KR20100023429A - Optimized drug delivery system manuplating ir/sr gastric retentive applied to combination drug indicated for diabetes mellitus(dm) - Google Patents

Abstract

PURPOSE: A therapeutic agent for diabetes having optimized drug delivery system by controlling sustained release and immediate release is provided to effectively release complex tablet and optimize drug effect. CONSTITUTION: A method for manufacturing a therapeutic composition having optimized drug delivery system by controlling sustained and immediate release comprises: a step of mixing metformin hydrochloride with hydrophilic polymer; a step of coating particles with mucosal adhesion polymer solution and drying to obtain granules; a step of mixing the carbon gas generating agent or thiazolidinedione system diabetes therapeutic agent with the granules; and adding binder, disintegrant, excipient, and lubricating agent and tabletizing. The thiazolidinedione diabetes therapeutic agent is pioglitazone or rosiglitazone. The hydrophilic polymer is Hydroxyl propyl cellulose or carboxyl methyl cellulose.

Description

Optimized Drug Delivery System manuplating IR / SR Gastric Retentive applied to Combination drug indicated for Diabetes Mellitus (DM)}

The present invention relates to an optimized drug delivery system through the control of the sustained and immediate release of the diabetic complex system.

Diabetes can be largely classified into the genetic causes of type 1 and the acquired factors of type 2, and the type 1 can be cured by the administration of insulin. Blood glucose lowering agents can control the concentration of sugar in the blood. Therefore, it is more effective as evidence-based therapeutics (EBT) to control the production and metabolism of diabetes by concomitant administration rather than the administration of a single agent according to the pharmacological mechanism. Metformine hydrochloride (Metformine HCl) is a biguanide-based drug that mainly regulates blood sugar levels by inhibiting glucose production in the liver and inhibiting uptake of sugars. In addition, as a drug, sulfonyl urea (Glymepiride) of sulfonyl urea (glimepiride) directly stimulates the beta cells of the pancreas of Langerhans Island to promote insulin secretion and consume sugar metabolism. The composition of metformine hydrochloride (Metformine HCl) and glymepiride can regulate the concentration of sugars in three or more pathways through this pharmacological mechanism. In addition, thiazolindione-based pioglitazone (pioglitazone) and rosiglitazone (rosiglitazone), such as drugs act on the insulin receptor (receptor) itself by the action of gamma-PPAR (gamma-PPAR: peroxime proliferation activate receptor) By controlling the glucose tolerance of the blood sugar by promoting the function of insulin has the advantage that can compensate for the shortcomings of the side effects of insulin resistance that can occur in other diabetes treatment.

In Korea, the conventional technology for sustained-release preparations of metformine hydrochloride (Metformine HCl) as a type 2 diabetes treatment is KR 1020080009016 of Handok Pharmaceuticals. Drug delivery system that controls mucoadhesion and drug release.

Patent KR 1020070045940 on a complex preparation of Chong Kun Dang is a pharmaceutical composition that shows slow release and pH-dependent rapid release. It is a 6-hour release drug delivery system, metformin HCl in the first layer, and pH-dependent standing in the outer layer. After the release, the second layer was adjusted to contain Glymepiride.

Yuhan KR 1020080001772 is a sustained release formulation containing metformin or a salt thereof, and a method of preparing the same, which is a sustained release formulation of 8 hours, which is sustained by a pH dependent coating (Eudragit 90SH) by mixing granules of Metformine HCl and HPMC. System. Hanmi Pharmaceutical's KR 1020070022134 relates to sustained-release drugs for oral administration of metformin, which are formed by mixing Metformine, PEO and Gum to form granules, followed by mixing with PVP and PVA, and KR 1020060077812 is a sustained release for oral administration of diabetes treatment. It is a formulation prepared by mixing Metformin and PEO with a sex composite agent and a method for preparing the same, followed by mixing with PVP, PVA, and Xanthan Gum. In addition, KR 1020050097269 is a sustained-release drug for oral administration of metformin to form a granule of Metformin, PEO, Xanthan Gum and PVP, and then developed a drug delivery system to control drug release for about 10 hours by tableting PVA and PVP blend. . Hanol Pharm made granules of metformin sustained-release tablet of KR 1020070113382 with metformin hydrochloride (Metformine HCl) and excipient HPMC as granules and granulated to produce a 24-hour sustained release formulation as GLUCODOWN OR.

KR 2003-0036877 metformin of USV Ltd. sustained-release pharmaceutical compositions containing metformin and a method for preparing the same, granulated by mixing metformin hydrochloride (Metformine HCl), Klucel EF (Klucel EF), CMC Na and excipients, and then After blend, it was developed as a system to control the dissolution of the drug for 8 hours with a compressed preparation.

Ranbaxy Lab. Ltd. controlled the dissolution of the drug for 12 hours through granulation after mixing metformin hydrochloride (Metformine HCl), Na CMC and HPMC in a controlled release metformin tablet in KR 1020050043765.

Andrex Cop. Is a release-controlled metformin composition in KR 20030061392 consisting of metformin hydrochloride (Metformine HCl), a binder and SLS in the core core layer, and a polymer, PEG, and ethyl acetate in the coating layer of the outer layer. System was designed to allow controlled release of the drug for 10-15 hours,

Alza Co. has developed a hybridization technique through ion exchange by mixing metformin hydrochloride (Metformine HCl) and SLS in compositions and formulations for improved absorption of metformin in KR 1020060108692. Patents related to gastrointestinal drug delivery system applied at home and abroad are mainly swelling system followed by floating system and biological chop system.

KR 1020027017415 from Deformed Incorporated is a swellable system that extends gastric retention in swelling controlled-release oral dosage forms.

The Teva Pharmaceutical Industries Limited has designed a rapid swelling system for controlling gastric retention and release of therapeutic agents in KR 1020027017538.

Pornsak et al, et al. Designed a system using oil-entrapped calcium pectinate gel beads. Pate et al, et al., Ranitidine hydrochloride using Gelucire 43/01. HCl) was developed. Shoufeng et al. Et al. Designed a gastric retention system by controlling the composition ratio of HPMC and its citric acid, and Ali et al. Et al. Used a PEO 60K and Eudragit RL 100 to design a floating system capsule of celecoxib, an arthritis treatment. Kumar et al. Et al. Proposed the suspension system of cimetidine by preparing microspheres using HPMC and EC.

As a type 2 diabetes treatment, it combines one or more drugs selected from biguanide-based metformin hydrochloride (Metformine HCl), thiazolindione-based pioglitazone and rosiglitazone. Hydrochloride (Metformine HCl) is a sustained-release formulation for sustained release, so that the residence time in the stomach can be maintained for more than 5 hours, and the oral hypoglycemic agent blended with it has to be developed to control the release to the immediate release. No drug delivery system has been developed that differentiates two different ingredients of different classes to enable the dissolution of the drug, and the development has been completed by the present invention.

In the present invention, as an oral hypoglycemic agent for the treatment of type 2 diabetes, one species selected from metformin hydrochloride (Metformine HCl) and thiazolindione series of pioglitazone and rosiglitazone By combining the drugs of the phase to differentiate the drug dissolution of each component to optimize the absorption of each drug. The drug delivery system is metformin hydrochloride (Metformine HCl) as a persistent gastroretentive system, and the drug is a rapid release to develop a system that can control the dissolution of the two types of drugs.

In terms of drug efficacy, metformine hydrochloride (metformine HCl) can be expected to have the best effect when combined with two classes of drugs.In the pharmaceutical and technical aspects, it is possible to develop an optimized drug delivery system by controlling drug release in immediate and sustained release. I think you can.

Metformine hydrochloride (Metformine HCl) is mainly absorbed in the stomach to maximize the drug efficacy by controlling the release of the drug gradually while delaying gastric mucoadhesion in the stomach to prolong gastric retention time. At the same time, oral hypoglycemic agents, which are complexed, may promote immediate absorption of the small intestine and the lower organ through the gastrointestinal tract as a rapid release of the drug. Permanent preparations can control drug release using a hydrophilic polymer and adhesion to the gastric mucosa can prolong gastric retention time by controlling the viscosity of the bioadhesive polymer. It is considered that the diabetic complex preparations in the present invention are superior technology in terms of drug efficacy and absorption by developing rapid-release preparations of drugs that are combined with a gastric retention system of metformine hydrochloride (metformine HCl) as a main component.

In the present invention, as a type 2 diabetes treatment agent, a combination of one or more drugs selected from biguanide-based metformine hydrochloride (Metformine HCl), thiazolindione-based pioglitazone and rosiglitazone Metformine hydrochloride (Metformine HCl) is a sustained-release formulation for sustained release in the stomach for more than 5 hours, and the oral hypoglycemic agent combined with it is controlled to be released immediately. The aim is to develop a drug delivery system that enables the dissolution of drugs by differentiating two different ingredients from different classes. Therefore, the high content of metformine hydrochloride (metformine HCl) is made of a hydrophilic polymer polymer and then coated with a bio-adhesive polymer so that it can be attached to the gastric mucosa. To obtain a composition.

The present invention is to prepare a long-lasting granules by mixing metformin hydrochloride, a biguanide-based diabetic drug, with a hydrophilic polymer, followed by particle coating with an aqueous mucoadhesive polymer solution in vivo, followed by drying; Optimized by mixing the carbon dioxide generator and thiazolidinedione type diabetes treatment with the granules obtained in the previous step, adding by adding a binder, disintegrant, excipient and glidant, and adjusting the sustained and immediate release prepared by tableting Provided is a diabetes therapeutic composition having a drug delivery system.

As a thiazolidinedione-based drug used in the present invention, a drug selected from pioglitazone and rosiglitazone is used.

In the present invention, a polymer selected from hydroxypropyl cellulose and carboxymethyl cellulose is used as the hydrophilic polymer.

In the present invention, polyethylene oxide is used as an in vivo mucoadhesive polymer.

In the present invention, as a carbon dioxide gas generator, calcium carbonate (CaCO ₃ ), sodium carbonate (Na ₂ CO ₃ ), sodium bicarbonate (NaHCO ₃ ), potassium carbonate (K ₂ CO ₃ ), potassium hydrogen carbonate (KHCO ₃ ) and magnesium carbonate ( MgCO ₃ ) is used for the reagent selected.

In the present invention, at least one selected from low-substituted hydroxy propyl cellulose, povidone, gelatin, and corn starch as a binder, crospovidone ( crosspovidone) at least one selected from sodium starch glycolate and carboxymethyl cellulose, and excipients selected from micro-crystalline cellulose and lactose. Use at least one species.

In the present invention, it is preferable to contain 100 mg to 1000 mg of metformin hydrochloride, and 1 mg to 100 mg, preferably 1 mg to 30 mg, of one or more drugs selected from the thiazolidine-based diabetes treatment.

In the present invention, the viscosity of the hydrophilic polymer is adjusted in the range of 4,000 cps to 100,000 cps.

In this invention, it is preferable to adjust so that the residence time of metformin hydrochloride may be 5-8 hours.

In the present invention, by developing a gas-retentive delivery system with the persistence of metformine hydrochloride (Metformine HCl) to promote the absorption rate of the metformin hydrochloride in the gastrointestinal tract and to reduce the consumption of tablets in the lower intestine and prolonged the transition time of the tablet In order to prevent gastric resident drug delivery system, the present invention regulates the component ratio of the pharmaceutical composition and the amount of the polymer polymer with respect to the main component to delay the gastric residence time by up to 5-8 hours. The drug was allowed to elute during the dwell time. Metformin hydrochloride does not receive any P450 enzymatic activity during metabolism in the liver, so it can be used in combination with the same or different types of oral hypoglycemic agents. In consideration of the drug interaction with the pioglitazone or rosiglitazone, the cyclohexyl hydroxyl methyl derivative and the carboxy derivative of the cyclochrome P450 through 2C9 are considered. The combination of the two oral hypoglycemic agents is an ideal combination since it releases and releases the pioglitazone sustained-release drug in the gastrointestinal tract. .

Next, the present invention will be described in more detail by way of examples.

First, metformin hydrochloride (Metformine HCl), which is a main component, is mixed with a hydrophilic polymer and then particle-coated with an aqueous solution of PEO using a fluidized bed, followed by drying to form a durable granule. The prepared granules are evaluated for the particle size, binding strength, tensile strength, etc. of the granules according to the molecular weight of the polymer used.

After analyzing the dissolution pattern of the drug through pellet analysis of the persistent granules, the granularity and the viscosity of the polymer used are checked to derive the optimized dissolution rate.

Tableting of designed tablets

Accurately weigh 850 mg of Metformine HCl, the main component, to form a hydrophilic polymer, hydroxypropyl methyl cellulose (HPMC), 4,000 cps, 1,500 cps, and 100,000 cps, depending on the viscosity. Granulation is performed while controlling the composition ratio of the polymer to the polymer. In this case, as the binder, PEO (polyethylene oxide), which is a bioadhesive polymer, is used to perform granulation coating using a fluidized bed granulator. The polyox WSR used at this time also adjusts the content ratio of the binder while controlling the component ratio according to the size of the molecular weight to control the binding force and viscosity of the granules and to maintain the continuous action and increase the adhesion ability in the gastric mucosa layer in the stomach The residence time of is to be maintained for at least 5 hours. As a method for maintaining a suspended state in the stomach, calcium carbonate and sodium bicarbonate, which can generate gas, are controlled at a ratio of 1: 2.

Pioglitazone, rosiglitazone, or a mixture thereof, which is a blending component, is a mixture of the above-described persistence granules and the listed excipients in a blender according to the content ratio of the technology, and then mixed with the lubricant after the post-mixing tableting. Do it. Use a rectangular punch and die to make the total amount of tablets 1060 mg.

Test Example

Dissolution test in the gastrointestinal tract

The dissolution test of the designed persistent tablet is conducted under the following conditions.

______________________________________________

   Time 850-mg Tablet

   (hours) Amount dissolved

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    2 not more than 30%

    8 between 65% and 90%

   16 not less than 90%

______________________________________________

The dissolution test of the drug for tablets tableted according to the above example is performed for 16 hours at 37 ^° C. and 50 rpm in a dissolution tester using 900 ml of gastric acid solution of pH 1.2.

Metformine hydrochloride (Metformine HCl), the main component, measures the time of suspension in gastric fluid, and each of the two components measures the absorption region at 228 nm and 233 nm in the UV wavelength range.

HPLC analysis conditions for each component are as follows.

HPLC analysis method

1) Metformine HCl

   Mobile phase: 0.01M phosphate buffer (pH 6.5): acetonitrile (30:70)

Column: 300x3.9mm (id) C ₁₈ um bondpack (10 um)

   Injection volume: 50 ul

Column temperature: 37 ^o C

   Flow rate: 1ml / min

   Absorption Wavelength: 233 nm

2) Pioglitazone

   Mobile phase: phosphate buffer (pH 7.0) -acetonitrile-tetrahydrofuran (73:18:09, v / v / v)

Column: 250 mm x 4.6 mm (id) C ₁₈ um bondpack (10 um)

Column temperature: 37 ^o C

   Flow rate: 1ml / min

   Absorption Wavelength: 228 nm

1 is a schematic diagram of a gastric retention drug delivery system.

은 메트포르민 염산염 + HPMC,

은 위접착성 폴리머 코팅,

배합성분 : 피오글리타존 또는/ 및 로시글리타존.From here

Silver metformin hydrochloride + HPMC,

Silver gastric polymer coating,

Ingredients: pioglitazone or / and rosiglitazone.

Figure 2 is a drug dissolution graph from the gastroretentive system of metformin hydrochloride according to the embodiment.

Figure 3 is a graph showing the drug dissolution from the IR / SR gastric DDS of the optimized diabetes complex.

Claims (9)

A long-term granule is prepared by mixing metformin hydrochloride, a biguanide-based diabetic drug, with a hydrophilic polymer, followed by particle coating with an aqueous mucoadhesive polymer solution in vivo, followed by drying; Sustained release prepared by mixing the granules obtained in the previous process with at least one drug selected from a carbon dioxide generator and a thiazolidinedione type diabetes treatment, adding by adding a binder, a disintegrant, an excipient and a lubricant, Diabetic therapeutic composition having an optimized drug delivery system by adjusting the immediate release. The diabetes mellitus according to claim 1, wherein the thiazolidinedione-based drug has an optimized drug delivery system by controlling the sustained and immediate release prepared by using a drug selected from pioglitazone and rosiglitazone. Therapeutic composition. The drug optimized by controlling the sustained release and rapid release prepared using a polymer selected from hydroxypropyl cellulose and carboxymethyl cellulose as a hydrophilic polymer. Diabetic therapeutic composition having a delivery system. [Claim 2] The composition for treating diabetes of claim 1, wherein the drug delivery system is optimized by controlling the sustained and rapid release prepared by using polyethylene oxide as the in vivo mucoadhesive polymer. The method of claim 1, wherein the carbon dioxide gas generator is calcium carbonate (CaCO ₃ ), sodium carbonate (Na ₂ CO ₃ ), sodium bicarbonate (NaHCO ₃ ), potassium carbonate (K ₂ CO ₃ ), potassium hydrogen carbonate (KHCO ₃ ) and A composition for treating diabetes having a drug delivery system optimized by controlling sustained and rapid release prepared using a reagent selected from magnesium carbonate (MgCO ₃ ). The method of claim 1, wherein the binder is a low-substituted hydroxy propyl cellulose (hydroxy propyl cellulose), povidone (povidone), gelatin (gelatine), corn starch (corn starch) at least one selected from Uses at least one selected from crosspovidone sodium starch glycolate and carboxymethyl cellulose, and excipients include micro-crystalline cellulose and lactose ( A composition for treating diabetes having a drug delivery system optimized by controlling the sustained release and immediate release prepared using one paper selected from lactose). The method of claim 1, wherein the metformin hydrochloride containing 100mg to 1000mg, the antidiabetic composition having an optimized drug delivery system by controlling the sustained release and immediate release prepared by containing 1mg ~ 100mg of thiazolidine-based diabetes treatment. The anti-diabetic composition of claim 1, wherein the hydrophilic polymer has a drug delivery system optimized by controlling the sustained and rapid release rate of the viscosity controlled in the range of 4,000 cps to 100,000 cps. The method of claim 1, wherein the composition for treating diabetes having a drug delivery system optimized by controlling the sustained release and rapid release in which the gastric residence time of metformin hydrochloride is adjusted to 5-8 hours.

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