WO2021133046A1 - Metformin sustained release formulation and method for preparation thereof - Google Patents

Metformin sustained release formulation and method for preparation thereof Download PDF

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Publication number
WO2021133046A1
WO2021133046A1 PCT/KR2020/018958 KR2020018958W WO2021133046A1 WO 2021133046 A1 WO2021133046 A1 WO 2021133046A1 KR 2020018958 W KR2020018958 W KR 2020018958W WO 2021133046 A1 WO2021133046 A1 WO 2021133046A1
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sustained
metformin
release
weight
granules
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PCT/KR2020/018958
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French (fr)
Korean (ko)
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이재협
김지연
김보훈
김관영
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주식회사 대웅제약
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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2063—Proteins, e.g. gelatin

Definitions

  • the present invention relates to a metformin sustained-release formulation and a method for preparing the same.
  • Metformin is a biguanide drug that is used as a treatment for non-insulin dependent diabetes mellitus (NIDDM). It is also a drug of choice for many diabetic patients. to be.
  • NIDDM non-insulin dependent diabetes mellitus
  • metformin Since the metformin has high water solubility, when it is prepared as a general tablet, it may cause excessive blood sugar drop and gastrointestinal disturbances due to rapid release. In addition, since metformin is usually taken as an immediate-release tablet in a large amount of 250 mg to 1000 mg (up to 2550 mg per day) 2 to 3 times a day, a rapid change in blood concentration due to the rapid release of metformin Due to this, there is a problem that further aggravates side effects and tolerance.
  • metformin since metformin has a short blood half-life of 2 to 6 hours, it is necessary to develop a sustained-release formulation that releases metformin slowly.
  • a method of increasing the volume of the formulation such as a method of slowly releasing the drug in the formulation using a large amount of a sustained-release agent or excipient, may be considered preferentially.
  • a drug having a large unit dose and poor compressibility such as metformin
  • the volume of the formulation becomes too large, which makes it difficult for patients to take it.
  • the present inventors completed the present invention by identifying a metformin sustained-release formulation capable of exhibiting a sustained-release pattern while reducing the size of the formulation.
  • An object of the present invention is to provide a sustained-release formulation of metformin or a pharmaceutically acceptable salt thereof, which can exhibit a sustained-release pattern while reducing the size of the formulation, and a method for preparing the same.
  • the present invention provides a sustained-release formulation of metformin or a pharmaceutically acceptable salt thereof, comprising:
  • 'metformin' used in the present invention is a compound having the following formula, and is used as an active ingredient of the sustained-release preparation according to the present invention.
  • a pharmaceutically acceptable salt thereof in addition to metformin, a pharmaceutically acceptable salt thereof may be used.
  • a salt commonly used in the art such as an acid addition salt formed by a pharmaceutically acceptable free acid, may be used without limitation.
  • pharmaceutically acceptable salt refers to any and all organic or inorganic addition salts in which the side effects attributable to the salt do not reduce the beneficial efficacy of metformin at a concentration having an effective action that is relatively non-toxic and harmless to the patient. it means.
  • a pharmaceutically acceptable salt can be obtained by a conventional method using an inorganic acid or an organic acid.
  • metformin is dissolved in a water-miscible organic solvent, such as acetone, methanol, ethanol, or acetonitrile, and an organic or inorganic acid is added to filter the precipitated crystals, which are prepared and dried to obtain a pharmaceutically acceptable salt.
  • a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile
  • an organic or inorganic acid is added to filter the precipitated crystals, which are prepared and dried to obtain a pharmaceutically acceptable salt.
  • it can be prepared by reducing the solvent or excess acid in the reaction mixture to which the acid is added, drying the residue, or filtering the salt precipitated by adding another organic solvent.
  • the pharmaceutically acceptable salt of metformin is metformin hydrochloride.
  • metformin In addition to high water solubility, metformin has a high daily dose and a short blood half-life, so tablets of metformin must be manufactured as a sustained-release formulation.
  • a sustained-release formulation using a large amount of a sustained-release agent is generally considered, but has a problem in that it is difficult for patients to take because the volume is too large.
  • a formulation exhibiting an effective sustained-release effect while having a small volume is prepared by controlling the content and manufacturing process of each component while using a small amount of the sustained-release agent.
  • the term 'binder' used in the present invention is a component used to bind the components in the sustained-release formulation according to the present invention to each other, and each component is compressed during the process of preparing the sustained-release formulation or by providing adhesion after compression. combine them
  • the binder is used together with metformin in the wet granulation process.
  • each component can be more densely bound by using the binder, which is advantageous for sustained release of metformin.
  • the binder is used in an amount of 1 to 10 parts by weight based on 100 parts by weight of the metformin or a pharmaceutically acceptable salt thereof.
  • the content is less than 1 part by weight, the content of the binder is insignificant, so it is difficult to exhibit a sustained-release effect of metformin, and when it exceeds 10 parts by weight, there is a problem in that the volume of the formulation becomes excessively large.
  • the binder is used in an amount of 2 to 5 parts by weight based on 100 parts by weight of the metformin or a pharmaceutically acceptable salt thereof.
  • the binder may be selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, povidone, or a combination thereof, and in addition, it is commonly used in the pharmaceutical field in the formulation of oral solid preparations. Anything can be used.
  • the term 'sustained-release agent' used in the present invention is a component that slows the release rate of the active ingredient in the sustained-release preparation according to the present invention.
  • the sustained-release agent forms a high-viscosity gel layer on the surface of the formulation to slowly release the drug into the body.
  • the sustained-release agent is used in the dry granulation process. In this case, the sustained-release agent is effective in controlling the release of metformin by stronger adhesion to the active ingredient.
  • the sustained-release agent is used in an amount of 15 to 30 parts by weight based on 100 parts by weight of the metformin or a pharmaceutically acceptable salt thereof.
  • the sustained-release agent is used in an amount of 15 to 20 parts by weight based on 100 parts by weight of the metformin or a pharmaceutically acceptable salt thereof.
  • the sustained-release agent is a polyvinylpyrrolidone derivative, a cellulose derivative, starch, gelatin, or a combination thereof. More preferably, the polyvinylpyrrolidone derivative is povidone, copovidone, or a combination thereof. More preferably, the cellulose derivative is methylcellulose, ethylcellulose, sodium carboxymethylcellulose, or a combination thereof. Most preferably, the sustained release agent is hydroxypropyl methylcellulose.
  • the term 'lubricating agent' used in the present invention is a component that prevents the granules from adhering to the machine and provides smooth flowability to the preparation when pressure, etc. is applied during the manufacture of the sustained-release preparation according to the present invention.
  • the lubricant is added in the form of surrounding the surface of the granules, which is advantageous to release metformin in a sustained release.
  • the lubricant is used in the wet granulation process and post-mixing together with metformin.
  • the lubricant in the wet granulation process it is added in a form that partially surrounds the metformin, which is advantageous for the sustained release of metformin. Do.
  • the lubricant is used in an amount of 1 to 5 parts by weight based on 100 parts by weight of the metformin or a pharmaceutically acceptable salt thereof.
  • the amount of the lubricant is insignificant, making it difficult to prepare the sustained-release preparation according to the present invention, and when it exceeds 5 parts by weight, there is a problem in that the volume of the preparation becomes excessively large.
  • the lubricant is used in an amount of 2 to 3 parts by weight based on 100 parts by weight of the metformin or a pharmaceutically acceptable salt thereof.
  • the lubricant is magnesium stearate, magnesium aluminumsilicate metasilicate, silica oxide (SiO 2 ), colloidal silicon dioxide, colloidal silica, talc, or a combination thereof.
  • the lubricant is magnesium stearate or magnesium aluminumsilicate metasilicate.
  • the sustained-release preparation according to the present invention is an uncoated tablet, a film-coated tablet, a single-layer tablet, a double-layer tablet, a multi-layer tablet, or a core-coated tablet.
  • additives commonly used in the field of formulation to which the present invention belongs may be used without limitation.
  • the sustained-release formulation according to the present invention contains 60 to 90% by weight of metformin or a pharmaceutically acceptable salt thereof, based on the total weight of the formulation, more preferably 61% by weight or more, 62% by weight or more, 63 at least 64 wt%, at least 65 wt%, at least 66 wt%, at least 67 wt%, at least 68 wt%, at least 69 wt%, at least 70 wt%; 89 wt% or less, 88 wt% or less, 87 wt% or less, 86 wt% or less, 85 wt% or less, 84 wt% or less, 83 wt% or less, 82 wt% or less, 81 wt% or less, 80 wt% or less .
  • the present invention provides a method for preparing a sustained-release formulation of the above-described metformin or a pharmaceutically acceptable salt thereof, comprising the following steps:
  • step 1 1) preparing granules of metformin or a pharmaceutically acceptable salt thereof, a binder and a lubricant by a wet granulation method (step 1);
  • step 2 2) preparing granules using the dry granulation method of the granules and sustained-release agent of step 1 (step 2);
  • step 3 mixing the granules, sustained-release agent and lubricant of step 2 (step 3).
  • Step 1 is to prepare primary granules by applying the wet granulation method, and is a step of preparing granules using the wet granulation method with metformin or a pharmaceutically acceptable salt thereof, a binder, and a lubricant.
  • the wet granulation method refers to manufacturing granules by combining the components of each formulation with a binding solution and drying the granules.
  • the wet granulation method is advantageous in that each component can be more tightly bound together with a binder, and thus the active ingredient is released in a sustained release.
  • the present invention means to prepare granules by granulating and drying a mixture comprising metformin or a pharmaceutically acceptable salt thereof, a binder, and a lubricant in association with a binding solution.
  • the binding solution may be water, ethanol, isopropanol, acetone, or a combination thereof.
  • the drying is performed at a temperature of 10° C. to 60° C., preferably 20° C. to 40° C. so that the stability of each component is maintained.
  • the step of sieving the prepared granules if necessary may be further included.
  • Step 2 is a step of preparing granules using the dry granulation method using the granules and sustained-release agent prepared in step 1 above.
  • the dry granulation method is to prepare granules by combining the components by compressing the components of each formulation, and unlike the wet granulation method described above, a binder is not used.
  • the dry granulation method is a method of manufacturing the powder by applying pressure while passing the powder between two rollers by roller compacting.
  • the step of sieving the prepared granules if necessary may be further included.
  • Step 3 is a step of mixing a sustained-release agent and a lubricant with the granules prepared in step 2 above.
  • a sustained-release agent and a lubricant By adding a sustained-release agent and a lubricant to the granules prepared in step 2 above, a release control effect is added and smooth flowability of the granules is imparted.
  • the content ratio of the sustained-release agent used in step 2 to the sustained-release agent used in step 3 is 1:1 to 1:6.
  • the sustained-release agent used in step 2 and the sustained-release agent used in step 3 are the same material.
  • the manufacturing method according to the present invention may further include the step of coating the formulation prepared in step 3.
  • the present invention provides a sustained-release formulation of metformin or a pharmaceutically acceptable salt thereof, which can exhibit a sustained-release pattern while reducing the size of the formulation, thereby effectively shearing metformin in the body, It can also improve the convenience of taking the patient.
  • Example 1 shows a dissolution graph for the formulation prepared in Example 1 of the present invention.
  • Figure 2 shows a dissolution graph for the formulation prepared in Example 1 of the present invention.
  • Example 3 shows a dissolution graph for the formulation prepared in Example 1 of the present invention.
  • a sustained-release formulation was prepared by a wet granulation process and a dry granulation process with the components and contents shown in Table 1 below.
  • metformin hydrochloride, HEC or HPC, and magnesium stearate were sieved with 25 mesh, put into a high-speed mixer, and mixed (Agitator 100 rpm, Chopper 600 rpm, 1 min), and the kneading process (Agitator 100 rpm) , Chopper 800 rpm, 3 min) was added with purified water (100 mg/T) and granulated (Agitator 100 rpm, Chopper 1000 rpm, 5 min). Then, the prepared granules were dried (60° C., LOD 1.5% or less).
  • the prepared granules were sieved with 18 mesh, mixed with HPMC sieved with 25 mesh, and dry granulated (3 rpm, 5 MPa) with a roller compactor.
  • the prepared granules were sieved with an oscillator 18 mesh, and then mixed with HPMC and magnesium metasilicate sieved with a 25 mesh sieve, and then with a second simple mixing of magnesium stearate sieved with a 30 mesh sieve to prepare granules.
  • the prepared granules were compressed into tablets of 15 to 20 kp with a rotary tableting machine, and film-coated with a coating machine to prepare a formulation.
  • formulations of #1-3, #1-4 and #1-5 were prepared by omitting the dry granulation process.
  • the prepared formulation and the control formulation were tested according to the dissolution test method 2 (paddle method) among the general test methods of the Korean Pharmacopoeia at 100 rpm in the dissolution solution (900 mL of water at 37°C), and the dissolution rate was measured by HPLC was analyzed and the results are shown in FIG. 1 .
  • formulations of #1-1 and #1-2 were able to secure a stable average dissolution rate of up to 3-4% compared to the control group.
  • formulations #1-3 and #1-4 had an increased initial dissolution rate, and as with formulations #1-5, the dissolution rate did not decrease even if the content of the sustained-release agent was increased. Therefore, it was confirmed that the dissolution rate of the formulation prepared by sequentially applying the wet granulation process and the dry granulation process showed excellent dissolution rate without increasing the usage of the sustained-release agent.
  • a formulation was prepared in the same manner as in #1-2 of Example 1, except that components and contents were adjusted as shown in Table 2 below.
  • the dissolution rate of the prepared sustained-release formulation was measured in the same manner as in Example 1 above, and the results are shown in FIG. 2 . As shown in FIG. 2 , results similar to #1-2 were obtained even with some changes in the content of HPMC used in the dry granulation process.
  • a formulation was prepared in the same manner as in #1-2 of Example 1, except that components and contents were adjusted as shown in Table 3 below.
  • the dissolution rate of the prepared formulation was measured in the same manner as in Example 1 above, and the results are shown in FIG. 3 . As shown in FIG. 3, despite the miniaturization to 1290 mg per formulation, it was possible to secure an equivalent dissolution profile of about 5% with the formulation of the control group.

Abstract

The present invention provides a sustained release formulation of metformin, or a pharmaceutically acceptable salt thereof, which can exhibit a sustained release pattern even if the size of the formulation is reduced, and thus not only can metformin be effectively delivered to the inside of the body but convenience of administration for a patient is also improved.

Description

메트포르민 서방성 제제 및 이의 제조 방법Metformin sustained-release formulation and method for preparing the same
본 발명은 메트포르민 서방성 제제 및 이의 제조 방법에 관한 것이다. The present invention relates to a metformin sustained-release formulation and a method for preparing the same.
메트포르민(Metformin)은 비구아나이드(Biguanide) 계열의 약물로 인슐린 비의존성 진성 당뇨병(non-insulin dependent diabetes mellitus, NIDDM)의 치료제로 사용되며, 당뇨병의 1차 선택 약으로도 많은 당뇨병 환자가 복용 중인 약물이다.Metformin is a biguanide drug that is used as a treatment for non-insulin dependent diabetes mellitus (NIDDM). It is also a drug of choice for many diabetic patients. to be.
상기 메트포르민은 수용해도가 높기 때문에 일반적인 정제로 제조하는 경우 급격한 방출로 인해 과도한 혈당 강하 및 위장관 장애를 불러올 수 있다. 또한, 메트포르민은 통상적으로 250 mg 내지 1000 mg(하루 최대 2550 mg)의 많은 양을 하루에 2회 내지 3회에 걸쳐서 속방출성 정제로 복용하기 때문에, 메트포르민의 빠른 방출에 인한 급격한 혈중 농도의 변화로 인해, 부작용 및 내성을 더욱 심화시키는 문제가 있다. Since the metformin has high water solubility, when it is prepared as a general tablet, it may cause excessive blood sugar drop and gastrointestinal disturbances due to rapid release. In addition, since metformin is usually taken as an immediate-release tablet in a large amount of 250 mg to 1000 mg (up to 2550 mg per day) 2 to 3 times a day, a rapid change in blood concentration due to the rapid release of metformin Due to this, there is a problem that further aggravates side effects and tolerance.
또한, 상기와 같은 문제 외에도, 메트포르민은 2시간 내지 6시간의 짧은 혈중 반감기를 가지기 때문에, 메트포르민을 천천히 방출시키는 서방성 제제의 개발이 필요하다. In addition to the above problems, since metformin has a short blood half-life of 2 to 6 hours, it is necessary to develop a sustained-release formulation that releases metformin slowly.
한편, 서방성 제제로 제조시 일반적으로 제제의 부피를 늘리는 방안, 예컨대 서방화제 또는 부형제를 다량 사용하여 제제 내 약물이 천천히 방출시키는 방법이 우선적으로 고려될 수 있다. 그러나, 메트포르민과 같이 단위 투여량이 많고 압축성이 좋지 않은 약물의 경우, 상기와 같은 방법으로 정제를 제조하면 제제의 부피가 지나치게 커져 환자들이 복용하기가 어렵다는 문제가 있다. On the other hand, when manufacturing a sustained-release formulation, a method of increasing the volume of the formulation, such as a method of slowly releasing the drug in the formulation using a large amount of a sustained-release agent or excipient, may be considered preferentially. However, in the case of a drug having a large unit dose and poor compressibility, such as metformin, when a tablet is manufactured by the above method, the volume of the formulation becomes too large, which makes it difficult for patients to take it.
이에, 본 발명자들은 제제의 크기를 축소하면서도 서방성 방출 패턴을 나타낼 수 있는 메트포르민 서방성 제제를 확인하여 본 발명을 완성하였다.Accordingly, the present inventors completed the present invention by identifying a metformin sustained-release formulation capable of exhibiting a sustained-release pattern while reducing the size of the formulation.
본 발명은 제제의 크기를 축소하면서도 서방성 방출 패턴을 나타낼 수 있는 메트포르민 또는 이의 약학적으로 허용 가능한 염의 서방성 제제, 및 이의 제조 방법을 제공하기 위한 것이다. An object of the present invention is to provide a sustained-release formulation of metformin or a pharmaceutically acceptable salt thereof, which can exhibit a sustained-release pattern while reducing the size of the formulation, and a method for preparing the same.
상기 과제를 해결하기 위하여, 본 발명은 하기를 포함하는 메트포르민 또는 이의 약학적으로 허용 가능한 염의 서방성 제제를 제공한다:In order to solve the above problems, the present invention provides a sustained-release formulation of metformin or a pharmaceutically acceptable salt thereof, comprising:
1) 메트포르민 또는 이의 약학적으로 허용 가능한 염 100 중량부;1) 100 parts by weight of metformin or a pharmaceutically acceptable salt thereof;
2) 결합제 1 내지 10 중량부;2) 1 to 10 parts by weight of a binder;
3) 서방화제 15 내지 30 중량부; 및3) 15 to 30 parts by weight of a sustained-release agent; and
4) 활택제 1 내지 5 중량부.4) 1 to 5 parts by weight of a lubricant.
본 발명에서 사용하는 용어 '메트포르민'은 하기의 화학식을 가지는 화합물로서, 본 발명에 따른 서방성 제제의 활성 성분으로 사용된다. The term 'metformin' used in the present invention is a compound having the following formula, and is used as an active ingredient of the sustained-release preparation according to the present invention.
Figure PCTKR2020018958-appb-img-000001
Figure PCTKR2020018958-appb-img-000001
또한, 본 발명은 상기 메트포르민 외에도 이의 약학적으로 허용 가능한 염을 사용할 수 있다. 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산부가염과 같이, 당업계에서 통상적으로 사용되는 염을 제한 없이 사용할 수 있다. 본 발명의 용어 "약학적으로 허용 가능한 염"이란 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 메트포르민의 이로운 효능을 저하시키지 않는 임의의 모든 유기 또는 무기 부가염을 의미한다.Also, in the present invention, in addition to metformin, a pharmaceutically acceptable salt thereof may be used. As the salt, a salt commonly used in the art, such as an acid addition salt formed by a pharmaceutically acceptable free acid, may be used without limitation. As used herein, the term "pharmaceutically acceptable salt" refers to any and all organic or inorganic addition salts in which the side effects attributable to the salt do not reduce the beneficial efficacy of metformin at a concentration having an effective action that is relatively non-toxic and harmless to the patient. it means.
무기산 또는 유기산을 사용하여 통상적인 방법으로 약학적으로 허용 가능한 염을 얻을 수 있다. 예를 들어 메트포르민을 수혼화성 유기용매, 예를 들면 아세톤, 메탄올, 에탄올, 또는 아세토나이트릴에 용해시키고, 유기산 또는 무기산을 가하여 침전된 결정을 여과하여 제조, 건조시켜 약학적으로 허용 가능한 염을 얻을 수 있다. 또는 산이 부가된 반응 혼합물에서 용매나 과량의 산을 감압하여, 잔사를 건조시켜서 제조하거나, 또는 다른 유기용매를 가하여 석출된 염을 여과하여 제조할 수 있다. 이때 바람직한 염으로서, 염산, 브롬화수소산, 황산, 인산, 질산, 아세트산, 글리콜산, 락트산, 피루브산, 말론산, 석신산, 글루타르산, 푸마르산, 말산, 만델산, 타르타르산, 시트르산, 아스코르브산, 팔미트산, 말레산, 하이드록시말레산, 벤조산, 하이드록시벤조산, 페닐아세트산, 신남산, 살리실산, 메탄술폰산, 벤젠술폰산 또는 톨루엔술폰산 등으로부터 유도된 염을 들 수 있다. 가장 바람직하게는, 상기 메트포르민의 약학적으로 허용 가능한 염은 메트포르민 염산염이다. A pharmaceutically acceptable salt can be obtained by a conventional method using an inorganic acid or an organic acid. For example, metformin is dissolved in a water-miscible organic solvent, such as acetone, methanol, ethanol, or acetonitrile, and an organic or inorganic acid is added to filter the precipitated crystals, which are prepared and dried to obtain a pharmaceutically acceptable salt. can Alternatively, it can be prepared by reducing the solvent or excess acid in the reaction mixture to which the acid is added, drying the residue, or filtering the salt precipitated by adding another organic solvent. At this time, as preferred salts, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, pal and salts derived from mic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid. Most preferably, the pharmaceutically acceptable salt of metformin is metformin hydrochloride.
메트포르민은 수용해도가 높다는 점 외에도, 일일 복용량이 많고 짧은 혈중 반감기를 가져, 메트포르민의 정제는 서방성 제제로 제조되어야 한다. 이를 위하여 통상적으로 다량의 서방화제를 사용한 서방성 제제가 고려되나 부피가 지나치게 커져 환자들이 복용하기가 어렵다는 문제가 있다. In addition to high water solubility, metformin has a high daily dose and a short blood half-life, so tablets of metformin must be manufactured as a sustained-release formulation. For this purpose, a sustained-release formulation using a large amount of a sustained-release agent is generally considered, but has a problem in that it is difficult for patients to take because the volume is too large.
이에 본 발명에서는 서방화제를 적게 사용하면서도 각 성분의 함량 및 제조 과정을 조절하여 부피가 작으면서도 효과적인 서방성 방출 효과를 나타내는 제제를 제조한다. Accordingly, in the present invention, a formulation exhibiting an effective sustained-release effect while having a small volume is prepared by controlling the content and manufacturing process of each component while using a small amount of the sustained-release agent.
본 발명에서 사용하는 용어 '결합제'란, 본 발명에 따른 서방성 제제 내 성분들을 서로 결합시키기 위해 사용되는 성분으로, 서방성 제제를 제조하는 과정에서 압축하는 과정 또는 압축 후에 점착성을 제공하여 각 성분들을 결합시킨다. 특히, 후술할 바와 같이, 상기 결합제는 메트포르민과 함께 습식과립 공정에서 사용되는데, 이때 결합제를 사용함으로써 각 성분들이 보다 치밀하게 결합할 수 있으며, 따라서 메트포르민이 서방성으로 방출되도록 하는데 유리하다. The term 'binder' used in the present invention is a component used to bind the components in the sustained-release formulation according to the present invention to each other, and each component is compressed during the process of preparing the sustained-release formulation or by providing adhesion after compression. combine them In particular, as will be described later, the binder is used together with metformin in the wet granulation process. In this case, each component can be more densely bound by using the binder, which is advantageous for sustained release of metformin.
상기 결합제는 상기 메트포르민 또는 이의 약학적으로 허용 가능한 염 100 중량부 대비 1 내지 10 중량부로 사용한다. 상기 함량이 1 중량부 미만인 경우 결합제의 함량이 미미하여 메트포르민의 서방성 방출 효과를 나타내기 어렵고, 10 중량부 초과에서는 제제의 부피가 지나치게 커지는 문제가 있다. 바람직하게는, 상기 결합제는 상기 메트포르민 또는 이의 약학적으로 허용 가능한 염 100 중량부 대비 2 내지 5 중량부로 사용한다.The binder is used in an amount of 1 to 10 parts by weight based on 100 parts by weight of the metformin or a pharmaceutically acceptable salt thereof. When the content is less than 1 part by weight, the content of the binder is insignificant, so it is difficult to exhibit a sustained-release effect of metformin, and when it exceeds 10 parts by weight, there is a problem in that the volume of the formulation becomes excessively large. Preferably, the binder is used in an amount of 2 to 5 parts by weight based on 100 parts by weight of the metformin or a pharmaceutically acceptable salt thereof.
바람직하게는, 상기 결합제는 하이드록시에틸 셀룰로오스, 하이드록시프로필 셀룰로오스, 포비돈, 또는 이들의 조합으로 이루어진 군으로부터 선택될 수 있으며, 그 외에도 경구용 고형제제의 제형화에 있어 약학적 분야에서 일반적으로 사용되는 것은 모두 사용될 수 있다.Preferably, the binder may be selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, povidone, or a combination thereof, and in addition, it is commonly used in the pharmaceutical field in the formulation of oral solid preparations. Anything can be used.
본 발명에서 사용하는 용어 '서방화제'란, 본 발명에 따른 서방성 제제 내 활성 성분의 방출 속도를 느리게 하는 성분이다. 이론적으로 제한되는 것은 아니나, 상기 서방화제는 제제 표면에 고점도의 겔 층을 형성하여 체내에 약물을 서서히 방출하게 한다. 특히, 후술할 바와 같이, 상기 서방화제는 건식과립 공정에서 사용되는데, 이때 서방화제를 사용함으로써 활성 성분과 더욱 강하게 점착시켜 메트포르민 방출을 제어하는데 효과적이다. The term 'sustained-release agent' used in the present invention is a component that slows the release rate of the active ingredient in the sustained-release preparation according to the present invention. Although not limited by theory, the sustained-release agent forms a high-viscosity gel layer on the surface of the formulation to slowly release the drug into the body. In particular, as will be described later, the sustained-release agent is used in the dry granulation process. In this case, the sustained-release agent is effective in controlling the release of metformin by stronger adhesion to the active ingredient.
상기 서방화제는, 상기 메트포르민 또는 이의 약학적으로 허용 가능한 염 100 중량부 대비 15 내지 30 중량부로 사용한다. 상기 함량이 15 중량부 미만에서는 서방화제의 함량이 미미하여 메트포르민의 서방성 방출 효과를 나타내기 어렵고, 30 중량부 초과에서는 서방성 방출 효과가 실질적으로 증가하지 않을 뿐만 아니라 제제의 부피가 지나치게 커지는 문제가 있다. 바람직하게는, 상기 서방화제는 상기 메트포르민 또는 이의 약학적으로 허용 가능한 염 100 중량부 대비 15 내지 20 중량부로 사용한다.The sustained-release agent is used in an amount of 15 to 30 parts by weight based on 100 parts by weight of the metformin or a pharmaceutically acceptable salt thereof. When the content is less than 15 parts by weight, the content of the sustained-release agent is insignificant, so it is difficult to exhibit the sustained-release effect of metformin, and when the content exceeds 30 parts by weight, the sustained-release effect does not substantially increase and the volume of the formulation becomes excessively large. have. Preferably, the sustained-release agent is used in an amount of 15 to 20 parts by weight based on 100 parts by weight of the metformin or a pharmaceutically acceptable salt thereof.
바람직하게는, 상기 서방화제는 폴리비닐피롤리돈 유도체, 셀룰로오스 유도체, 전분, 젤라틴, 또는 이들의 조합이다. 보다 바람직하게는, 상기 폴리비닐피롤리돈 유도체는 포비돈, 코포비돈, 또는 이들의 조합이다. 보다 바람직하게는, 상기 셀룰로오스 유도체는, 메틸셀룰로오스, 에틸셀룰로오스, 카르복시메틸셀룰로오스 나트륨, 또는 이들의 조합이다. 가장 바람직하게는, 상기 서방화제는 하이드록시프로필 메틸셀룰로오스이다. Preferably, the sustained-release agent is a polyvinylpyrrolidone derivative, a cellulose derivative, starch, gelatin, or a combination thereof. More preferably, the polyvinylpyrrolidone derivative is povidone, copovidone, or a combination thereof. More preferably, the cellulose derivative is methylcellulose, ethylcellulose, sodium carboxymethylcellulose, or a combination thereof. Most preferably, the sustained release agent is hydroxypropyl methylcellulose.
본 발명에서 사용하는 용어 '활택제'란, 본 발명에 따른 서방성 제제 제조시 압력 등을 가하였을 때 과립이 기계에 부착되는 것을 방지하고 또한 제제에 원활한 흐름성을 주는 성분이다. 또한, 본 발명에서는 상기 활택제가 과립 표면을 둘러싸는 형태로 첨가되어 메트포르민이 서방성으로 방출되도록 하는데 유리하다. 후술할 바와 같이, 상기 활택제는 메트포르민과 함께 습식과립 공정 및 후혼합에서 사용되는데, 특히 습식과립 공정에서 활택제를 사용함으로써 메트포르민을 일부 둘러싸는 형태로 첨가되어 메트포르민이 서방성으로 방출되도록 하는데 유리하다. The term 'lubricating agent' used in the present invention is a component that prevents the granules from adhering to the machine and provides smooth flowability to the preparation when pressure, etc. is applied during the manufacture of the sustained-release preparation according to the present invention. In addition, in the present invention, the lubricant is added in the form of surrounding the surface of the granules, which is advantageous to release metformin in a sustained release. As will be described later, the lubricant is used in the wet granulation process and post-mixing together with metformin. In particular, by using the lubricant in the wet granulation process, it is added in a form that partially surrounds the metformin, which is advantageous for the sustained release of metformin. Do.
상기 활택제는, 상기 메트포르민 또는 이의 약학적으로 허용 가능한 염 100 중량부 대비 1 내지 5 중량부로 사용한다. 상기 함량이 1 중량부 미만에서는 활택제의 함량이 미미하여 본 발명에 따른 서방성 제제의 제조가 어려우며, 5 중량부 초과에서는 제제의 부피가 지나치게 커지는 문제가 있다. 바람직하게는, 상기 활택제는 상기 메트포르민 또는 이의 약학적으로 허용 가능한 염 100 중량부 대비 2 내지 3 중량부로 사용된다. The lubricant is used in an amount of 1 to 5 parts by weight based on 100 parts by weight of the metformin or a pharmaceutically acceptable salt thereof. When the content is less than 1 part by weight, the amount of the lubricant is insignificant, making it difficult to prepare the sustained-release preparation according to the present invention, and when it exceeds 5 parts by weight, there is a problem in that the volume of the preparation becomes excessively large. Preferably, the lubricant is used in an amount of 2 to 3 parts by weight based on 100 parts by weight of the metformin or a pharmaceutically acceptable salt thereof.
바람직하게는, 상기 활택제는 스테아린산 마그네슘(magnesium stearate), 메타규산알루민산마그네슘(magnesium aluminumsilicate), 산화 실리카(SiO 2), 콜로이드성 이산화규소, 콜로이드성 실리카, 탈크(talc), 또는 이들의 조합일 수 있으며, 그 외에도 경구용 고형 제제의 제형화에 있어 약학적 분야에서 일반적으로 사용되는 것은 제한 없이 사용될 수 있다. 보다 바람직하게는, 상기 활택제는 스테아린산 마그네슘(magnesium stearate), 메타규산알루민산마그네슘(magnesium aluminumsilicate)이다. Preferably, the lubricant is magnesium stearate, magnesium aluminumsilicate metasilicate, silica oxide (SiO 2 ), colloidal silicon dioxide, colloidal silica, talc, or a combination thereof. may be, and in addition, those generally used in the pharmaceutical field in the formulation of oral solid preparations may be used without limitation. More preferably, the lubricant is magnesium stearate or magnesium aluminumsilicate metasilicate.
또한, 본 발명에 따른 서방성 제제는 나정, 필름코팅정, 단층정, 이층정, 다층정 또는 유핵정이다. 또한, 본 발명에 따른 서방성 제제는 상술한 메트포르민의 서방성 방출 효과를 저해하지 않는 한, 본 발명이 속하는 제제 분야에 통상적으로 사용되는 첨가제를 제한 없이 사용할 수 있다. In addition, the sustained-release preparation according to the present invention is an uncoated tablet, a film-coated tablet, a single-layer tablet, a double-layer tablet, a multi-layer tablet, or a core-coated tablet. In addition, as long as the sustained-release formulation according to the present invention does not inhibit the above-described sustained-release effect of metformin, additives commonly used in the field of formulation to which the present invention belongs may be used without limitation.
바람직하게는, 본 발명에 따른 서방성 제제는 메트포르민 또는 이의 약학적으로 허용 가능한 염을 제제 총 중량에 대해서 60 내지 90 중량% 포함하며, 보다 바람직하게는 61 중량% 이상, 62 중량% 이상, 63 중량% 이상, 64 중량% 이상, 65 중량% 이상, 66 중량% 이상, 67 중량% 이상, 68 중량% 이상, 69 중량% 이상, 70 중량% 이상이고; 89 중량% 이하, 88 중량% 이하, 87 중량% 이하, 86 중량% 이하, 85 중량% 이하, 84 중량% 이하, 83 중량% 이하, 82 중량% 이하, 81 중량% 이하, 80 중량% 이하이다.Preferably, the sustained-release formulation according to the present invention contains 60 to 90% by weight of metformin or a pharmaceutically acceptable salt thereof, based on the total weight of the formulation, more preferably 61% by weight or more, 62% by weight or more, 63 at least 64 wt%, at least 65 wt%, at least 66 wt%, at least 67 wt%, at least 68 wt%, at least 69 wt%, at least 70 wt%; 89 wt% or less, 88 wt% or less, 87 wt% or less, 86 wt% or less, 85 wt% or less, 84 wt% or less, 83 wt% or less, 82 wt% or less, 81 wt% or less, 80 wt% or less .
또한, 본 발명은 하기의 단계를 포함하는 상술한 메트포르민 또는 이의 약학적으로 허용 가능한 염의 서방성 제제의 제조 방법을 제공한다:In addition, the present invention provides a method for preparing a sustained-release formulation of the above-described metformin or a pharmaceutically acceptable salt thereof, comprising the following steps:
1) 메트포르민 또는 이의 약학적으로 허용 가능한 염, 결합제 및 활택제를 습식과립법으로 과립을 제조하는 단계(단계 1);1) preparing granules of metformin or a pharmaceutically acceptable salt thereof, a binder and a lubricant by a wet granulation method (step 1);
2) 상기 단계 1의 과립 및 서방화제를 건식과립법으로 과립을 제조하는 단계(단계 2); 및2) preparing granules using the dry granulation method of the granules and sustained-release agent of step 1 (step 2); and
3) 상기 단계 2의 과립, 서방화제 및 활택제를 혼합하는 단계(단계 3).3) mixing the granules, sustained-release agent and lubricant of step 2 (step 3).
상기 단계 1은 습식과립법을 적용하여 1차 과립을 제조하는 것으로, 메트포르민 또는 이의 약학적으로 허용 가능한 염, 결합제 및 활택제를 습식과립법으로 과립을 제조하는 단계이다. Step 1 is to prepare primary granules by applying the wet granulation method, and is a step of preparing granules using the wet granulation method with metformin or a pharmaceutically acceptable salt thereof, a binder, and a lubricant.
습식과립법이란, 각 제제의 성분들을 결합액과 연합하여 제립하고 건조하여 과립을 제조하는 것을 의미한다. 상기 습십과립법은 결합제와 함께 각 성분들이 보다 치밀하게 결합할 수 있으며, 따라서 활성 성분이 서방성으로 방출되도록 하는데 유리하다. The wet granulation method refers to manufacturing granules by combining the components of each formulation with a binding solution and drying the granules. The wet granulation method is advantageous in that each component can be more tightly bound together with a binder, and thus the active ingredient is released in a sustained release.
구체적으로 본 발명에서는, 메트포르민 또는 이의 약학적으로 허용 가능한 염, 결합제 및 활택제를 포함하는 혼합물을 결합액과 연합하여 제립하고 건조하여 과립을 제조하는 것을 의미한다. 상기 결합액은 물, 에탄올, 이소프로판올, 아세톤, 또는 이들의 조합일 수 있다. 또한, 상기 건조는 각 성분의 안정성이 유지되도록 10℃ 내지 60℃, 바람직하게는 20℃ 내지 40℃의 온도에서 수행한다. Specifically, in the present invention, it means to prepare granules by granulating and drying a mixture comprising metformin or a pharmaceutically acceptable salt thereof, a binder, and a lubricant in association with a binding solution. The binding solution may be water, ethanol, isopropanol, acetone, or a combination thereof. In addition, the drying is performed at a temperature of 10° C. to 60° C., preferably 20° C. to 40° C. so that the stability of each component is maintained.
또한, 상기 제조된 과립이 뭉쳐있는 경우, 필요에 따라 상기 제조된 과립을 체과하는 단계를 추가로 포함할 수 있다. In addition, when the prepared granules are agglomerated, the step of sieving the prepared granules if necessary may be further included.
상기 단계 2는, 앞서 단계 1에서 제조한 과립 및 서방화제를 건식과립법으로 과립을 제조하는 단계이다. Step 2 is a step of preparing granules using the dry granulation method using the granules and sustained-release agent prepared in step 1 above.
앞서 단계 1에서 습식과립법으로 치밀한 과립을 제조하였기 때문에, 서방화제를 적은 양으로 사용하여도 효과적인 서방성 방출 효과를 나타내는 제제를 제조할 수 있다. Since dense granules were prepared by the wet granulation method in step 1 above, a formulation exhibiting an effective sustained-release effect can be prepared even when a small amount of the sustained-release agent is used.
건식과립법이란, 각 제제의 성분들을 압축하여 각 성분들을 결합시켜 과립을 제조하는 것으로, 상술한 습식과립법과 달리 결합액이 사용되지 않는다. 구체적으로, 건식과립법은 롤러 압착법(roller compacting)으로 두 개의 롤러 사이로 분말을 통과시키면서 압력을 가하여 상기 분말을 압축하여 제조하는 방법이다. The dry granulation method is to prepare granules by combining the components by compressing the components of each formulation, and unlike the wet granulation method described above, a binder is not used. Specifically, the dry granulation method is a method of manufacturing the powder by applying pressure while passing the powder between two rollers by roller compacting.
또한, 상기 제조된 과립이 뭉쳐있는 경우, 필요에 따라 상기 제조된 과립을 체과하는 단계를 추가로 포함할 수 있다. In addition, when the prepared granules are agglomerated, the step of sieving the prepared granules if necessary may be further included.
상기 단계 3은, 앞서 단계 2에서 제조한 과립에 서방화제 및 활택제를 혼합하는 단계이다. 앞서 단계 2에서 제조한 과립에 서방화제 및 활택제를 추가하여 방출제어 효과를 더해줌과 동시에 과립의 원활한 흐름성을 부여한다. Step 3 is a step of mixing a sustained-release agent and a lubricant with the granules prepared in step 2 above. By adding a sustained-release agent and a lubricant to the granules prepared in step 2 above, a release control effect is added and smooth flowability of the granules is imparted.
바람직하게는, 상기 단계 2에서 사용한 서방화제와 상기 단계 3에서 사용한 서방화제의 함량비가 1:1 내지 1:6이다. 또한 바람직하게는, 상기 단계 2에서 사용한 서방화제와 상기 단계 3에서 사용한 서방화제는 서로 동일한 물질이다. Preferably, the content ratio of the sustained-release agent used in step 2 to the sustained-release agent used in step 3 is 1:1 to 1:6. Also preferably, the sustained-release agent used in step 2 and the sustained-release agent used in step 3 are the same material.
또한, 본 발명에 따른 제조 방법은, 상기 단계 3에서 제조한 제제를 코팅하는 단계를 추가로 포함할 수 있다. In addition, the manufacturing method according to the present invention may further include the step of coating the formulation prepared in step 3.
상술한 바와 같이, 본 발명은 제제의 크기를 축소하면서도 서방성 방출 패턴을 나타낼 수 있는 메트포르민 또는 이의 약학적으로 허용 가능한 염의 서방성 제제를 제공함으로써, 메트포르민을 효과적으로 체내에 전단할 수 있을 뿐만 아니라, 환자의 복용 편의도 개선할 수 있다. As described above, the present invention provides a sustained-release formulation of metformin or a pharmaceutically acceptable salt thereof, which can exhibit a sustained-release pattern while reducing the size of the formulation, thereby effectively shearing metformin in the body, It can also improve the convenience of taking the patient.
도 1은 본 발명의 실시예 1에서 제조한 제제에 대한 용출 그래프를 나타낸 것이다. 1 shows a dissolution graph for the formulation prepared in Example 1 of the present invention.
도 2는 본 발명의 실시예 1에서 제조한 제제에 대한 용출 그래프를 나타낸 것이다. Figure 2 shows a dissolution graph for the formulation prepared in Example 1 of the present invention.
도 3은 본 발명의 실시예 1에서 제조한 제제에 대한 용출 그래프를 나타낸 것이다. 3 shows a dissolution graph for the formulation prepared in Example 1 of the present invention.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시하나, 하기 실시예는 본 발명을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다.Hereinafter, preferred examples are presented to help the understanding of the present invention, but the following examples are only illustrative of the present invention and the scope of the present invention is not limited to the following examples.
실시예 1Example 1
하기 표 1의 성분과 함량으로 습식 과립 공정 및 건식 과립 공정으로 서방성 제제를 제조하였다. A sustained-release formulation was prepared by a wet granulation process and a dry granulation process with the components and contents shown in Table 1 below.
구체적으로, 습식 과립 공정으로, 메트포르민 염산염, HEC 또는 HPC, 스테아르산 마그네슘을 25 mesh 체과하여 고속혼합기에 투입한 후 혼합(Agitator 100 rpm, Chopper 600 rpm, 1 min)하고, 연합 공정(Agitator 100 rpm, Chopper 800 rpm, 3 min)에 정제수(100 mg/T)를 넣어 제립(Agitator 100 rpm, Chopper 1000 rpm, 5 min)하였다. 이어 제조된 과립을 건조(60℃, LOD 1.5% 이하)하였다. Specifically, in the wet granulation process, metformin hydrochloride, HEC or HPC, and magnesium stearate were sieved with 25 mesh, put into a high-speed mixer, and mixed (Agitator 100 rpm, Chopper 600 rpm, 1 min), and the kneading process (Agitator 100 rpm) , Chopper 800 rpm, 3 min) was added with purified water (100 mg/T) and granulated (Agitator 100 rpm, Chopper 1000 rpm, 5 min). Then, the prepared granules were dried (60° C., LOD 1.5% or less).
상기 제조된 과립을 18 mesh 체과하고, 여기에 25 mesh 체과한 HPMC를 혼합하여 Roller compactor로 건식 과립(3 rpm, 5 MPa)하였다. The prepared granules were sieved with 18 mesh, mixed with HPMC sieved with 25 mesh, and dry granulated (3 rpm, 5 MPa) with a roller compactor.
상기 제조된 과립을 Oscillator로 18 mesh 체과하고, 여기에 25 mesh 체과한 HPMC 및 메타규산알루민산마그네슘와 1차 단순 혼합하고, 이어 30 mesh 체과한 스테아르산 마그네슘을 2차 단순 혼합하여 과립을 제조하였다. The prepared granules were sieved with an oscillator 18 mesh, and then mixed with HPMC and magnesium metasilicate sieved with a 25 mesh sieve, and then with a second simple mixing of magnesium stearate sieved with a 30 mesh sieve to prepare granules.
상기 제조된 과립을 로터리 타정기로 15~20kp의 정제로 타정하였고, 코팅기로 필름 코팅하여 제제를 제조하였다.The prepared granules were compressed into tablets of 15 to 20 kp with a rotary tableting machine, and film-coated with a coating machine to prepare a formulation.
한편, #1-3, #1-4 및 #1-5의 제제는, 상기 건식 과립 공정을 생략하여 제제를 제조하였다. On the other hand, formulations of #1-3, #1-4 and #1-5 were prepared by omitting the dry granulation process.
공정fair 원료명Raw material name #1-1#1-1 #1-2#1-2 #1-3#1-3 #1-4#1-4 #1-5#1-5
습식과립wet granulation Metformin HClMetformin HCl 1,000 mg1,000 mg 1,000 mg1,000 mg 1,000 mg1,000 mg 1,000 mg1,000 mg 1,000 mg1,000 mg
Hydroxyethylcellulose (HEC)Hydroxyethylcellulose (HEC) 40 mg40 mg -- 40 mg40 mg -- 40 mg40 mg
Hydroxypropyl cellulose (HPC)Hydroxypropyl cellulose (HPC) -- 40 mg40 mg -- 40 mg40 mg --
Magnesium stearateMagnesium stearate 5 mg5 mg 5 mg5 mg 5 mg5 mg 5 mg5 mg 5 mg5 mg
건식과립dry granules Hydroxypropyl methylcellulose(HPMC)Hydroxypropyl methylcellulose (HPMC) 65 mg65 mg 65 mg65 mg -- -- --
후혼합post-mix Hydroxypropyl methylcellulose(HPMC)Hydroxypropyl methylcellulose (HPMC) 210 mg210 mg 210 mg210 mg 275 mg275 mg 275 mg275 mg 350 mg350 mg
Magnesium aluminometasilicateMagnesium aluminometasilicate 15 mg15 mg 15 mg15 mg 15 mg15 mg 15 mg15 mg 15 mg15 mg
Magnesium stearateMagnesium stearate 5 mg5 mg 5 mg5 mg 5 mg5 mg 5 mg5 mg 5 mg5 mg
코팅 coating Opadry 85F17438Opadry 85F17438 40 mg40 mg 40 mg40 mg 40 mg40 mg 40 mg40 mg 45 mg45 mg
총량total amount 1380 mg1380 mg 1380 mg1380 mg 1380 mg1380 mg 1380 mg1380 mg 1460 mg1460 mg
한편, 대조군으로 글루코파지XR 1000 mg 서방정 제제를 사용하였다. Meanwhile, as a control, a 1000 mg sustained-release formulation of Glucophage XR was used.
상기 제조한 제제 및 대조군 제제를 용출액(37℃의 물 900 mL)에서 100 rpm으로 대한민국약전 일반시험법 중 용출시험법 제2법(패들법)에 따라 시험하고 각 시간대 별로 용출액을 취해 용출율을 HPLC로 분석하여 그 결과를 도 1에 나타내었다. The prepared formulation and the control formulation were tested according to the dissolution test method 2 (paddle method) among the general test methods of the Korean Pharmacopoeia at 100 rpm in the dissolution solution (900 mL of water at 37°C), and the dissolution rate was measured by HPLC was analyzed and the results are shown in FIG. 1 .
도 1에 나타난 바와 같이, #1-1 및 #1-2의 제제는 대조군 대비 최대 3~4% 이내의 안정적인 평균 용출율을 확보할 수 있었다. 또한, #1-3 및 #1-4의 제제는 초기 용출 속도가 빨라졌으며, #1-5의 제제와 같이 서방화제의 함량을 높여도 용출율이 더 낮아지지는 않았다. 따라서, 습식과립 공정과 건식과립 공정을 순차적으로 적용하여 제조한 제제의 용출율이 서방화제의 사용량을 높이지 않으면서도 용출율이 우수하게 나타남을 확인할 수 있었다. As shown in FIG. 1 , formulations of #1-1 and #1-2 were able to secure a stable average dissolution rate of up to 3-4% compared to the control group. In addition, formulations #1-3 and #1-4 had an increased initial dissolution rate, and as with formulations #1-5, the dissolution rate did not decrease even if the content of the sustained-release agent was increased. Therefore, it was confirmed that the dissolution rate of the formulation prepared by sequentially applying the wet granulation process and the dry granulation process showed excellent dissolution rate without increasing the usage of the sustained-release agent.
실시예 2Example 2
하기 표 2와 같이 성분과 함량을 조절한 것을 제외하고는, 상기 실시예 1의 #1-2와 동일한 방법으로 제제를 제조하였다. A formulation was prepared in the same manner as in #1-2 of Example 1, except that components and contents were adjusted as shown in Table 2 below.
공정fair 원료명Raw material name #1-2#1-2 #2-1#2-1
습식과립wet granulation Metformin HClMetformin HCl 1,000 mg1,000 mg 1,000 mg1,000 mg
Hydroxypropyl cellulose (HPC)Hydroxypropyl cellulose (HPC) 40 mg40 mg 40 mg40 mg
Magnesium stearateMagnesium stearate 5 mg5 mg 5 mg5 mg
건식과립dry granules Hydroxypropyl methylcellulose(HPMC)Hydroxypropyl methylcellulose (HPMC) 65 mg65 mg 130 mg130 mg
후혼합post-mix Hydroxypropyl methylcellulose(HPMC)Hydroxypropyl methylcellulose (HPMC) 210 mg210 mg 145 mg145 mg
Magnesium aluminometasilicateMagnesium aluminometasilicate 15 mg15 mg 15 mg15 mg
Magnesium stearateMagnesium stearate 5 mg5 mg 5 mg5 mg
코팅 coating Opadry 85F17438Opadry 85F17438 40 mg40 mg 40 mg40 mg
총량total amount 1380 mg1380 mg 1380 mg1380 mg
상기 제조한 서방성 제제를 앞서 실시예 1과 동일한 방법으로 용출율을 측정하였으며, 그 결과를 도 2에 나타내었다. 도 2에 나타난 바와 같이, 건식 과립 공정에서 사용되는 HPMC의 함량의 일부 변화에도 #1-2와 유사한 결과를 나타내었다. The dissolution rate of the prepared sustained-release formulation was measured in the same manner as in Example 1 above, and the results are shown in FIG. 2 . As shown in FIG. 2 , results similar to #1-2 were obtained even with some changes in the content of HPMC used in the dry granulation process.
실시예 3Example 3
하기 표 3과 같이 성분과 함량을 조절한 것을 제외하고는, 상기 실시예 1의 #1-2와 동일한 방법으로 제제를 제조하였다. A formulation was prepared in the same manner as in #1-2 of Example 1, except that components and contents were adjusted as shown in Table 3 below.
공정fair 원료명Raw material name #1-2#1-2 #3-1#3-1
습식과립wet granulation Metformin HClMetformin HCl 1,000 mg1,000 mg 1,000 mg1,000 mg
Hydroxypropyl cellulose (HPC)Hydroxypropyl cellulose (HPC) 40 mg40 mg 35 mg35 mg
Magnesium stearateMagnesium stearate 5 mg5 mg 5 mg5 mg
건식과립dry granules Hydroxypropyl methylcellulose(HPMC)Hydroxypropyl methylcellulose (HPMC) 65 mg65 mg 30 mg30 mg
후혼합post-mix Hydroxypropyl methylcellulose(HPMC)Hydroxypropyl methylcellulose (HPMC) 210 mg210 mg 160 mg160 mg
Magnesium aluminometasilicateMagnesium aluminometasilicate 15 mg15 mg 15 mg15 mg
Magnesium stearateMagnesium stearate 5 mg5 mg 5 mg5 mg
코팅 coating Opadry 85F17438Opadry 85F17438 40 mg40 mg 40 mg40 mg
총량total amount 1380 mg1380 mg 1290 mg1290 mg
상기 제조한 제제를 앞서 실시예 1과 동일한 방법으로 용출율을 측정하였으며, 그 결과를 도 3에 나타내었다. 도 3에 나타난 바와 같이, 제제당 1290 mg로 소형화하였음에도 불구하고, 대조군의 제제와 5% 내외의 동등한 용출 프로파일을 확보할 수 있었다.The dissolution rate of the prepared formulation was measured in the same manner as in Example 1 above, and the results are shown in FIG. 3 . As shown in FIG. 3, despite the miniaturization to 1290 mg per formulation, it was possible to secure an equivalent dissolution profile of about 5% with the formulation of the control group.

Claims (14)

1) 메트포르민 또는 이의 약학적으로 허용 가능한 염 100 중량부;1) 100 parts by weight of metformin or a pharmaceutically acceptable salt thereof;
2) 결합제 1 내지 10 중량부;2) 1 to 10 parts by weight of a binder;
3) 서방화제 15 내지 30 중량부; 및3) 15 to 30 parts by weight of a sustained-release agent; and
4) 활택제 1 내지 5 중량부를 포함하는,4) containing 1 to 5 parts by weight of a lubricant,
메트포르민 또는 이의 약학적으로 허용 가능한 염의 서방성 제제.A sustained-release preparation of metformin or a pharmaceutically acceptable salt thereof.
제1항에 있어서, According to claim 1,
상기 결합제는 2 내지 5 중량부로 포함되는,The binder is included in 2 to 5 parts by weight,
서방성 제제.sustained release formulations.
제1항에 있어서, According to claim 1,
상기 결합제는 하이드록시에틸 셀룰로오스, 하이드록시프로필 셀룰로오스, 포비돈, 또는 이들의 조합인,The binder is hydroxyethyl cellulose, hydroxypropyl cellulose, povidone, or a combination thereof,
서방성 제제.sustained release formulations.
제1항에 있어서, According to claim 1,
상기 서방화제는 15 내지 20 중량부로 포함되는,The sustained-release agent is included in an amount of 15 to 20 parts by weight,
서방성 제제.sustained release formulations.
제1항에 있어서, According to claim 1,
상기 서방화제는 폴리비닐피롤리돈 유도체, 셀룰로오스 유도체, 전분, 젤라틴, 또는 이들의 조합인,The sustained-release agent is a polyvinylpyrrolidone derivative, a cellulose derivative, starch, gelatin, or a combination thereof,
서방성 제제.sustained release formulations.
제1항에 있어서,According to claim 1,
상기 서방화제는 하이드록시프로필 메틸셀룰로오스인,The sustained release agent is hydroxypropyl methylcellulose,
서방성 제제.sustained release formulations.
제1항에 있어서, According to claim 1,
상기 활택제는 2 내지 3 중량부로 포함되는,The lubricant is included in 2 to 3 parts by weight,
서방성 제제.sustained release formulations.
제1항에 있어서, According to claim 1,
상기 활택제는 스테아린산 마그네슘(magnesium stearate), 메타규산알루민산마그네슘(magnesium aluminumsilicate), 산화 실리카(SiO 2), 콜로이드성 이산화규소, 콜로이드성 실리카, 탈크(talc), 또는 이들의 조합인,The lubricant is magnesium stearate, magnesium aluminumsilicate metasilicate, silica oxide (SiO 2 ), colloidal silicon dioxide, colloidal silica, talc, or a combination thereof,
서방성 제제.sustained release formulations.
제1항에 있어서, According to claim 1,
상기 서방성 제제는 나정, 필름코팅정, 단층정, 이층정, 다층정 또는 유핵정인,The sustained-release formulation is an uncoated tablet, a film-coated tablet, a single-layer tablet, a double-layer tablet, a multi-layer tablet, or a core tablet,
서방성 제제.sustained release formulations.
제1항에 있어서, According to claim 1,
상기 메트포르민의 약학적으로 허용 가능한 염은 메트포르민 염산염인,The pharmaceutically acceptable salt of metformin is metformin hydrochloride,
서방성 제제.sustained release formulations.
1) 메트포르민 또는 이의 약학적으로 허용 가능한 염, 결합제 및 활택제를 습식과립법으로 과립을 제조하는 단계(단계 1);1) preparing granules of metformin or a pharmaceutically acceptable salt thereof, a binder and a lubricant by a wet granulation method (step 1);
2) 상기 단계 1의 과립 및 서방화제를 건식과립법으로 과립을 제조하는 단계(단계 2); 및2) preparing granules using the dry granulation method of the granules and sustained-release agent of step 1 (step 2); and
3) 상기 단계 2의 과립, 서방화제 및 활택제를 혼합하는 단계(단계 3)를 포함하는,3) comprising the step of mixing the granules, sustained-release agent and lubricant of step 2 (step 3),
메트포르민 또는 이의 약학적으로 허용 가능한 염의 서방성 제제의 제조 방법.A method for producing a sustained-release formulation of metformin or a pharmaceutically acceptable salt thereof.
제11항에 있어서, 12. The method of claim 11,
상기 단계 1은, 메트포르민 또는 이의 약학적으로 허용 가능한 염, 결합제 및 활택제를 결합액과 연합하여 제립하고 건조하여 과립을 제조하여 수행하는,In step 1, metformin or a pharmaceutically acceptable salt thereof, a binder and a lubricant are combined with a binding solution to form granules and dried to prepare granules,
제조 방법.manufacturing method.
제12항에 있어서, 13. The method of claim 12,
상기 결합액은 물, 에탄올, 이소프로판올, 아세톤, 또는 이들의 조합인,The binding solution is water, ethanol, isopropanol, acetone, or a combination thereof,
제조 방법.manufacturing method.
제11항에 있어서, 12. The method of claim 11,
상기 단계 2에서 사용한 서방화제와 상기 단계 3에서 사용한 서방화제의 함량비가 1:1 내지 1:6인,The content ratio of the sustained-release agent used in step 2 to the sustained-release agent used in step 3 is 1:1 to 1:6,
제조 방법.manufacturing method.
PCT/KR2020/018958 2019-12-23 2020-12-23 Metformin sustained release formulation and method for preparation thereof WO2021133046A1 (en)

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