KR101093781B1 - Solid pharmaceutical composition of moxifloxacin comprising ph adjustment agent - Google Patents

Solid pharmaceutical composition of moxifloxacin comprising ph adjustment agent Download PDF

Info

Publication number
KR101093781B1
KR101093781B1 KR1020110051595A KR20110051595A KR101093781B1 KR 101093781 B1 KR101093781 B1 KR 101093781B1 KR 1020110051595 A KR1020110051595 A KR 1020110051595A KR 20110051595 A KR20110051595 A KR 20110051595A KR 101093781 B1 KR101093781 B1 KR 101093781B1
Authority
KR
South Korea
Prior art keywords
moxifloxacin
solid composition
cellulose
sodium
tablet
Prior art date
Application number
KR1020110051595A
Other languages
Korean (ko)
Inventor
서혜란
전명관
안태군
최주현
서현미
서상교
Original Assignee
(주)비씨월드제약
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by (주)비씨월드제약 filed Critical (주)비씨월드제약
Priority to KR1020110051595A priority Critical patent/KR101093781B1/en
Application granted granted Critical
Publication of KR101093781B1 publication Critical patent/KR101093781B1/en

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • 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
    • A61K9/20—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)

Abstract

PURPOSE: A moxifloxacin solid composition containing pH adjusting agent is provided to maintain clinical availability and to enhance elution rate of moxifloxacin in an acidic solution. CONSTITUTION: A moxifloxacin solid composition contains 0.1-5 wt% of pH adjusting agent. The pH adjusting agent contains sodium bicarbonate and meglumine. The solid composition is manufactured in the form of a tablet, powder, capsule, or granule. The solid composition additionally contains pharmaceutically acceptable additives of disintegrant, binder, lubricant, excipient, antifoaming agent, or coloring agent.

Description

ｐＨ조절제를 함유하는 목시플록사신 고형 조성물 {Solid pharmaceutical composition of moxifloxacin comprising pH adjustment agent}Solid pharmaceutical composition of moxifloxacin comprising pH adjustment agent

본 발명은 pH조절제를 함유한 목시플록사신 고형 조성물에 관한 것이다.The present invention relates to a moxifloxacin solid composition containing a pH adjusting agent.

목시플록사신(Moxifloxacin)은 4세대 합성 플루오르퀴놀론 항생제로, 바이엘사(Bayer AG, 독일)에서 개발되었다. 이 약물은 그람양성균과 그람음성균 모두에 효과가 있는 광역항생물질로서, 세균의 DNA를 분리하는데 필요한 DNA자이레이즈, 2형 토포이소머라아제, 토포이소머라아제 4를 억제하는 역할을 하여, 세포 복제를 억제하는 것으로 알려져 있다.Moxifloxacin is a fourth generation synthetic fluoroquinolone antibiotic developed by Bayer AG, Germany. This drug is a broad-spectrum antibiotic that is effective against both Gram-positive and Gram-negative bacteria. It inhibits DNA gyase, type 2 topoisomerase, and topoisomerase 4, which are necessary to separate bacterial DNA. It is known to suppress.

목시플록사신의 경구 투여시, 생체이용율은 90% 정도로 비교적 높은 편이고 최고혈중농도에 도달하는 시간은 평균 2시간 정도로 흡수가 비교적 빠른 편이기 때문에 경구 투여에 적합한 약물이라고 할 수 있으며, 이 약물은 경구 정제의 형태로 각각 "아벨록스(Avelox®)", "아발록스(Avalox®)"또는 "아벨론(Avelon®)"이라는 상품명으로 판매되고 있다.When oral administration of moxifloxacin, the bioavailability is relatively high (90%) and the peak blood concentration is relatively high absorption of about 2 hours, which is suitable for oral administration. each "Abel Rocks (Avelox ®)" in the form of a tablet, sold under the trade name of "Raroia Rocks (Avalox ®)" or "Abel Ron (Avelon ®)".

목시플록사신은 높은 생체이용율과 빠른 흡수속도로 인하여 경구투여에 적합한 약물로 평가되지만, 목시플록사신 염산염의 경우 1회 복용량이 436.8 밀리그램으로 제형설계에 있어서 크기를 축소하기 위한 별도의 연구가 없다면, 제형 자체의 크기가 필연적으로 커질 수밖에 없다. 하지만 제형의 크기가 커지면, 연하력이 약한 환자(예를 들면, 소아 또는 노인 환자 등)들이 약물을 복용하기가 쉽지 않기 때문에 복약순응도가 낮아지는 등의 단점이 발생한다. Moxifloxacin is considered to be a suitable drug for oral administration due to its high bioavailability and fast absorption rate.However, in the case of moxifloxacin hydrochloride, one dose is 436.8 milligrams. The size of the formulation itself is inevitably large. However, when the size of the formulation increases, patients with weak swallowing power (for example, children or elderly patients, etc.) are not easy to take the drug, so there is a disadvantage, such as lower medication compliance.

현재 시판중인 "아벨록스®정"의 경우 정제 중량이 약 700 밀리그램 정도로 연하력이 약한 환자들이 복용하기에는 부담스러운 중량일 수 있다. Currently available Abelox ® tablets can be a burden for patients with weak swallowing, such as about 700 milligrams of tablet weight.

대한민국특허 제10-0531065호에 서방성 정제에 대해 제시되어 있지만, 제제에 서방성을 부여하기 위해서는 일정 비율의 서방성 첨가제를 필요로 하기 때문에 정제 중량이 더 늘어날 수밖에 없으며, 구체적으로 실시예를 살펴보면 보통 1000 밀리그램이 넘는 정제 중량을 제시하고 있다. 또한 목시플록사신이 위장관의 하부 구간(결장, 직장)에서 흡수된다는 사실로부터 서방성 제제의 가능성을 제시하고 있으나, 약물 자체의 특성을 살펴보면 경구 투여시 빠른 흡수속도를 나타낼 뿐만 아니라 혈중에서의 약물 반감기가 15.4 시간으로 비교적 긴 반감기를 갖고 있어 속방성 정제인 "아벨록스"정의 경우 1일 1회 투여되고 있음에 따라 투여횟수 측면에서 환자의 복약순응도를 고려한 서방성 제제의 필요성에 대해서는 심도 있게 고려해야할 문제일 뿐만 아니라 제제의 임상적 유효성은 아직 밝혀지지 않은 상태이다. 추가로, 대한민국특허 공개 제10-2008-0048461호에 위장체류 제제에 대해 개시되어 있으나, 여전히 정제 중량이 685 밀리그램 이상의 크기가 큰 정제 제형을 제시하고 있어 연하력이 약한 환자들의 복용 편의성을 개선시키기에는 문제가 있었다.Although the Republic of Korea Patent No. 10-0531065 discloses a sustained release tablet, in order to impart sustained release to the formulation, a certain ratio of sustained-release additives are required, which inevitably increases the weight of the tablet. It is usually presented in tablet weights of more than 1000 milligrams. In addition, the fact that moxifloxacin is absorbed in the lower sections of the gastrointestinal tract (colon and rectum) suggests the possibility of sustained release preparations. Has a relatively long half-life of 15.4 hours, so the rapid release tablet "Abelox" tablets are administered once a day. Therefore, the necessity of sustained-release preparation in consideration of the patient's medication compliance should be taken into consideration. Not only is it a problem but the clinical effectiveness of the formulation is still unknown. In addition, Korean Patent Publication No. 10-2008-0048461 discloses a gastroretentive preparation, but still provides a tablet formulation with a large tablet weight of more than 685 milligrams to improve the ease of taking of patients with weak swallowing power. Had a problem.

이에 본 발명자들은 목시플록사신의 빠른 흡수속도를 유지시키면서 연하력이 약한 환자들이 보다 쉽게 약물을 복용할 수 있도록 고형 조성물 중량을 줄이기 위한 방안을 집중 연구하던 중, 도 1에 나타난 바와 같이 목시플록사신의 용출속도가 산성용액에서는 낮고 알칼리성용액에서는 높다는 사실을 발견하여 소량의 첨가제로 산성용액에서 목시플록사신의 용출속도를 증진시킬 수 있다면 고형 조성물 중량을 획기적으로 줄여 고형 조성물 크기를 줄일 수 있어 연하력이 약한 환자들의 복약순응도를 높일 수 있을 것으로 기대하였다. 왜냐하면 목시플록사신의 최고혈중농도 도달시간이 평균 2시간 정도이기 때문에 목시플록사신을 경구 투여하였을 경우 pH가 1.2정도인 위에서의 용출율이 약물의 흡수에 지배적인 역할을 한다는 점에 착안하여 목시플록사신 고형 조성물 내에 소량의 pH조절제를 첨가하여 고형 조성물이 산성용액에 노출되었을 때 고형 조성물 내부 pH 환경이 일시적으로 알칼리성 또는 중성이 되도록 하여 산성용액에서의 목시플록사신의 용출속도를 증가시킴으로써 고형 조성물 중량을 획기적으로 줄일 수 있음을 확인함으로써 본 발명을 완성하게 되었다.Therefore, the inventors of the present invention focused on reducing the weight of the solid composition to maintain the rapid absorption rate of moxifloxacin so that patients with weak swallowing power can take the drug more easily, as shown in Figure 1 moxifloxacin It was found that the dissolution rate of was low in acidic solution and high in alkaline solution. If small amount of additive could improve the dissolution rate of moxifloxacin in acidic solution, it could drastically reduce the weight of solid composition and reduce the size of solid composition. Expected to increase medication compliance of these weak patients. Because moxifloxacin reaches an average peak time of about 2 hours, moxifloxacin is known to have a predominant role in the absorption of the drug by oral administration of moxifloxacin, which has a pH of about 1.2. The addition of a small amount of pH regulator in the solid composition makes the internal pH environment of the solid composition temporarily alkaline or neutral when the solid composition is exposed to an acidic solution, thereby increasing the dissolution rate of moxifloxacin in the acidic solution, thereby increasing the weight of the solid composition. The present invention has been completed by confirming that the present invention can be significantly reduced.

상기와 같은 문제점을 해결하기 위하여, 본 발명자들은 목시플록사신의 빠른 흡수속도를 유지시키면서 연하력이 약한 환자들이 보다 쉽게 약물을 복용할 수 있도록 고형 조성물 중량을 줄이기 위한 방안을 집중 연구하던 중, 목시플록사신의 용출속도가 산성용액에서는 낮고 알칼리성용액에서는 높다는 사실을 발견하고, 이에 기초하여 소량의 첨가제로 산성용액에서 목시플록사신의 용출속도를 증가시킴으로써 고형 조성물 중량을 획기적으로 줄일 수 있음을 확인하고, 본 발명을 완성하게 되었다. In order to solve the above problems, the inventors of the present invention focused on reducing the weight of the solid composition in order to maintain the rapid absorption rate of moxifloxacin while patients with weaker swallowing power to take the drug more easily, We found that the dissolution rate of floxacin was low in acidic solution and high in alkaline solution. Based on this, it was confirmed that the weight of solid composition can be significantly reduced by increasing the dissolution rate of moxifloxacin in acidic solution with a small amount of additive. The present invention has been completed.

따라서 본 발명의 목적은 임상적 유효성을 유지시킬 뿐만 아니라, 소량의 pH조절제를 사용하여 산성용액에서 목시플록사신의 용출속도를 증진시켜 고형 조성물의 크기를 획기적으로 줄임으로써 연하력이 약한 환자들의 복용 편의성이 개선된 목시플록사신 고형 조성물을 제공하는 것이다.Therefore, the purpose of the present invention is not only to maintain the clinical effectiveness, but also to improve the dissolution rate of moxifloxacin in acidic solution using a small amount of pH adjuster to drastically reduce the size of the solid composition, so as to take patients with weak swallowing power. It is to provide a moxifloxacin solid composition with improved convenience.

본 발명은 산성용액에서 약물의 용출율을 증진시키기 위한 pH조절제를 함유하는 목시플록사신 고형 조성물을 제공한다. The present invention provides a moxifloxacin solid composition containing a pH adjusting agent for enhancing the dissolution rate of the drug in an acidic solution.

상기 고형 조성물은 정제, 분말제, 캡슐제, 및 과립제 등을 포함한다. The solid composition includes tablets, powders, capsules, granules and the like.

본 발명의 일 구현예로, 상기 고형 조성물은 그 중량이 550 밀리그램 이하인 것을 특징으로 한다.In one embodiment of the invention, the solid composition is characterized in that its weight is 550 mg or less.

본 발명의 다른 구현예로, 상기 목시플록사신은 활성성분으로써 고형 조성물 전체 중량에 대하여 72.7 내지 95 중량%를 함유하는 것을 특징으로 한다.In another embodiment of the invention, the moxifloxacin is characterized in that it contains 72.7 to 95% by weight based on the total weight of the solid composition as an active ingredient.

본 발명의 또 다른 구현예로, 상기 pH조절제는 상기 고형 조성물이 산성용액에 노출되었을 때 일시적으로 고형 조성물 내부 환경을 중성 또는 알칼리성으로 유지시키는 물질을 포함하는 것을 특징으로 한다.In another embodiment of the present invention, the pH adjusting agent is characterized in that it comprises a material that temporarily maintains the internal environment of the solid composition neutral or alkaline when the solid composition is exposed to an acidic solution.

본 발명의 또 다른 구현예로, 상기 pH조절제는 메글루민(Meglumine), 탄산수소나트륨(Sodium bicarbonate), 탄산나트륨일수화물(Sodium carbonate monohydrate), 암모니아수(Ammonia water), 수산화나트륨(Sodium hydroxide), 구연산나트륨(Sodium citrate) 및 건조탄산나트륨(Dried sodium carbonate)으로 이루어지는 군에서 선택되는 하나 이상인 것을 특징으로 한다.In another embodiment of the present invention, the pH adjusting agent is meglumine, sodium bicarbonate, sodium carbonate monohydrate, ammonia water, sodium hydroxide, Sodium citrate (Sodium citrate) and dried sodium carbonate (Dried sodium carbonate) is characterized in that at least one selected from the group consisting of.

본 발명의 또 다른 구현예로, 상기 pH조절제는 고형 조성물 전체 중량에 대하여 0.1 내지 5 중량%를 함유하는 것을 특징으로 한다.In another embodiment, the pH adjusting agent is characterized in that it contains 0.1 to 5% by weight based on the total weight of the solid composition.

본 발명의 또 다른 구현예로, 상기 고형 조성물은 약제학적으로 허용 가능한 첨가제를 추가로 포함할 수 있다. 상기 첨가제는 붕해제, 결합제, 활택제, 부형제, 발포제, 및 착색제 등을 포함한다.
In another embodiment of the invention, the solid composition may further comprise a pharmaceutically acceptable additive. Such additives include disintegrants, binders, glidants, excipients, blowing agents, coloring agents, and the like.

이하, 본 발명을 상세하게 설명한다.EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

상기 본 발명의 고형물은 하기 단계를 포함하는 방법으로 제조될 수 있다:The solid of the present invention may be prepared by a method comprising the following steps:

(i)목시플록사신, (ii)pH조절제, 및 (iii)붕해제, 결합제, 활택제, 부형제, 발포제, 또는 착색제 등과 같은 1종 이상의 약제학적으로 허용 가능한 첨가제를 적당한 비율로 혼합하여 혼합물을 제조하는 단계; 및The mixture is prepared by mixing (i) moxifloxacin, (ii) pH modifiers, and (iii) one or more pharmaceutically acceptable additives such as disintegrants, binders, lubricants, excipients, blowing agents, or coloring agents in suitable proportions. Manufacturing; And

상기 혼합물을 타정기를 이용하여 고형 조성물(정제)을 제조하는 단계.
Preparing a mixture (tablet) using the mixture using a tablet press.

본 발명에서 사용되는 "목시플록사신"은 목시플록사신(moxifloxacin) 또는 그의 염 및(또는) 수화물을 포함하는 것을 특징으로 한다.As used herein, "moxifloxacin" is characterized by including moxifloxacin or salts and / or hydrates thereof.

본 발명에서 사용되는 "붕해제"는 고형 조성물(정제)의 붕해성을 촉진하는 물질을 포함하며, 구체적인 예로는 크로스포비돈, 전분글리콘산나트륨(sodium starch glycolate), 저치환도히드록시프로필셀룰로오스(low-substituted hydroxypropyl cellulose), 카르복시메칠셀룰로오스칼슘(carboxymethylcellulose calcium), 카르복시메칠셀룰로오스나트륨(carboxymethylcellulose sodium), 크로스카르복시메칠셀룰로오스나트륨(cross-linked carboxymethylcellulose sodium), 인산칼슘, 유당, 옥수수전분, 시메치콘(simethicone), 소르비톨, 미결정셀룰로오스(microcrystalline cellulose), 라우릴황산나트륨(sodium lauryl sulfate), 글루콘산나트륨(sodium gluconate), 결정셀룰로오스(crystalline cellulose), 경질무수규산, 히드록시프로필셀룰로오스, 호화전분(gelatinized starch), 폴리에칠렌글리콜 6000, 폴리소르베이트 80 (polysorbate 80), 폴리소르베이트 20(polysorbate 20), 폴록사머(poloxamer), 포비돈(povidone), 탄산수소나트륨(sodium bicarbonate) 또는 침강탄산칼슘 등이며, 바람직하게는 크로스포비돈, 전분글리콘산나트륨(sodium starch glycolate), 저치환도히드록시프로필셀룰로오스(low-substituted hydroxypropyl cellulose), 카르복시메칠셀룰로오스칼슘(carboxymethylcellulose calcium), 카르복시메칠셀룰로오스나트륨(carboxymethylcellulose sodium), 크로스카르복시메칠셀룰로오스나트륨(cross-linked carboxymethylcellulose sodium), 인산칼슘, 옥수수전분, 미결정셀룰로오스(microcrystalline cellulose), 탄산수소나트륨(sodium bicarbonate), 또는 침강탄산칼슘이며, 보다 바람직하게는 크로스포비돈, 전분글리콘산나트륨(sodium starch glycolate), 저치환도히드록시프로필셀룰로오스(low-substituted hydroxypropyl cellulose), 카르복시메칠셀룰로오스칼슘(carboxymethylcellulose calcium), 카르복시메칠셀룰로오스나트륨(carboxymethylcellulose sodium), 크로스카르복시메칠셀룰로오스나트륨(cross-linked carboxymethylcellulose sodium), 미결정셀룰로오스(microcrystalline cellulose), 탄산수소나트륨(sodium bicarbonate), 및 침강탄산칼슘으로 이루어지는 군에서 선택되는 1종 이상의 붕해제를 사용할 수 있다.As used herein, the "disintegrant" includes a substance that promotes disintegration of a solid composition (tablet), and specific examples thereof include crospovidone, sodium starch glycolate, and low-substituted hydroxypropyl cellulose. (low-substituted hydroxypropyl cellulose), carboxymethylcellulose calcium, carboxymethylcellulose sodium, cross-linked carboxymethylcellulose sodium, calcium phosphate, lactose, corn starch, simethicone simethicone, sorbitol, microcrystalline cellulose, sodium lauryl sulfate, sodium gluconate, crystalline cellulose, hard silicic acid, hydroxypropyl cellulose, gelatinized starch ), Polyethylene glycol 6000, polysorbate 80, poly Polysorbate 20, poloxamer, povidone, sodium bicarbonate or precipitated calcium carbonate, and the like, preferably crospovidone, sodium starch glycolate, Low-substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, cross-linked carboxymethylcellulose sodium, calcium phosphate, corn Starch, microcrystalline cellulose, sodium bicarbonate, or precipitated calcium carbonate, more preferably crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose (low) -substituted hydroxypropyl cellulose, carboxymethylcellulo se calcium, carboxymethylcellulose sodium, cross-linked carboxymethylcellulose sodium, microcrystalline cellulose, sodium bicarbonate, and precipitated calcium carbonate One or more disintegrants may be used.

본 발명에서 사용되는 "결합제"는 고형 조성물(정제)을 구성하는 혼합물에 결합력을 주어 성형을 용이하게 하는 물질을 포함하며, 구체적인 예로는 히드록시프로필셀룰로오스, 히드록시프로필메칠셀룰로오스, 히드록시에칠셀룰로오스, 호화전분, 프탈산히드록시프로필메칠셀룰로오스(hydroxypropylmethylcellulose phthalate), 폴리에칠렌글리콜 6000, 폴리에칠렌글리콜 4000, 폴리비닐알코올, 폴록사머, 포비돈, 탈크, 크로스포비돈, 크로스카르복시메칠셀룰로오스나트륨, 코포비돈, 카르복시메칠셀룰로오스칼슘, 카르복시메칠셀룰로오스나트륨, 카르복시메칠셀룰로오스, 젤라틴, 정제쉘락(purified Shellac), 정제수(purified water), 전호화전분(pregelatinized starch), 전분글리콘산나트륨, 전분, 저치환도히드록시프로필셀룰로오스, 이산화규소, 유동파라핀, 유당, 옥수수전분, 에탄올, 에칠셀룰로오스, 아라비아고무, 스테아린산마그네슘, 스테아린산, 세토스테아릴알코올(cetostearyl alcohol), 분말셀룰로오스(powdered cellulose), 백당, 미결정셀룰로오스, 메타아크릴산공중합체(methacrylic acid copolymer), 메칠셀룰로오스, 메글루민(meglumine), 만니톨, 레시친(lecithin), 꿀(honey), 글리세린, 경화피마자유(hydrogenated castor oil), 경질무수규산 또는 결정셀룰로오스 등이며, 바람직하게는 히드록시프로필셀룰로오스, 히드록시프로필메칠셀룰로오스, 히드록시에칠셀룰로오스, 호화전분, 프탈산히드록시프로필메칠셀룰로오스(hydroxypropylmethylcellulose phthalate), 폴리에칠렌글리콜 6000, 폴리에칠렌글리콜 4000, 폴리비닐알코올, 포비돈, 크로스카르복시메칠셀룰로오스나트륨, 코포비돈, 카르복시메칠셀룰로오스칼슘, 카르복시메칠셀룰로오스나트륨, 카르복시메칠셀룰로오스, 젤라틴, 정제쉘락(purified Shellac), 정제수(purified water), 전호화전분(pregelatinized starch), 전분, 유동파라핀, 유당, 옥수수전분, 에탄올, 에칠셀룰로오스, 아라비아고무, 세토스테아릴알코올(cetostearyl alcohol), 분말셀룰로오스(powdered cellulose), 백당, 미결정셀룰로오스, 메타아크릴산공중합체(methacrylic acid copolymer), 메칠셀룰로오스, 메글루민(meglumine), 레시친(lecithin), 꿀(honey), 글리세린, 경화피마자유(hydrogenated castor oil), 또는 결정셀룰로오스이며, 보다 바람직하게는 히드록시프로필셀룰로오스, 히드록시프로필메칠셀룰로오스, 포비돈, 크로스카르복시메칠셀룰로오스나트륨, 코포비돈, 카르복시메칠셀룰로오스나트륨, 카르복시메칠셀룰로오스, 젤라틴, 정제수(purified water), 전호화전분(pregelatinized starch), 전분, 및 결정셀룰로오스로 이루어지는 군에서 선택되는 1종 이상의 결합제를 사용할 수 있다.As used herein, the "binder" includes a substance which gives a bonding force to the mixture constituting the solid composition (tablet) to facilitate molding, and specific examples thereof include hydroxypropyl cellulose, hydroxypropyl methyl cellulose and hydroxyethyl. Cellulose, gelatinized starch, hydroxypropylmethylcellulose phthalate, polyethylene glycol 6000, polyethylene glycol 4000, polyvinyl alcohol, poloxamer, povidone, talc, crospovidone, sodium crosscarboxymethyl cellulose, copovidone, carboxymethyl cellulose Calcium, Sodium Carboxymethyl Cellulose, Carboxymethyl Cellulose, Gelatin, Purified Shellac, Purified Water, Pregelatinized Starch, Sodium Glycolate, Starch, Low Substituted Hydroxypropyl Cellulose, Silicon dioxide, liquid paraffin, lactose, corn starch, Ethanol, ethyl cellulose, gum arabic, magnesium stearate, stearic acid, cetostearyl alcohol, powdered cellulose, white sugar, microcrystalline cellulose, methacrylic acid copolymer, methyl cellulose, meglumine (meglumine), mannitol, lecithin, honey, glycerin, hydrogenated castor oil, hard silicic anhydride or crystalline cellulose, and the like, preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose, Hydroxyethyl cellulose, gelatinized starch, hydroxypropylmethylcellulose phthalate, polyethylene glycol 6000, polyethylene glycol 4000, polyvinyl alcohol, povidone, sodium cross carboxymethyl cellulose, copovidone, carboxymethyl cellulose calcium, carboxymethyl Sodium cellulose, carboxy Methylcellulose, gelatin, purified Shellac, purified water, pregelatinized starch, starch, liquid paraffin, lactose, corn starch, ethanol, ethylcellulose, gum arabic, cetostearyl alcohol alcohol, powdered cellulose, white sugar, microcrystalline cellulose, methacrylic acid copolymer, methyl cellulose, meglumine, lecithin, honey, glycerin, hardened castor oil (hydrogenated castor oil), or crystalline cellulose, more preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, sodium cross-carboxymethyl cellulose, copovidone, sodium carboxymethyl cellulose, carboxymethyl cellulose, gelatin, purified water ( purified water), pregelatinized starch, starch, and crystalline cellulose One or more binders selected from can be used.

본 발명에서 사용되는 "부형제"는 고형 조성물(정제) 내에서 활성성분을 희석시키는 역할을 하는 물질을 포함하며, 구체적인 예로는 히드록시프로필셀룰로오스, 히드록시프로필메칠셀룰로오스, 히드록시에칠셀룰로오스, 황산칼슘, 황납, 홍화유, 호화전분, 합성규산알루미늄, 피마자유, 프탈산히드록시프로필메칠셀룰로오스, 폴리옥실40경화피마자유, 폴리에틸렌글리콜 6000, 폴리에틸렌글리콜 4000, 폴록사머, 포비돈, 포도당, 펙틴, 파라핀, 탈크, 탄산수소나트륨, 탄산마그네슘, 탄산나트륨, 크로스포비돈, 크로스카르복시메칠셀룰로오스나트륨, 코포비돈, 카올린, 카르복시메칠셀룰로오스칼슘, 카르복시메칠셀룰로오스나트륨, 카르복시메칠셀룰로오스, 침강탄산칼슘, 젤라틴, 전호화전분, 전분글리콘산나트륨, 전분, 저치환도히드록시프로필셀룰로오스, 자일리톨, 자당지방에스텔, 인산칼슘, 인산수소칼슘, 이산화규소, 유드라짓, 유당, 옥수수전분, 에칠셀룰로오스, 스테아릴알코올, D-소르비톨, 셀락토오스, 세탄올, 산화폴리에칠렌, 산화마그네슘, 산탄검, 베타-시클로덱스트린, 백당, 미결정셀룰로오스, D-만니톨, 루디프레스, 덱스트린, 글리세릴베헤네이트, 규산알루민산마그네슘, 규산알루미늄마그네슘, 규산마그네슘, 구연산, 경질무수규산 또는 결정셀룰로오스로 등이며, 바람직하게는 히드록시프로필셀룰로오스, 히드록시프로필메칠셀룰로오스, 히드록시에칠셀룰로오스, 호화전분, 프탈산히드록시프로필메칠셀룰로오스, 폴리에틸렌글리콜 6000, 폴리에틸렌글리콜 4000, 폴록사머, 포비돈, 포도당, 펙틴, 크로스포비돈, 크로스카르복시메칠셀룰로오스나트륨, 코포비돈, 카올린, 카르복시메칠셀룰로오스칼슘, 카르복시메칠셀룰로오스나트륨, 카르복시메칠셀룰로오스, 침강탄산칼슘, 젤라틴, 전호화전분, 전분, 저치환도히드록시프로필셀룰로오스, 자일리톨, 인산칼슘, 인산수소칼슘, 이산화규소, 유드라짓, 유당, 옥수수전분, 에칠셀룰로오스, 스테아릴알코올, D-소르비톨, 셀락토오스, 세탄올, 산화폴리에칠렌, 산탄검, 베타-시클로덱스트린, 백당, 미결정셀룰로오스, D-만니톨, 루디프레스, 덱스트린, 경질무수규산 또는 결정셀룰로오스이며, 보다 바람직하게는 히드록시프로필셀룰로오스, 히드록시프로필메칠셀룰로오스, 히드록시에칠셀룰로오스, 폴록사머, 카르복시메칠셀룰로오스칼슘, 전호화전분, 저치환도히드록시프로필셀룰로오스, 인산수소칼슘, 유드라짓, 유당, 옥수수전분, 미결정셀룰로오스, D-만니톨, 및 경질무수규산으로 이루어지는 군에서 선택되는 1종 이상의 부형제를 사용할 수 있다.As used herein, the "excipient" includes a substance that serves to dilute the active ingredient in a solid composition (tablet), specific examples of which are hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sulfuric acid Calcium, lead, safflower oil, luxury starch, synthetic aluminum silicate, castor oil, hydroxypropyl methyl cellulose, polyoxyl 40 hardened castor oil, polyethylene glycol 6000, polyethylene glycol 4000, poloxamer, povidone, glucose, pectin, paraffin, talc Sodium bicarbonate, magnesium carbonate, sodium carbonate, crospovidone, crosscarboxymethylcellulose sodium, copovidone, kaolin, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethylcellulose, precipitated calcium carbonate, gelatin, pregelatinized starch, starch Sodium lyconate, starch, low-substituted hydroxypropyl cellulose Xylitol, sucrose fat ester, calcium phosphate, calcium hydrogen phosphate, silicon dioxide, eudragit, lactose, corn starch, ethylcellulose, stearyl alcohol, D-sorbitol, cellulose, cetanol, polyethylene oxide, magnesium oxide, Xanthan gum, beta-cyclodextrin, white sugar, microcrystalline cellulose, D-mannitol, rudipress, dextrin, glyceryl behenate, magnesium aluminate silicate, magnesium silicate, citric acid, light anhydrous silicic acid or crystalline cellulose. , Preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, gelatinized starch, hydroxypropyl methyl cellulose, polyethylene glycol 6000, polyethylene glycol 4000, poloxamer, povidone, glucose, pectin, crospovidone , Crosscarboxymethyl cellulose sodium, copovidone, kaolin, carboxymethylcell Loose calcium, sodium carboxymethyl cellulose, carboxymethyl cellulose, precipitated calcium carbonate, gelatin, pregelatinized starch, starch, low-substituted hydroxypropyl cellulose, xylitol, calcium phosphate, calcium hydrogen phosphate, silicon dioxide, eudragit, lactose , Corn starch, ethylcellulose, stearyl alcohol, D-sorbitol, cellulose, cetanol, polyethylene oxide, xanthan gum, beta-cyclodextrin, white sugar, microcrystalline cellulose, D-mannitol, rudipress, dextrin, hard silicic acid or Crystalline cellulose, more preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, poloxamer, carboxymethyl cellulose calcium, pregelatinized starch, low-substituted hydroxypropyl cellulose, calcium hydrogen phosphate, oil Consists of dragit, lactose, corn starch, microcrystalline cellulose, D-mannitol, and hard silicic acid It may be one or more excipients selected from the group.

본 발명에서 사용되는 "활택제"는 고형 조성물(정제) 제조시 혼합물의 압축조작을 원활하게 진행시키는 역할을 하는 물질을 포함하며, 구체적인 예로는 스테아린산마그네슘, 스테아린산, 탈크, 합성규산알루미늄, 푸마르산스테아릴나트륨(sodium stearyl fumarate), 폴리에칠렌글리콜 6000, 폴리에칠렌글리콜 4000, 카올린(Kaolin), 전분글리콘산나트륨, 자당지방산에스텔(sucrose esters of fatty acids), 이산화규소, 옥수수전분, 실리콘액 350 센티스톡스(silicone fluid 350 centistokes), 시메치콘(simethicone), 스테아린산폴리옥실 40 (polyoxyl 40 stearate), 모노스테아린산글리세린(glyceryl monostearate), 라우릴황산나트륨, 글리세릴베헤네이트(glyceryl behenate), 규산마그네슘(magnesium silicate), 경화유(hydrogenated oil, hard fat), 또는 경질무수규산 등이며, 바람직하게는 스테아린산마그네슘, 스테아린산, 탈크, 합성규산알루미늄, 푸마르산스테아릴나트륨(sodium stearyl fumarate), 폴리에칠렌글리콜 6000, 폴리에칠렌글리콜 4000, 카올린(Kaolin), 이산화규소, 시메치콘(simethicone), 스테아린산폴리옥실 40 (polyoxyl 40 stearate), 모노스테아린산글리세린(glyceryl monostearate), 라우릴황산나트륨, 글리세릴베헤네이트(glyceryl behenate), 규산마그네슘(magnesium silicate), 경화유(hydrogenated oil, hard fat), 또는 경질무수규산이며, 보다 바람직하게는 스테아린산마그네슘, 스테아린산, 탈크, 합성규산알루미늄, 푸마르산스테아릴나트륨(sodium stearyl fumarate), 폴리에칠렌글리콜 6000, 폴리에칠렌글리콜 4000, 이산화규소, 규산마그네슘(magnesium silicate), 및 경질무수규산으로 이루어지는 군에서 선택되는 1종 이상의 활택제를 사용할 수 있다."Lubricant" used in the present invention includes a material that serves to facilitate the compression operation of the mixture when preparing a solid composition (tablet), specific examples are magnesium stearate, stearic acid, talc, synthetic aluminum silicate, fumaric acid stearate Sodium aryl (sodium stearyl fumarate), polyethylene glycol 6000, polyethylene glycol 4000, kaolin, sodium starch glycolate, sucrose esters of fatty acids, silicon dioxide, corn starch, silicone fluid 350 centistox ( silicone fluid 350 centistokes, simethicone, polyoxyl 40 stearate, glyceryl monostearate, sodium lauryl sulfate, glyceryl behenate, magnesium silicate, Hydrogenated oil, hard fat, hard silicic anhydride and the like, preferably magnesium stearate, stearin , Talc, synthetic aluminum silicate, sodium stearyl fumarate, polystyrene glycol 6000, polyethylene glycol 4000, kaolin, silicon dioxide, simethicone, polyoxyl 40 stearate, mono Glyceryl monostearate, sodium lauryl sulfate, glyceryl behenate, magnesium silicate, hydrogenated oil, hard fat, or hard anhydrous silicic acid, more preferably magnesium stearate, stearic acid At least one lubricant selected from the group consisting of talc, synthetic aluminum silicate, sodium stearyl fumarate, polyethylene glycol 6000, polyethylene glycol 4000, silicon dioxide, magnesium silicate, and hard silicic acid Can be used.

본 발명에서 사용되는 "발포제"는 물과 작용하여 기포를 발생시키는 물질을 포함하며, 구체적인 예로는 탄산수소나트륨 또는 탄산수소나트륨 및 유기산을 혼합하여 사용하며, 바람직하게는 탄산수소나트륨, 탄산수소나트륨 및 구연산 혼합물 또는 탄산수소나트륨 및 주석산 혼합물을 사용할 수 있다.As used herein, the "foaming agent" includes a substance that generates bubbles by interacting with water, and specific examples thereof include sodium bicarbonate or sodium bicarbonate and an organic acid, preferably sodium bicarbonate, sodium bicarbonate. And citric acid mixtures or sodium bicarbonate and tartaric acid mixtures.

또한 필요한 경우, 착색제를 정제에 포함시킬 수 있으며, 이산화티탄, 산화철, 탄산마그네슘, 황산칼슘, 산화마그네슘, 수산화마그네슘 또는 알루미늄레이크 (aluminium lake)등에서 선택된 1종 이상을 사용할 수 있다.If necessary, a colorant may be included in the tablet, and one or more selected from titanium dioxide, iron oxide, magnesium carbonate, calcium sulfate, magnesium oxide, magnesium hydroxide, aluminum lake, or the like may be used.

본 발명의 "고형 조성물"은 목시플록사신 및 pH조절제, 부가적으로 붕해제, 결합제, 발포제, 부형제 또는 활택제 등에서 선택되는 1종 이상의 약제학적 첨가제로 구성되는 것이 바람직하며, 조성물 전체 중량에 대하여 활성성분인 목시플록사신은 72.7 내지 95 중량% 이하, pH조절제는 0.1 내지 5 중량% 이하, 붕해제는 0.1 내지 5 중량%, 결합제는 0.1 내지 40 중량%, 발포제는 0.1 내지 10 중량%, 부형제는 1 내지 10 중량%, 활택제는 0.1 내지 5 중량% 이하로 구성되는 것이 보다 바람직하다.The "solid composition" of the present invention preferably consists of one or more pharmaceutical additives selected from moxifloxacin and pH adjusting agents, additionally disintegrants, binders, blowing agents, excipients or glidants, etc., with respect to the total weight of the composition The active ingredient moxifloxacin is 72.7 to 95% by weight, pH adjuster is 0.1 to 5% by weight, disintegrant is 0.1 to 5% by weight, binder is 0.1 to 40% by weight, foaming agent is 0.1 to 10% by weight, excipient Is more preferably from 1 to 10% by weight, the lubricant is 0.1 to 5% by weight or less.

상기 고형 조성물에 이용될 수 있는 약제학적 첨가제의 구체적인 예는 Handbook of Pharmaceutical Excipients(R.C. Rowe, et al., Handbook of Pharmaceutical Excipients, Pharmaceutical Press, Fifth Edition, 2006)에 기술되어 있으며, 고형 조성물 제조를 위한 기술은 Remington: The Science and Practice of Pharmacy(D.B. Troy, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Twenty - first Edition, 2005)에 기술되어 있다. 상기 기술된 방법을 함유하는 약제학 분야의 숙련가에게 공지되어 있는 방법으로 본 발명의 pH조절제를 함유하는 목시플록사신 고형 조성물을 제조할 수 있다.Specific examples of pharmaceutical additives that can be used in the solid composition are described in Handbook of Pharmaceutical Excipients (RC Rowe, et al., Handbook of Pharmaceutical Excipients, Pharmaceutical Press, Fifth Edition , 2006), for preparing solid compositions Technology is described in Remington: The Science and Practice of Pharmacy (DB Troy, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Twenty - first Edition , 2005). Moxifloxacin solid compositions containing the pH adjusting agents of the present invention can be prepared by methods known to those skilled in the pharmaceutical art containing the methods described above.

본 발명은 pH조절제를 함유한 목시플록사신의 고형 조성물을 제공함으로써, 목시플록사신의 임상적 유효성을 유지시킬 뿐만 아니라 정제 크기를 획기적으로 줄여 연하력이 약한 환자들의 복약순응도를 높일 수 있다.The present invention by providing a solid composition of moxifloxacin containing a pH adjuster, not only maintain the clinical efficacy of moxifloxacin, but also significantly reduce the size of the tablet can increase the medication compliance of patients with weak swallowing power.

도 1은 목시플록사신의 pH에 따른 용출속도를 나타낸 그래프이고,
도 2는 산성용액(pH 1.2)에서 목시플록사신 정제의 용출속도를 나타낸 그래프이며,
도 3은 실시예 5에서 제조한 정제 및 비교예 2의 시판제제를 경구 투여 후 시간에 따른 목시플록사신의 혈중 농도를 비교한 그래프이다.1 is a graph showing the dissolution rate according to the pH of moxifloxacin,
Figure 2 is a graph showing the dissolution rate of moxifloxacin tablets in acidic solution (pH 1.2),
Figure 3 is a graph comparing the blood concentration of moxifloxacin with time after oral administration of the tablet prepared in Example 5 and the commercial preparation of Comparative Example 2.

이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.
Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the following examples.

[[ 실시예Example ] ] 목시플록사신Moxifloxacin 고형 조성물의 제조  Preparation of Solid Composition

실시예 1. 목시플록사신 고형 조성물의 제조(1)Example 1 Preparation of Moxifloxacin Solid Composition (1)

pH조절제를 함유한 목시플록사신 정제를 제조하기 위하여, 하기 표 1에 나타낸 바와 같은 비율로 목시플록사신 염산염 및 구연산나트륨을 혼합 후, 정제수로 연합하여 과립물을 얻었다. 얻어진 과립물을 건조하고 정립하여 크로스카르복시메칠셀룰로오스나트륨 및 스테아린산마그네슘을 최종 혼합한 후, 통상의 타정방법으로 정제를 제조하였다.
In order to prepare a moxifloxacin tablet containing a pH adjusting agent, moxifloxacin hydrochloride and sodium citrate were mixed in the ratio as shown in Table 1 below, and then combined with purified water to obtain granules. The granules thus obtained were dried and granulated to finally mix cross-carboxymethyl cellulose sodium and magnesium stearate, and then tablets were prepared by a conventional tableting method.

실시예 2. 목시플록사신 고형 조성물의 제조(2)Example 2. Preparation of Moxifloxacin Solid Composition (2)

pH조절제를 함유한 목시플록사신 정제를 제조하기 위하여, 하기 표 1에 나타낸 바와 같은 비율로 목시플록사신 염산염 및 미결정셀룰로오스를 혼합 후, 정제수로 연합하여 과립물을 얻었다. 얻어진 과립물을 건조하고 정립하여 탄산수소나트륨, 크로스카르복시메칠셀룰로오스나트륨 및 스테아린산마그네슘을 최종 혼합한 후, 통상의 타정방법으로 정제를 제조하였다.
In order to prepare a moxifloxacin tablet containing a pH adjusting agent, moxifloxacin hydrochloride and microcrystalline cellulose were mixed in the ratio as shown in Table 1 below, and then combined with purified water to obtain granules. The granules thus obtained were dried and granulated to finally mix sodium bicarbonate, sodium crosscarboxymethylcellulose, and magnesium stearate, and then tablets were prepared by a conventional tableting method.

실시예 3. 목시플록사신 고형 조성물의 제조(3)Example 3. Preparation of Moxifloxacin Solid Composition (3)

pH조절제를 함유한 목시플록사신 정제를 제조하기 위하여, 하기 표 1에 나타낸 바와 같은 비율로 목시플록사신 염산염 및 미결정셀룰로오스를 혼합 후, 정제수로 연합하여 과립물을 얻었다. 얻어진 과립물을 건조하고 정립하여 탄산수소나트륨, 크로스카르복시메칠셀룰로오스나트륨 및 스테아린산마그네슘을 최종 혼합한 후, 통상의 타정방법으로 정제를 제조하였다.
In order to prepare a moxifloxacin tablet containing a pH adjusting agent, moxifloxacin hydrochloride and microcrystalline cellulose were mixed in the ratio as shown in Table 1 below, and then combined with purified water to obtain granules. The granules thus obtained were dried and granulated to finally mix sodium bicarbonate, sodium crosscarboxymethylcellulose, and magnesium stearate, and then tablets were prepared by a conventional tableting method.

실시예 4. 목시플록사신 고형 조성물의 제조(4)Example 4 Preparation of Moxifloxacin Solid Composition (4)

pH조절제를 함유한 목시플록사신 정제를 제조하기 위하여, 하기 표 1에 나타낸 바와 같은 비율로 목시플록사신 염산염, 메글루민, 탄산수소나트륨 및 미결정셀룰로오스를 혼합 후, 정제수로 연합하여 과립물을 얻었다. 얻어진 과립물을 건조하고 정립하여 크로스카르복시메칠셀룰로오스나트륨 및 스테아린산마그네슘을 최종 혼합한 후, 통상의 타정방법으로 정제를 제조하였다.
In order to prepare a moxifloxacin tablet containing a pH adjusting agent, moxifloxacin hydrochloride, meglumine, sodium hydrogen carbonate and microcrystalline cellulose were mixed at a ratio as shown in Table 1 below, and then combined with purified water to obtain granules. . The granules thus obtained were dried and granulated to finally mix cross-carboxymethyl cellulose sodium and magnesium stearate, and then tablets were prepared by a conventional tableting method.

실시예 5. 목시플록사신 고형 조성물의 제조(5)Example 5 Preparation of Moxifloxacin Solid Composition (5)

pH조절제를 함유한 목시플록사신 정제를 제조하기 위하여, 하기 표 1에 나타낸 바와 같은 비율로 목시플록사신 염산염, 메글루민, 크로스카르복시메칠셀룰로오스나트륨(5 밀리그램), 탄산수소나트륨 및 미결정셀룰로오스를 혼합 후, 정제수로 연합하여 과립물을 얻었다. 얻어진 과립물을 건조하고 정립하여 크로스카르복시메칠셀룰로오스나트륨(5 밀리그램) 및 스테아린산마그네슘을 최종 혼합한 후, 통상의 타정방법으로 정제를 제조하였다. 제조된 정제를 히드록시프로필메칠셀룰로오스 2910, 폴리에칠렌글리콜 4000, 적색산화철 및 이산화티탄으로 이루어진 코팅제로 코팅하여 최종 코팅된 정제를 제조하였다.
In order to prepare a moxifloxacin tablet containing a pH adjusting agent, moxifloxacin hydrochloride, meglumine, cross-carboxymethyl cellulose sodium (5 mg), sodium bicarbonate and microcrystalline cellulose were mixed in the ratio as shown in Table 1 below. Then, the mixture was combined with purified water to obtain granules. The granules thus obtained were dried and granulated to finally mix crosscarboxymethyl cellulose sodium (5 mg) and magnesium stearate, and then tablets were prepared by a conventional tableting method. The tablets thus prepared were coated with a coating agent consisting of hydroxypropylmethylcellulose 2910, polyethylene glycol 4000, red iron oxide and titanium dioxide to prepare a final coated tablet.

성분명Ingredient Name 배합목적Purpose of Mixing 실시예 (중량, mg)Example (weight, mg) 1One 22 33 44 55 목시플록사신 염산염Moxifloxacin Hydrochloride 활성성분Active ingredient 436.8436.8 436.8436.8 436.8436.8 436.8436.8 436.8436.8 메글루민Meglumine pH조절제pH regulator 5.05.0 5.05.0 탄산수소나트륨Sodium bicarbonate pH조절제/
발포제pH adjuster /
blowing agent 5.05.0 5.05.0 2.02.0 2.02.0 구연산나트륨Sodium citrate pH조절제pH regulator 9.09.0 크로스카르복시메칠
셀룰로오스나트륨Cross-carboxymethyl
Sodium cellulose 붕해제Disintegrant 9.09.0 10.010.0 16.016.0 10.010.0 10.010.0 미결정셀룰로오스Microcrystalline cellulose 결합제/부형제Binders / Excipients 55.055.0 55.055.0 30.030.0 20.020.0 스테아린산마그네슘Magnesium stearate 활택제Lubricant 4.04.0 4.04.0 4.04.0 4.04.0 4.04.0 히드록시프로필메칠
셀룰로오스 2910Hydroxypropylmethyl
Cellulose 2910 코팅제Coating agent 9.69.6 폴리에칠렌글리콜 4000Polyethylene Glycol 4000 가소제Plasticizer 1.91.9 적색산화철Red iron oxide 착색제coloring agent 0.250.25 이산화티탄Titanium dioxide 착색제coloring agent 2.42.4 정제 중량 (mg)Tablet weight (mg) 458.8458.8 510.8510.8 516.8516.8 487.8487.8 492.0492.0

비교예Comparative example 1.  One. 목시플록사신Moxifloxacin 정제의 제조 Manufacture of tablets

목시플록사신의 pH에 따른 용출속도를 측정하기 위하여, 첨가제 없이 목시플록사신 염산염(436.8 밀리그램)만으로 통상의 직타법을 이용하여 정제를 제조하였다.
In order to measure the elution rate according to the pH of moxifloxacin, tablets were prepared using the conventional direct method with moxifloxacin hydrochloride (436.8 mg) without additives.

비교예Comparative example 2.  2. 시판제제Commercially available

시판중인 목시플록사신 정제인 "아벨록스"정(바이엘사)을 사용하였다.
A commercially available moxifloxacin tablet "Abelox" tablet (Bayer Corporation) was used.

실험예Experimental Example 1.  One. pHpH 에 따른 In accordance 목시플록사신의Moxifloxacin 용출속도 측정 Dissolution Rate Measurement

목시플록사신의 pH에 따른 용출속도를 측정하기 위하여, 상기 비교예 1에서 제조한 정제 각 3정씩 pH 1.2, pH 4.0, 정제수 및 pH 6.8 용액 900 mL에 넣고 대한약전 용출시험법(제2법)을 이용하여 목시플록사신의 용출속도를 측정하고, 그 결과를 도 1에 나타내었다.In order to measure the dissolution rate according to the pH of moxifloxacin, each of the tablets prepared in Comparative Example 1 was added to 900 mL of pH 1.2, pH 4.0, purified water and pH 6.8 solution of the Korean Pharmacopoeia dissolution test method (method 2) The dissolution rate of moxifloxacin was measured using the results, and the results are shown in FIG. 1.

도 1에 나타난 바와 같이, 용액의 pH가 낮아질수록 목시플록사신의 용출속도가 낮아짐을 확인할 수 있었다.
As shown in Figure 1, the lower the pH of the solution was confirmed that the dissolution rate of moxifloxacin lowered.

실험예Experimental Example 2. 산성용액에서  2. In acidic solution 목시플록사신의Moxifloxacin 용출속도 측정 Dissolution Rate Measurement

산성용액(pH 1.2)에서 목시플록사신의 용출속도를 측정하기 위하여, 상기 실시예 1 내지 실시예 5에서 제조한 정제 및 비교예 2의 정제 각각 3정씩을 pH 1.2 용액 900 mL에 넣고 대한약전 용출시험법(제2법)을 이용하여 목시플록사신의 용출속도를 측정하고, 그 결과를 도 2에 나타내었다.In order to measure the dissolution rate of moxifloxacin in an acidic solution (pH 1.2), 3 tablets of the tablets prepared in Examples 1 to 5 and the tablets of Comparative Example 2 were each added to 900 mL of a pH 1.2 solution, and eluted with pharmacopeia. The dissolution rate of moxifloxacin was measured using the test method (the second method), and the results are shown in FIG. 2.

도 2에 나타난 바와 같이, 상기 실시예 1 내지 5 모두 비교예 2와 동등한 용출속도를 나타냄을 확인할 수 있었다.
As shown in Figure 2, it was confirmed that all of Examples 1 to 5 showed the same dissolution rate as Comparative Example 2.

실험예Experimental Example 3. 경구 투여 후 시간에 따른 생체 내에서의  3. In vivo with time after oral administration 목시플록사신Moxifloxacin 농도 측정 Concentration measurement

목시플록사신의 임상적 유효성을 확인하기 위해서, 상기 실시예 5에서 제조한 정제 및 비교예 2의 시판제제를 건강한 성인 남자 30명을 대상으로 경구 투여 후, 시간에 따른 목시플록사신의 혈중 농도를 비교하고, 그 결과를 도 3에 나타내었다.In order to confirm the clinical effectiveness of moxifloxacin, the tablets prepared in Example 5 and the commercial preparation of Comparative Example 2 were orally administered to 30 healthy adult males, and then blood concentrations of moxifloxacin with time were measured. The results are shown in FIG. 3.

도 3에 나타난 바와 같이, 실시예 5 및 비교예 2는 생물학적으로 동등함을 확인할 수 있었다.
As shown in Figure 3, it was confirmed that Example 5 and Comparative Example 2 are biologically equivalent.

전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예 및 실험예들은 모든 면에서 예시적인 것이며 한정적인 아닌 것으로 이해해야만 한다.The foregoing description of the present invention is intended for illustration, and it will be understood by those skilled in the art that the present invention may be easily modified in other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments and the experimental examples described above are exemplary in all respects and not limiting.

Claims (9)

pH 조절제를 함유하는 목시플록사신 고형 조성물로서, 상기 pH 조절제는 탄산수소나트륨(Sodium bicarbonate) 및 메글루민(Meglumine)을 포함하는 것을 특징으로 하는 조성물.
A moxifloxacin solid composition containing a pH adjusting agent, wherein the pH adjusting agent comprises sodium bicarbonate and meglumine.
제 1항에 있어서,
상기 고형 조성물은 정제, 분말제, 캡슐제, 또는 과립제인 것을 특징으로 하는 조성물.
The method of claim 1,
The solid composition is a composition, characterized in that the tablet, powder, capsule, or granules.
삭제delete 제 1항에 있어서,
상기 고형 조성물은 그 중량이 550 밀리그램 이하인 것을 특징으로 하는 조성물.
The method of claim 1,
Wherein said solid composition has a weight of 550 milligrams or less.
제 1항에 있어서,
상기 목시플록사신은 활성성분으로써 고형 조성물 전체 중량에 대하여 72.7 내지 95 중량%를 함유하는 것을 특징으로 하는 조성물.
The method of claim 1,
The moxifloxacin is an active ingredient, characterized in that it contains 72.7 to 95% by weight based on the total weight of the solid composition.
삭제delete 삭제delete 제 1항에 있어서,
상기 pH조절제는 고형 조성물 전체 중량에 대하여 0.1 내지 5 중량%를 함유하는 것을 특징으로 하는 조성물.
The method of claim 1,
The pH adjusting agent is characterized in that it contains 0.1 to 5% by weight based on the total weight of the solid composition.
제 1항에 있어서,
상기 고형 조성물은 붕해제, 결합제, 활택제, 부형제, 발포제, 및 착색제로 이루어지는 군으로부터 선택된 하나 이상의 약제학적으로 허용 가능한 첨가제를 추가로 포함하는 것을 특징으로 하는 조성물.The method of claim 1,
Wherein said solid composition further comprises one or more pharmaceutically acceptable additives selected from the group consisting of disintegrants, binders, lubricants, excipients, blowing agents, and colorants.
KR1020110051595A 2011-05-30 2011-05-30 Solid pharmaceutical composition of moxifloxacin comprising ph adjustment agent KR101093781B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1020110051595A KR101093781B1 (en) 2011-05-30 2011-05-30 Solid pharmaceutical composition of moxifloxacin comprising ph adjustment agent

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
KR1020110051595A KR101093781B1 (en) 2011-05-30 2011-05-30 Solid pharmaceutical composition of moxifloxacin comprising ph adjustment agent

Publications (1)

Publication Number Publication Date
KR101093781B1 true KR101093781B1 (en) 2011-12-19

Family

ID=45506273

Family Applications (1)

Application Number Title Priority Date Filing Date
KR1020110051595A KR101093781B1 (en) 2011-05-30 2011-05-30 Solid pharmaceutical composition of moxifloxacin comprising ph adjustment agent

Country Status (1)

Country Link
KR (1) KR101093781B1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013097003A1 (en) * 2011-12-26 2013-07-04 Ems S/A. Solid pharmaceutical composition comprising an antibiotic from the quinolone family and method for the production thereof
KR102022694B1 (en) * 2019-02-20 2019-09-18 주식회사 네비팜 Pharmaceutical composition
KR20200077712A (en) 2018-12-21 2020-07-01 한미약품 주식회사 Moxifloxacin solid preparation and method for preparing the same

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013097003A1 (en) * 2011-12-26 2013-07-04 Ems S/A. Solid pharmaceutical composition comprising an antibiotic from the quinolone family and method for the production thereof
KR20200077712A (en) 2018-12-21 2020-07-01 한미약품 주식회사 Moxifloxacin solid preparation and method for preparing the same
KR102022694B1 (en) * 2019-02-20 2019-09-18 주식회사 네비팜 Pharmaceutical composition
WO2020171404A1 (en) * 2019-02-20 2020-08-27 주식회사 네비팜 Pharmaceutical composition

Similar Documents

Publication Publication Date Title
US20200000726A1 (en) Gastroresistant pharmaceutical formulations containing rifaximin
EP2079446B1 (en) Paliperidone sustained release formulation
AU2012340759C1 (en) Pharmaceutical formulations
JP2018500353A (en) Ileum-jejunum drug delivery composition
KR20100129776A (en) Extended release forumulation containing a wax
WO2009034541A2 (en) Controlled release pharmaceutical dosage forms of trimetazidine
KR101269829B1 (en) Sustained release preparation using gastric retentive drug delivery system
JP2015501808A5 (en)
KR101907881B1 (en) Fixed dose combination formulation comprising losartan, amlodipine and hydrochlorothiazide
JP2022123032A (en) Edaravone pharmaceutical composition
KR101093781B1 (en) Solid pharmaceutical composition of moxifloxacin comprising ph adjustment agent
US8563035B2 (en) Oral tablet compositions of dexlansoprazole
WO2010023690A2 (en) Prolonged release formulation of amisulpride
WO2021254409A1 (en) Pharmaceutical composition of complex and preparation method therefor
ES2963886T3 (en) Tablets containing tamsulosin and solifenacin
EP3331502B1 (en) Controlled release propiverine formulations
KR101811700B1 (en) Sustained Release Tablets Containing Levodropropizine and Manufacturing Method for the same
EP3796908B1 (en) Controlled release propiverine formulations
KR20180096530A (en) Immediate-release and sustained-release pharmaceutical preparation comprising Itopride hydrochloride
KR20130121717A (en) Sustained release preparation using gastric retentive drug delivery system
US20080089936A1 (en) Prolonged release formulation of active principles having a ph-dependent solubility
KR20200061225A (en) Dry manufacturing method of sustained release pharmaceutical formulation of varenicline
RU2603469C2 (en) Controlled-release pharmaceutical tablet for oral administration methods for preparation thereof
KR20120122558A (en) Sustained-release pharmaceutical composition comprising donepezil or pharmaceutically acceptable salt thereof having improved dissolution stability and method for manufacturing the same
EP4079296A1 (en) A bilayer tablet formulation comprising amorphous dapagliflozin and metformin

Legal Events

Date Code Title Description
A201 Request for examination
AMND Amendment
E601 Decision to refuse application
X091 Application refused [patent]
AMND Amendment
X701 Decision to grant (after re-examination)
GRNT Written decision to grant
FPAY Annual fee payment

Payment date: 20150916

Year of fee payment: 5

FPAY Annual fee payment

Payment date: 20161205

Year of fee payment: 6

FPAY Annual fee payment

Payment date: 20181128

Year of fee payment: 8

FPAY Annual fee payment

Payment date: 20191125

Year of fee payment: 9