient diabetic tablet comprising a sustained-release formulation of a single-dose form or a sustained-release tablet of metformin hydrochloride and a coating layer of glymepiride. It was made.

The present invention provides a sustained release formulation comprising a sustained release pellet composed of a drug requiring sustained release.

The present invention provides a composite sustained release tablet further coated with a second drug that does not require sustained release in a sustained release pellet composed of a drug that requires sustained release.

The present invention provides a process for the preparation of a sustained release formulation comprising a sustained release pellet composed of a drug requiring sustained release.

The present invention provides a method for producing a composite sustained release tablet in which a sustained release pellet comprising a drug requiring sustained release is further coated with a second drug that does not require sustained release.

In one embodiment, the present invention provides a sustained release formulation comprising a sustained release pellet consisting of a drug that requires sustained release. More specifically, the present invention provides a sustained-release formulation in the form of a multiple unit comprising a sustained-release pellet prepared by coating a water-insoluble polymer material on granules consisting of a drug requiring sustained release and a sustained-release polymer that is a water-insoluble polymer.

Drugs that require sustained release are short-acting drugs that require several doses per day to maintain a therapeutically effective amount. Such drugs may include diabetes treatment, antibiotics, angiotensin conversion inhibitors, nonsteroidal anti-inflammatory drugs, hyperlipidemia treatment, cardiovascular medications, asthma treatment, antidepressants, antihistamines, and the like.

In the present invention, a drug that requires sustained release is preferably a biguanide-based diabetes treatment agent, and more preferably metformin hydrochloride as a biguanide-based diabetes treatment agent. The dose of metformin hydrochloride of the present invention preferably comprises 250 to 1500 mg.

The water-insoluble polymer used as the sustained release base in the present invention refers to a water-insoluble cellulose and its derivatives, polymethacrylate or a mixture of polymethacrylate and polyalkyl acrylate. Here, the water-insoluble cellulose and its derivatives include cellulose acetate, cellulose acetate phthalate, hydroxypropylene methylcellulose phthalate, ethyl cellulose and the like. And a mixture of polymethacrylate or polymethacrylate and polyalkylacrylate 2 paper is a mixture of polymethacrylate, polymethacrylate and polymethyl methacrylate in a ratio of 1: 1, polyethylacrylate And a polymethyl methacrylate and a polytrimethylammonioethyl methacrylate chloride are mixed in two ratios of 1: 2: 0.1 and 1: 2: 0.2. The most suitable of these is ethylcellulose having a viscosity of 7 to 14 cps.

The water-insoluble polymer is non-swellable. Representative swellable water-soluble polymers HPMC (hydroxypropyl methyl cellulose) and non-swellable water-insoluble polymer EC (ethyl cellulose) is A.H. As shown in Kibbe's Handbook of Pharmaceutical Excipients (The Pharmaceutical Press, Washington, 2000), it is an excipient of the same chemical family that is generally used extensively for oral food and medicine as a non-toxic, non-irritating substance. However, due to the difference in solubility in water and physical structure, different properties are exhibited. First, when looking at the structure of HPMC and EC through scanning electron microscope (SEM), while HPMC has a cohesive structure, EC is more fragile and shows a fine fibrous entangled structure on the surface. Journal of Controlled Releases, 95, 101-108, 2004). Thus, HPMC is water soluble and has an amorphous structure, which allows for constant hydration of granules, while EC is insoluble in water.

In addition, after preparing the tablet using the drug, the difference in the results of the dissolution test can be seen. Tablets using HPMC show a biphasic release pattern. In other words, it shows a slow release phase initially and a constant release phase until the dissolution process is completed. That is, while the eluate is in contact with the HPMC, macromolecular chains swell on the tablet surface to form a gel layer around the core. Through this gel layer, drug diffusion between the core and the gel occurs. On the other hand, swelling of eroded layers and elution of the HPMC matrix itself are sometimes observed. In contrast, tablets using EC show a linear release pattern. This suggests that the drug is released by diffusion. The drug release is through a porous network formed by the drug dissolved in the matrix. Even after the dissolution test is completed, the form of the tablet consisting of EC is maintained. In other words, this suggests that the drug structure was diffused and released without damaging the matrix structure (Journal of Controlled Releases, 95, 101-108, 2004).

In the present invention, the drug requiring the sustained release is granulated with a non-swellable water-insoluble sustained release base such as ethyl cellulose, and a multiple unit in which the pellet particles recoated with the sustained release base are stacked. In terms of the formulation having, there is a difference from the existing invention in which the drug requiring the sustained release is dispersed in a matrix composed of a water-soluble sustained release base having swellability such as HPMC. In addition, in terms of the effect, a non-swellable insoluble sustained release base is used, and pellets coated using such a sustained release base are exhibited by showing sustained release from each pellet particle through the coating channel channel of the insoluble sustained release base. The elaborate release pattern is distinct from the surface release of matrices using existing water soluble sustained release mechanisms.

The sustained release base may be used by dissolving an insoluble polymer alone in an organic solvent or purified water, or by dissolving both an insoluble polymer and an organic acid in an organic solvent or purified water together. The organic solvent is one or two mixtures of organic solvents such as ethanol, acetone, isopropyl alcohol and chloroform, and the purified water is non-ionized. Most suitable is a 75% ethanol solution.

Sustained-release pellets comprising the above constituents preferably have a particle size between 0.05 and 2 mm suitable for formulation in the form of capsules or tablets.

Sustained release pellets may be formulated in the form of capsules or tablets.

Capsule formulations are prepared by filling the sustained release pellets into hard capsules. The filling method of the capsule is possible by injecting or flowing the pellets.

Tablets may be prepared by methods such as direct powder compaction or granular compaction. At this time, the tablet is preferably in the form of stacked sustained release pellets.

In one embodiment, the tablet of the present invention may be a film coated tablet with a film coating layer. An enteric or non-enteric film coating agent may be used as the film coating agent, and in the case of enteric application, it is cellulose acetate cellulose (CAP), polyvinyl acetate polyvinyl acetate (PVAP), methacrylic acid polymer (Eudragit L, S), and the like. Is hydroxy propyl cellulose (HPC), methyl cellulose (MC), ethyl cellulose (EC), hydroxypropyl methyl cellulose (HPMC), povidone (PVP). Polyvinyl alcohol (PVA), cellulose acetate (CA), and the like. As the coating method, a pan coating method, a fluidized bed coating method, an extrusion coating method, or the like may be used.

In another aspect, the present invention provides a composite sustained release tablet further coated with a second drug that does not require sustained release in the sustained release tablet comprising the sustained release pellet.

Drugs that do not require sustained release are drugs that can maintain a therapeutically effective amount in a single dose daily. In the present invention, the drug that does not require sustained release is preferably a sulfonylurea antidiabetic drug that can be used, such as metformin hydrochloride, which is referred to as a drug that requires sustained release, and such drugs include glymepiride and glybencla. Mead, glypide, glyclazide and the like. Most preferably, it is a glimepiride, and the dose is preferably between 1 and 8 mg.

Drugs that do not require sustained release are prepared as a coating solution by suspending together with the film coating agent and coated on the sustained release tablet. The polymer used in the film coating liquid containing these drugs is a group consisting of polyvinyl alcohol, polypropylene glycol, acrylic acid copolymer, hydroxyflofilmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, or a combination thereof. Can be selected from. The amount of coating at this time is preferably kept to a minimum to limit the size of the formulation and to make the preparation effective, and may be 1 to 10% by weight, preferably 2 to 8% by weight relative to the total weight of the sustained release formulation. . As the coating method, a pan coating method, a fluidized bed coating method, an extrusion coating method, or the like may be used.

The above-mentioned tablets of the present invention may include one or more pharmaceutically acceptable carriers such as excipients, binders, lubricants, colorants and the like which are commonly used. Excipients that can be used in the tablets according to the invention are conventional excipients, preferably lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose. Corn starch, potato starch, wheat starch, white sugar, di-mannitol, precipitated calcium carbonate, dextrin, pre-gelatinized starch and combinations thereof. Excipients are preferably included in amounts of 10 to 90 parts by weight, based on the total weight of the tablet.

The binder which may be included in the tablet according to the present invention is preferably a conventional binder, preferably polyvinylpyrrolidone, hydroxypropylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, dextrin, gelatin, methylcellulose, hydroxyethylcellulose, hydrate Oxymethylcellulose, polyvinyl alcohol, paste, gum arabic and combinations thereof. The binder is preferably included in an amount of 2 to 40 parts by weight, based on the total weight of the tablet.

Disintegrants that can be included in the tablets according to the invention are conventional disintegrants, preferably sodium starch glycolate, crospovidone, sodium chromosmellose, low substituted hydroxypropyl cellulose, starch, carboxymethyl cellulose calcium and these It is selected as a group consisting of a combination of. Disintegrants are preferably included in amounts of 0.1 to 32 parts by weight, based on the total weight of the tablet composition.

Glidants that may be included in the tablets according to the invention are conventional glidants and are preferably selected from the group consisting of magnesium stearate, talc, light silicic anhydride, and combinations thereof. Glidants are preferably included in amounts of 0.1 to 20 parts by weight, based on the total weight of the tablet.

In addition, if necessary, a colorant may be included in the tablet according to the present invention, and titanium dioxide, iron oxide, magnesium carbonate, calcium sulfate, magnesium oxide, magnesium hydroxide, aluminum lake, for example blue No. 1 aluminum lake, red No. 40 At least one selected from aluminum lakes and the like.

The human dosage of the sustained-release preparation or the combined sustained-release tablet containing the sustained-release pellet of the present invention is appropriately selected according to the absorption in the body, the inactivation rate, the rate of excretion, the age, sex and condition of the patient, the severity of the disease, and the like. Can be.

In another aspect, the present invention provides a process for the preparation of a sustained release formulation comprising a sustained release pellet composed of a drug requiring sustained release.

The sustained-release preparation of the present invention prepares granules composed of a drug and a water-insoluble high molecular material that need to be released, and then coated with a water-insoluble high molecular material to prepare a coated pellet, the pellet is put in a mixture of a pharmaceutically acceptable carrier Tablets may be prepared by tableting or they may be prepared in capsule form by filling the hard capsules.

As a preferred embodiment, the present invention comprises the steps of (1) preparing a granule by mixing the drug and the water-insoluble polymer that requires sustained release; (2) coating the water-insoluble polymer on the granules prepared in step (1) to produce a sustained release pellet; And (3) tableting the sustained release pellets prepared in step (2) into a multiple unit form together with a pharmaceutically acceptable carrier and / or the sustained release pellets prepared in step (2) into hard capsules. It provides a method for producing a sustained release formulation comprising a sustained release pellet, characterized in that it comprises the step of filling.

In a more preferred embodiment, the invention further comprises the step of coating with a film coating after the tableting in step (3).

The granules are generally prepared by soaking the powder or powder mixture and passing the mass through a sieve or granulator of a suitable size depending on the size of the granules in need. In some cases, the particles may be air-dried or heat-dried, or granulated granules may be prepared by compressing the powder without giving moisture. In the case of tablets, the pellet and the pharmaceutically acceptable carrier may be dry mixed using a conventional mixer, compressed and granulated, and compressed using a rotary tableting machine or the like. In the case of film coating, the film may be coated using various coating machines such as a conventional pan, a high coater, and a fluidized bed coating, and a method using a high coater is preferable.

In another aspect, the present invention provides a method for producing a composite sustained release tablet further coated with a second drug that does not require sustained release in a sustained release tablet comprising a sustained release pellet composed of a drug requiring sustained release.

The composite sustained-release tablet of the present invention provides a method for producing a sustained-release tablet including a sustained-release pellet comprising the drug requiring the sustained release, and for preparing a coating suspension containing a second drug which does not require sustained-release. Steps are included.

As a preferred embodiment, the present invention comprises the steps of (1) preparing a granule by mixing the drug and the water-insoluble polymer that requires sustained release; (2) coating the water-insoluble polymer on the granules prepared in step (1) to produce a sustained release pellet; And (3) tableting the sustained release pellets prepared in step (2) together with a pharmaceutically acceptable carrier in the form of multiple units; And (4) coating with a coating suspension comprising a second drug that does not require sustained release.

In a more preferred embodiment, the invention further comprises the step of coating with a film coating after the tableting in step (3).

Hereinafter, an Example demonstrates this invention concretely. However, the scope of the present invention is not limited by these examples.

Example 1 <Preparation of Sustained Release Formula Containing Sustained Release Pellets>

A. Preparation of granules for water-insoluble polymers

After adding 100 g of water-insoluble polymer ethyl cellulose, which is a sustained release base, to 100 g of 75% ethanol solution, the solution was dissolved in a mechanical mixer for 30 to 60 minutes.

B. Preparation of Granules Comprising Metformin Hydrochloride and Insoluble Polymers

After sufficiently drying and preheating the fluidized bed granulator under conditions of an inlet temperature of 60 to 80 ° C. and an exhaust temperature of 30 to 50 ° C., an inflow rate of 300 ml / hr to 1500 ml / hr of the well-insoluble, insoluble polymer, ethylcellulose solution 600 g of granules were prepared while adsorbing to low metformin hydrochloride (500 g). The most suitable spraying conditions are inlet temperature of 80 ~ 85 ℃, exhaust temperature of 60 ~ 65 ℃ and inflow of mixed liquid is 720ml / hr.

C. Coating Solution Preparation of Insoluble Polymer

75 g of water-insoluble polymer ethylcellulose, a sustained release base, was added to 750 g of a 75% ethanol solution, dissolved in a mechanical mixer for 30 to 60 minutes, and 15 g of talc was added and mixed.

D. Preparation of Sustained Release Pellets

After spraying 600 g of the granules prepared in B using a fluidized bed granulator, 690 g of sustained-release pellets were prepared while spraying 90 g of the insoluble polymer coating solution prepared in C.

E. Preparation of Sustained-Release Tablets Containing Sustained-Release Pellets

Sustained-release tablets were prepared by a direct tableting method (direct compression method), and after mixing 690 g of sustained-release pellets of metformin hydrochloride with 60 g of direct-type microcrystalline cellulose and 5 g of magnesium stearate mixed, 755 mg of hardness was 7-12 Kp. Tablets were prepared.

F. Preparation of Sustained Release Capsules Containing Sustained Release Pellets

Sustained-release pellets of metformin hydrochloride prepared in D were filled in No. 0 hard capsules.

Example 2 Preparation of Sustained-Release Coated Tablets Containing Sustained-Release Pellets

A. Preparation of Sustained-Release Tablets Containing Sustained-Release Pellets

In step A as in Example 1, by the step E, a sustained release tablet including the sustained release pellet was prepared.

B. Film Coating of Sustained Release Tablets Including Sustained Release Pellets

Film coating opadry ^®; were charged in the (HPMC collar konsa) coating 20 g of a coating solution and suspended in purified water to 200g, and the coating pan a sustained-release tablet of metformin hydrochloride prepared in A (Hi-coater). The dried tablets filled in the coating pan were kept at an intake air temperature of 75-85 ° C. and an exhaust air temperature of about 35-45 ° C. The coating liquid was sprayed onto the dried tablet with a spray device operated by air pressure, and then the air supply was continued to dry for about 30-40 minutes. OPA the tablet obtained here Dry ^® (HPMC; collar konsa) The coating amount of the coating was 2.58% relative to the tablet.

Example 3 <Preparation of Sustained Release Tablets Containing Sustained Release Pellets>

A. Preparation of Sustained-Release Tablets Containing Sustained-Release Pellets

In step A as in Example 1, by the step E, a sustained release tablet including the sustained release pellet was prepared.

B. Film Coating of Sustained Release Tablets Including Sustained Release Pellets

In the film coating, a coating solution was prepared by suspending 20 g of Opadry ^® (PVA; Colorcon) coating material in 200 g of purified water, and a sustained-release tablet of metformin hydrochloride prepared in A was filled in a coating coat (Hi-coater). The dried tablets filled in the coating pan were kept at an intake air temperature of 75-85 ° C. and an exhaust air temperature of about 35-45 ° C. The coating liquid was sprayed onto the dried tablet with a spray device operated by air pressure, and then the air supply was continued to dry for about 30-40 minutes. The coating amount of the Opadry ^® (PVA; Colorcon) coating material of the tablet obtained here was 2.58% with respect to the tablet.

Example 4 <Preparation of Composite Sustained Release Tablet Containing Sustained Release Pellets>

2 g of glimepiride and 10 g of Opadry ^® (HPMC) coating material and other excipients were suspended in 120 g of purified water to prepare a coating solution (see Table 1 below), and the sustained-release tablet prepared in Example 1 was coated with a coating pan (Hi- filled in a coater). In the dried tablets filled in the coating pan, the exhaust air temperature was maintained at about 35-45 ° C. The dried tablets were sprayed with a glimepiride-containing film coating liquid by means of a pneumatically actuated spraying device, and then the air supply was further dried for about 30-40 minutes. OPA the tablet obtained here Dry ^® (HPMC; collar konsa) The coating amount of the coating was 3.33% based on the tablet.

Example 5 <Preparation of Complex Sustained-Release Tablet Containing Sustained-Release Pellets>

2 g of glimepiride and 10 g of Opadry ^® (PVA; Coloron) coating material and other excipients were suspended in 120 g of purified water to prepare a coating solution (see Table 1 below), and the sustained-release tablet prepared in Example 1 was coated with a coating pan (Hi- filled in a coater). In the dried tablets filled in the coating pan, the exhaust air temperature was maintained at about 35-45 ° C. The dried tablets were sprayed with a glimepiride-containing film coating liquid by means of a pneumatically actuated spraying device, and then the air supply was further dried for about 30-40 minutes. Opadry ^® from the tablet obtained here (PVA; collar konsa) The coating amount of the coating was 3.33% based on the tablet.

Example 6 Preparation of Composite Sustained-Release Tablet Containing Sustained-Release Pellets

2 g of glimepiride and 10 g of Opadry ^® (HPMC; Colorcon) coating material and other excipients were suspended in 120 g of purified water to prepare a coating solution (see Table 1 below), and the sustained-release coated tablets prepared in Example 2 were coated with a coating pan (Hi -coater). In the dried tablets filled in the coating pan, the exhaust air temperature was maintained at about 35-45 ° C. The dried tablets were sprayed with a glimepiride-containing film coating liquid by means of a pneumatically actuated spraying device, and then the air supply was further dried for about 30-40 minutes. OPA the tablet obtained here Dry ^® (HPMC; collar konsa) The coating amount of the coating was 3.33% based on the tablet.

Example 7 Preparation of Complex Sustained-Release Tablet Containing Sustained-Release Pellets

A coating solution was prepared by suspending 2 g of glimepiride and 10 g of Opadry ^® (PVA; Caracon Co.) coating material and other excipients in 120 g of purified water (see Table 1 below), and applying a sustained-release coated tablet prepared in Example 3 to a coating pan (Hi -coater). In the dried tablets filled in the coating pan, the exhaust air temperature was maintained at about 35-45 ° C. The dried tablets were sprayed with a glimepiride-containing film coating liquid by means of a pneumatically actuated spraying device, and then the air supply was further dried for about 30-40 minutes. Opadry ^® from the tablet obtained here (PVA; collar konsa) The coating amount of the coating was 3.33% based on the tablet.

Example 8 <Formulation evaluation: tablet dissolution test and absorption test>

A. in vitro evaluation

A dissolution test was conducted on the tablets prepared above. The dissolution test method was carried out for 12 hours under the condition of 100 revolutions / minute with the eluate of water or pH 7.8 buffer for the tablets and capsules prepared above according to the dissolution test method 2 of the general test method. Start the dissolution test 15 minutes, 30 minutes, 60 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, every 12 hours take the eluate and filtered, and the filtrate As a sample solution, it was analyzed by high performance liquid chromatography.

The results of 500 mg of the metformin hydrochloride sustained-release tablet prepared through Example 1 are shown in Figure 1, wherein the dissolution rate of metformin hydrochloride was 20-40% in 1 hour, 40-60% in 3 hours, and 80% or more in 12 hours. In addition, the glucosage XR commercially available in the United States and the elution result were the same.

In addition, the dissolution test of the composite sustained-release tablet containing 500 mg of metformin hydrochloride prepared by Example 4 and 2 mg of glymepiride (denoted by CJ502) was performed by the sustained-release tablet containing 500 mg of metformin hydrochloride prepared by Example 3 (denoted by CJ500). Glucophage XR (indicated by B500) and amaryl tablet (indicated by Aventis, Korea, A) mainly composed of glymepiride components in the United States were used as a control. The results are shown in Figures 2a and 2b. In the composite sustained-release tablet (CJ502) prepared in Example 4, the metformin hydrochloride was able to confirm the dissolution rate of 20-40% in 1 hour, 40-60% in 3 hours, 80% or more in 12 hours, and in the case of glymepiride The dissolution rate (more than 80% in 15 minutes) of Amaryl tablet (Aventis, Korea) used as a reference drug was confirmed.

B. in vivo evaluation

Beagle dogs (Marshall Beijing, China, 13 months of age, weight 11.5 kg, males) were fasted the day before administration of the test substance. Glucophage XR (Glucophage) was used as a tablet and control of the metformin hydrochloride (labeled CJ metformin) prepared in Example 1 above. XR, with a metformin hydrochloride 500 mg) was forced orally administered. After administration, 10 mL of water was forcibly administered. Blood was collected from the experimental animals, and the blood collection time was progressed at 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 24 hours, and 30 hours after drug administration. Blood sampling was performed by collecting 1 mL from the lumbar cortical vein for each blood collection time according to the composition of each group, and the collected blood was centrifuged at 13,000 rpm for 3 minutes to separate plasma. Frozen in the freezer (-20 ° C.) until analysis. Sample pretreatment was performed by adding 20uL of internal standard solution phenformin (500 ng / mL) to 200uL plasma, adding 50uL of purified water, shaking for 1 minute, and performing HPLC analysis through drug extraction process. Based on the non-compartment model analysis method, the general pharmacokinetic index, such as the highest blood concentration, the highest blood concentration reaching time, and the area under the concentration curve, was calculated as shown in Table 2 below.

As a result, the relative bioavailability of CJ metformin (RBA) relative to the reference Glucophage XR is 90%, which is included in the compliance criteria range (80-125%), And no coefficient difference was found.

Tablets or capsules in sustained release formulations in the form of multiple units comprising sustained-release pellets of the drug in need of sustained release and agents which do not require sustained release in tablets comprising the sustained release pellets. The composite sustained release tablet prepared by further coating the drug of 2 can more precisely control drug release than a conventional single tablet formulation, and is a more stable formulation. Therefore, the sustained-release preparation or the composite sustained-release tablet of the present invention can be usefully used for the treatment of the second diabetes by enabling the administration once a day and improving the patient's compliance.

Claims (10)

 A sustained-release preparation in the form of a multiple unit comprising a sustained-release pellet prepared by granulating a drug requiring sustained release by granulation with a sustained release base which is a water-insoluble polymer, and then coated with a sustained release base that is a water-insoluble polymer. The sustained release formulation of claim 1, wherein the sustained release formulation is a tablet or capsule. The sustained-release preparation according to claim 1 or 2, wherein the drug requiring sustained release is metformin hydrochloride. The sustained-release base which is an insoluble polymer is selected from the group consisting of ethyl cellulose, cellulose acetate, cellulose acetate phthalate, hydroxypropylene methylcellulose phthalate, and methacrylic acid copolymer. Sustained release formulation. The sustained release formulation according to claim 1 or 2, wherein the coated sustained release pellets have a particle size of between 0.05 and 2 mm. A composite sustained release tablet further coated with a second drug that does not require sustained release in the sustained release tablet according to claim 2. 7. The complex sustained release drug according to claim 6, wherein the second drug which does not require sustained release is a sulfonylurea antidiabetic drug selected from the group consisting of glymepiride, glybenclamide, glyphidide, and glyclazide. refine. 8. A composite sustained release tablet according to claim 6 or 7, wherein the second drug-coated coating layer, which does not require sustained release, is 1 to 10% by weight based on the total weight of the sustained release pellets. (1) preparing a granule by mixing a drug requiring sustained release with a water-insoluble polymer;       (2) coating the granules prepared in step (1) with a water-insoluble polymer to prepare coated sustained release pellets; And       (3) preparing the sustained-release tablet of claim 2, comprising the step of tableting the sustained-release pellet prepared in step (2) together with a pharmaceutically acceptable carrier in the form of a multiple unit. Way.       (1) preparing a granule by mixing a drug requiring sustained release with a water-insoluble polymer;       (2) coating the granules prepared in step (1) with a water-insoluble polymer to prepare coated sustained release pellets;       (3) tableting the sustained release pellets prepared in step (2) together with a pharmaceutically acceptable carrier in the form of multiple units; And       (4) A process for producing the composite sustained release tablet of claim 6, comprising coating with a coating suspension comprising a second drug that does not require sustained release.

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