WO2010071321A2 - 메트포르민 및 α-글리코시다제 억제제를 포함하는 경구 제제 및 그 제조방법 - Google Patents

메트포르민 및 α-글리코시다제 억제제를 포함하는 경구 제제 및 그 제조방법 Download PDF

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Publication number
WO2010071321A2
WO2010071321A2 PCT/KR2009/007383 KR2009007383W WO2010071321A2 WO 2010071321 A2 WO2010071321 A2 WO 2010071321A2 KR 2009007383 W KR2009007383 W KR 2009007383W WO 2010071321 A2 WO2010071321 A2 WO 2010071321A2
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metformin
hydroxypropyl cellulose
preparation
solution
granules
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PCT/KR2009/007383
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English (en)
French (fr)
Korean (ko)
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WO2010071321A3 (ko
Inventor
조일환
홍일기
안태군
이용택
정선오
윤명식
권오억
이시범
오다원
최낙현
이희정
노현정
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씨제이 제일제당(주)
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Priority to JP2011540605A priority Critical patent/JP5371068B2/ja
Priority to CN2009801504351A priority patent/CN102245172B/zh
Publication of WO2010071321A2 publication Critical patent/WO2010071321A2/ko
Publication of WO2010071321A3 publication Critical patent/WO2010071321A3/ko

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to oral preparations useful for the treatment of type 2 diabetes containing metformin and bogliboose, and more particularly, to a method for preparing the same.
  • the present invention relates to an oral preparation and a method for preparing the same, which are easy to take while improving the compliance of the patient.
  • Type 2 diabetes an insulin-independent diabetes, is one of the most common metabolic diseases with a prevalence of about 5% worldwide, and will increase to 7% in 2010, and the total number of diabetic patients worldwide will increase over the next 10 years. It is expected to increase by about two times.
  • type 2 diabetes The pathophysiology of type 2 diabetes is characterized by insulin secretion disorders and insulin resistance, which can lead to hyperinsulin secretion from the beta cells of the pancreas, which in turn leads to hyperinsulinemia, which has already been diagnosed before diabetes. It exists and acts as an independent risk factor for many different diseases. In this process, beta-cell function eventually decreases, resulting in insulin deficiency. As a result, diabetes mellitus and fasting hyperglycemia occur after meals. Long-term diabetes eventually leads to a number of chronic complications, including microvascular complications such as retinopathy, neurodegeneration, or cardiac disease, or large vessel complications such as cardiovascular, cerebrovascular or peripheral arterial vessels. These chronic complications reduce the quality of life and significantly increase mortality in diabetics. Therefore, the management of type 2 diabetes is to prevent chronic complications, that is, to delay the onset and progression of such chronic complications.
  • the choice of a suitable drug may vary depending on individual circumstances, but it is preferable to use drugs having different mechanisms in consideration of complementary effects.
  • the combination of ⁇ -glucosidase inhibitor drug and metformin is an ideal combination therapy that can simultaneously control postprandial blood sugar and insulin resistance, two pathological mechanisms of type 2 diabetes. Indeed, many clinical trials have already demonstrated that a combination of ⁇ -glucosidase inhibitors and metformin is effective in terms of glycemic control compared to individual monotherapy (Clinical therapeutics vol.25 No. 12 2003, Diabetes Care vol. 24 No. 6 June 2001).
  • hypoglycemic agents are difficult for patients to persist for an unspecified long term in actual clinical practice. This low compliance is, after all, a major cause of failure of glycemic control in the vast majority of patients with type 2 diabetes who require combination therapy with oral hypoglycemic agents.
  • the combination combining two oral hypoglycemic agents in one dosage form is convenient to take, thus improving patient compliance with the drug, and may be an alternative for long-term effective glycemic control.
  • the compliance of the subjects who took each alone remained 54%, whereas the compliance of the patients who took the combination drug was 77%. It has been shown that the benefits of these combinations can go beyond simple possibilities and provide substantial benefits to a significant number of patients with type 2 diabetes who require long-term combination therapy.
  • Metformin a treatment for biguanide-based diabetes, is sold under the trademark Glucophage in the form of hydrochloride.
  • Metformin hydrochloride is a drug that increases the sensitivity of insulin by reducing glycosylation in the liver and increasing absorption at the ends. In addition, it is a hydrophilic drug having an oral bioavailability of 50-60%, and due to various biological half-lives of 1.5 to 4.5 hours, the drug must be repeatedly administered 500 mg three times a day to maintain an effective plasma concentration.
  • Metformin hydrochloride is inherently most absorbed from the upper gastrointestinal tract and poorly penetrating into the lower gastrointestinal tract, such as the small intestine, large intestine, and colon. Thus, if the formulation containing metformin migrates to the lower part of the gastrointestinal tract over time without rapidly releasing metformin, the bioavailability of metformin is reduced.
  • ⁇ -glucosidase inhibitors such as bogliose
  • bogliose are insulin-independent diabetes treatments that inhibit the conversion to glucose by inhibiting ⁇ -glucosidase in gastrointestinal tract cells in a binding manner different from the existing sulfonylurea system.
  • it exhibits sufficient glycemic control effect without the expression of hypoglycemia, thereby increasing patient compliance.
  • Such ⁇ -glucosidase inhibitors must also inhibit rapid blood glucose concentration rises immediately after meals, so they must be released and absorbed quickly in the formulation to have sufficient effect.
  • the dose of the drug administered is very high, 250-1000 metformin once, and very low, 0.2-0.3 mg of bogliose, which corresponds to the ⁇ -glucosidase inhibitor. Therefore, in the preparation of a combination formulation of these two drugs, it is difficult to show uniform mixing and dissolution between the preparations due to the low dose of boliboose, and the drugs required according to the respective pharmacokinetic and pharmacokinetic properties. Absorption conditions may be affected.
  • the secondary wet granules formed by coating the primary wet granules prepared by using an aqueous solution of hydroxypropyl cellulose as a binder solution with a mixed powder of metformin and hydroxypropyl cellulose with an aqueous solution of ⁇ -glycosidase inhibitor and hydroxypropyl cellulose mixed solution were prepared. It provides an oral preparation comprising.
  • Preparing a first wet granule by putting a mixed powder of metformin and hydroxypropyl cellulose into a fluidized bed granulator and spraying an aqueous solution of hydroxypropyl cellulose;
  • the oral preparation according to the present invention is a preparation comprising a metformin and an ⁇ -glycosidase inhibitor, wherein each active ingredient is to be administered separately while the metformin and ⁇ -glycosidase inhibitor exhibit a uniform mixing and dissolution between the preparations. It is an agent for showing the elution pattern which produces an effect more than the case.
  • the secondary wet granules formed by coating the ⁇ -glycosidase inhibitor and the hydroxypropyl cellulose mixed aqueous solution on the primary wet granules formed by using an aqueous solution of hydroxypropyl cellulose as a binder for the mixed powder of metformin and hydroxypropyl cellulose were prepared. It is characterized by including.
  • the formulation is a homogeneous mixture of metformin and hydroxypropylcellulose in the primary wet granules, and each granule is coated with the ⁇ -glycosidase inhibitor and the hydroxypropylcellulose, thereby forming metformin and ⁇ -glycosidase in the formulation.
  • the inhibitor is not a homogeneous form, it has a form in which the ⁇ -glycosidase inhibitor is uniformly distributed in metformin. Therefore, it is expected that there will be little variation in the mixing degree of the active ingredient between the preparations.
  • the ⁇ -glycosidase inhibitor which has to be pre-measured by the nature of the drug and has a rapid effect, is coated on the outside of the granules and dispersed together with hydroxypropyl cellulose, a hydrophilic polymer, so as to disintegrate and release rapidly outside the granules during administration. It can be more than the effect of the administration of the ⁇ - glycosidase inhibitor alone in the combination formulation.
  • Primary granules comprising metformin can also rapidly disintegrate and elute with hydroxypropylcellulose after disintegration of the coating layer containing the ⁇ -glycosidase inhibitor.
  • oral preparations according to the present invention can be rapidly absorbed into the blood by releasing each component more rapidly than the single formulations of each of the metformin and ⁇ -glycosidase inhibitors currently on the market.
  • the preparation of the primary wet granules and the preparation of the secondary wet granules may use a granule manufacturing method commonly used in the pharmaceutical field, and preferably, a mixture of metformin and hydroxypropyl cellulose may be fluidized bed granules. While spraying the hydroxypropyl cellulose aqueous solution binder while flowing in the air to form primary granules, and then spraying a mixed aqueous solution of ⁇ -glycosidase inhibitor and hydroxypropyl cellulose to the primary granules in a fluid bed granulator Secondary granules can be prepared.
  • the primary wet granules include hydroxypropyl cellulose in an amount of 1-50 parts by weight based on 100 parts by weight of metformin, and the ⁇ -glycosidase inhibitor and the hydroxypropyl cellulose mixed aqueous solution are ⁇ -glyco. It may be to include 500 to 5000 parts by weight of hydroxypropyl cellulose relative to 100 parts by weight of the oxidase inhibitor.
  • the amount of hydroxypropyl cellulose relative to the active ingredient may vary depending on the size and strength of the granule to be prepared, the specific surface area of the granule, the content of the active ingredient, and the dissolution rate of the desired active ingredient.
  • the oral preparations of the present invention may be granules as they are in the form of secondary granules, or may be further formulated into capsules or tablets containing granules.
  • the capsules may be prepared by filling the capsules alone or with excipients such as starch, lactose, cellulose, etc. according to the method for preparing capsules commonly used in the pharmaceutical field.
  • the oral preparation of the present invention is preferably a tablet, and the tablet may be prepared by tableting the secondary granules with a lubricant.
  • the glidant may be selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, talc, calcium stearate, carnauba wax, and combinations thereof.
  • Metformin contained as an active ingredient in the oral dosage form according to the present invention is metformin or a pharmaceutically acceptable salt of metformin, preferably metformin hydrochloride.
  • Another active ingredient ⁇ -glycosidase inhibitor may be, but is not limited to, acarbose, miglytol, or boliboss, preferably bogolibose.
  • the oral dosage form according to the present invention may contain 250-1000 mg of metformin hydrochloride and 0.1-0.4 mg of boliboose per dosage, and may be appropriately increased or decreased depending on the strength of the drug to be prepared.
  • the oral agent may be administered during or after meals for the effective action of each component.
  • oral dosage preparations according to the present invention were found to release metformin more rapidly in a medium of pH 1.2 to 7, compared to the conventional metformin single drug glucophage. It has been found to release boliboose more than or equal to.
  • the oral dosage form according to the present invention showed that the bioavailability of metformin was equal to or higher than that of glucophage. Therefore, the oral dosage form according to the present invention can be said to be a complex preparation for glycemic control, which allows each active ingredient to have the same or more effect as when administered in combination.
  • the present invention comprises the steps of preparing a first wet granule by putting a mixed powder of metformin and hydroxypropyl cellulose into a fluidized bed granulator and spraying an aqueous solution of hydroxypropyl cellulose;
  • Providing a method for preparing an oral preparation according to the present invention comprising spraying the primary wet granules with a mixed aqueous solution of ⁇ -glycosidase inhibitor and hydroxypropylcellulose to form secondary wet granules in a fluid bed granulator. do.
  • the preparation of the granules using the fluidized bed granulator used for the production of the primary wet granules and the secondary wet granules may be carried out at a temperature condition of 50-70 °C.
  • the method for preparing the oral preparation may further include the step of preparing a tablet by tableting the prepared secondary wet granules with a lubricant.
  • the lubricant may be selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, talc, calcium stearate, carnauba wax, and combinations thereof, but is not limited thereto.
  • a complex preparation for glycemic control that can not only have a uniform mixing degree and dissolution rate between the preparations, but also have the same or more effect as the co-administration of metformin and ⁇ -glucosidase inhibitor as separate drugs. can do.
  • Such a complex formulation can be said to be very effective in managing the blood sugar of diabetes, which requires long-term blood sugar control, since it can effectively control the blood sugar of the diabetic patients by combining the two drugs and increase the medication compliance of the patient.
  • FIG. 1 is a graph showing the results of a dissolution test over time in water using a glucophage tablet as a reference according to an embodiment of the present invention.
  • Figure 2 is a graph showing the results of the dissolution test over time in a phosphate buffer solution of pH 6.8 with a glucophage tablet as a reference according to an embodiment of the present invention.
  • Figure 3 is a graph showing the results of the dissolution test over time in a acetate buffer solution of pH 4.0 using a glucophage tablet as a reference according to an embodiment of the present invention.
  • Figure 4 is a graph showing the results of the dissolution test over time in a buffer solution of pH 1.2 using a glucophage tablet as a reference according to an embodiment of the present invention.
  • Figure 5 is a graph showing the results of measuring the plasma concentration of metformin over time after oral administration to a beagle dog tablets according to one embodiment of the present invention as glucophage as a reference.
  • Example 2 The granules prepared in Example 1 were mixed with 3 g of magnesium stearate as a lubricant for a suitable time and then compression molded into elliptical tablets at a weight of 585.3 ⁇ 30 mg. Each tablet contained 500 mg of mean metformin hydrochloride and 0.3 mg of boliboose.
  • Example 2 The granules prepared in Example 2 were mixed with 3 g of magnesium stearate as a lubricant for a suitable time and then compression molded into elliptical tablets at a weight of 585.3 ⁇ 30 mg. Each tablet contained 500 mg of average metformin hydrochloride and 0.2 mg of bogliose.
  • Example 3 The granules prepared in Example 3 were mixed with 3 g of magnesium stearate as a lubricant for a suitable time and then compression molded into elliptical tablets at a weight of 292.8 ⁇ 15 mg. Each tablet contained 250 mg of mean metformin hydrochloride and 0.3 mg of boliboose.
  • Example 2 The granules prepared in Example 1 were mixed with 3 g of magnesium stearate as a lubricant for a suitable time and then compression molded into elliptical tablets at a weight of 292.8 ⁇ 15 mg. Each tablet contained 292.8 ⁇ 15 mg of mean metformin hydrochloride and 0.2 mg of bogliose.
  • the tablet prepared in Example 7 was subjected to dissolution test for glucophage.
  • the dissolution test conditions were as follows.
  • the pH 1.2 buffer (1st solution) is dissolved in 2.0 g of NaCl and dissolved in 7.0 mL of c-HCl and water to make 1 L.
  • the solution is colorless and transparent.
  • the pH is about 1.2.
  • the pH 4.0 acetate buffer (acetate buffer solution) was adjusted to pH 4.0 by making 0.05 mol / L acetate solution and 0.05 mol / L sodium acetate solution (41: 9).
  • the complex preparation according to the present invention releases metformin rapidly in a medium of pH 1.2-7 compared to the conventional commercially available glucophage.
  • Example 5 The tablets prepared in Example 5 were administered orally to beagle dogs using glucophage as a reference, and tested for bioavailability.
  • Vortex Mixer (Thermolyne, USA; Type 37600 Mixer)
  • Preparation of Stock Solution Measure the weight of 3 mg or more in each glass vial (5 ml vial dried by wiping with water and ACN). Dissolved in methanol to a concentration of 1 mg / ml and used in experiments. Store at 4 °C until use. 1 mg / ml metformin stock solution is diluted 10-fold with 50% ACN to make 100 ⁇ g / ml stock solution and 2-fold diluted to 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39 ⁇ g / ml stock A solution is prepared and used for the calibration curve, and the high, medium and low concentrations and LLOQ concentrations are used as validation samples.
  • Pretreatment of the sample To 100 ⁇ l of blank plasma, 10 ⁇ l of IS (phenformin, 25 ⁇ g / ml) is added, followed by vortexing for 5 seconds, followed by vortexing with 500 ⁇ l of ACN. After centrifugation at 13,000 rpm and 4 ° C. for 5 minutes in a centrifuge, 50 ⁇ l of the supernatant is transferred to a new tube, and 500 ⁇ l of the mobile phase is vortexed for 1 minute. After centrifugation (13,000 rpm, 4 ° C., 2 minutes) and filtration (0.2 ⁇ m), analysis is performed by LC / MS / MS.
  • IS phenformin, 25 ⁇ g / ml
  • Declustering Potential 81V (Metformin), 86V (Penformin)
  • the complex formulation according to the present invention has a bioavailability equal to or higher than that of Basin, which is a conventional commercial formulation.
  • Example 5 The tablets prepared in Example 5 were subjected to stability tests with Glucophage and Basin under the following conditions.
  • Detector Fluorescence photometer (Excitation wavelength: 350nm Fluorescence wavelength: 430nm)
  • Sodium phosphate buffer pH 6.5 was dissolved in 1.38 g of sodium dihydrogen phosphate monohydrate and dissolved in 500 mL. The solution was dissolved in 1.42 g of sodium dihydrogen phosphate and adjusted to pH 6.5. will be.
  • Ignition solution Dissolve 6.25 g of taurine and 2.56 g of sodium periodate in 1 L of water.
  • the formulation according to the present invention was confirmed to have a stability or more equivalent to a single formulation of each component also in terms of storage stability.

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PCT/KR2009/007383 2008-12-15 2009-12-10 메트포르민 및 α-글리코시다제 억제제를 포함하는 경구 제제 및 그 제조방법 WO2010071321A2 (ko)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2011540605A JP5371068B2 (ja) 2008-12-15 2009-12-10 メトホルミンおよびα−グリコシダーゼ抑制剤を含む経口製剤、およびその製造方法
CN2009801504351A CN102245172B (zh) 2008-12-15 2009-12-10 包含二甲双胍和α-糖苷酶抑制剂的口服制剂及其制备方法

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KR10-2008-0127289 2008-12-15
KR1020080127289A KR101189639B1 (ko) 2008-12-15 2008-12-15 메트포르민 및 α-글리코시다제 억제제를 포함하는 경구 제제 및 그 제조방법

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WO2010071321A2 true WO2010071321A2 (ko) 2010-06-24
WO2010071321A3 WO2010071321A3 (ko) 2010-10-21

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018211137A1 (en) * 2017-05-19 2018-11-22 Università Degli Studi Di Milano Therapy and diagnosis of disease characterized by alterations in the dna damage response

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KR101336499B1 (ko) * 2013-03-06 2013-12-03 씨제이제일제당 (주) 당뇨병의 예방 또는 치료용 복합 조성물
CN111374952B (zh) * 2018-12-29 2022-07-26 甘李药业江苏有限公司 阿卡波糖药物组合物及其制备方法

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EP1935424A1 (en) * 2005-10-12 2008-06-25 ESPINOZA ABDALA, Leopoldo de Jesús Pharmaceutical compositions comprising combined antidiabetic substances for use in diabetes mellitus

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KR100705210B1 (ko) * 2004-09-23 2007-04-06 주식회사 한독약품 경구투여를 위한 당뇨병 치료용 약제학적 복합제제
EP1935424A1 (en) * 2005-10-12 2008-06-25 ESPINOZA ABDALA, Leopoldo de Jesús Pharmaceutical compositions comprising combined antidiabetic substances for use in diabetes mellitus
KR100812538B1 (ko) * 2006-10-23 2008-03-11 한올제약주식회사 약물 제어방출형 메트포르민-글리메피리드 복합제제

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018211137A1 (en) * 2017-05-19 2018-11-22 Università Degli Studi Di Milano Therapy and diagnosis of disease characterized by alterations in the dna damage response

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JP5671767B2 (ja) 2015-02-18
CN102245172A (zh) 2011-11-16
CN103143018A (zh) 2013-06-12
KR20100068811A (ko) 2010-06-24
CN102245172B (zh) 2013-04-10
JP2013189466A (ja) 2013-09-26
JP5371068B2 (ja) 2013-12-18
WO2010071321A3 (ko) 2010-10-21
KR101189639B1 (ko) 2012-10-12
JP2012511568A (ja) 2012-05-24

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