KR20190049023A - Controlled-release monolithic matrix tablets comprising bepotastine or its pharmaceutically acceptable salt and process for preparing the same - Google Patents
Controlled-release monolithic matrix tablets comprising bepotastine or its pharmaceutically acceptable salt and process for preparing the same Download PDFInfo
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- KR20190049023A KR20190049023A KR1020170144423A KR20170144423A KR20190049023A KR 20190049023 A KR20190049023 A KR 20190049023A KR 1020170144423 A KR1020170144423 A KR 1020170144423A KR 20170144423 A KR20170144423 A KR 20170144423A KR 20190049023 A KR20190049023 A KR 20190049023A
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- South Korea
- Prior art keywords
- acid
- release
- tablet
- controlled
- matrix tablet
- Prior art date
- Legal status (The legal status 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 status listed.)
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- YWGDOWXRIALTES-NRFANRHFSA-N bepotastine Chemical compound C1CN(CCCC(=O)O)CCC1O[C@H](C=1N=CC=CC=1)C1=CC=C(Cl)C=C1 YWGDOWXRIALTES-NRFANRHFSA-N 0.000 title claims abstract description 27
- 229960002071 bepotastine Drugs 0.000 title claims abstract description 27
- 238000013270 controlled release Methods 0.000 title claims abstract description 24
- 150000003839 salts Chemical class 0.000 title claims abstract description 23
- 239000011159 matrix material Substances 0.000 title claims description 16
- 238000004519 manufacturing process Methods 0.000 title description 11
- 239000013563 matrix tablet Substances 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 28
- 229920000642 polymer Polymers 0.000 claims abstract description 28
- 238000002360 preparation method Methods 0.000 claims abstract description 25
- 239000003826 tablet Substances 0.000 claims description 87
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 75
- 239000000203 mixture Substances 0.000 claims description 49
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 30
- 238000004090 dissolution Methods 0.000 claims description 30
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 27
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 26
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- 235000015165 citric acid Nutrition 0.000 claims description 25
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 22
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 22
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 20
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- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 16
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- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 16
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 16
- 239000000314 lubricant Substances 0.000 claims description 16
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 15
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- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 14
- 150000004781 alginic acids Chemical class 0.000 claims description 14
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 14
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 14
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 13
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- 235000011087 fumaric acid Nutrition 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 11
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- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 10
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 3
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- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 claims description 3
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- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims 1
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- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 7
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 20
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 8
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- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 7
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Abstract
Description
본 발명은 1일 1회 투여를 위한 방출제어 단일 매트릭스 정제 및 이의 제조방법에 관한 것이다. 더욱 상세하게는, 본 발명은 베포타스틴 또는 이의 약학적으로 허용가능한 염; 팽윤성 중합체; 및 특정 방출조절제를 포함하는, 1일 1회 투여를 위한 방출제어 단일 매트릭스 정제 및 이의 제조방법에 관한 것이다.The present invention relates to a controlled-release single matrix tablet for once-a-day administration and a method of making the same. More particularly, the present invention relates to a pharmaceutical composition comprising bevetastine or a pharmaceutically acceptable salt thereof; A swellable polymer; Controlled release single matrix tablets for once-a-day dosing, and a method of making the same.
베포타스틴(Bepotastine)은 화학명이 (S)-4-[4-[(4-클로로페닐)-2-피리딜메톡시] 피페리딘-1-일]부탄산으로서, 하기 화학식 1의 구조식을 갖는 화합물이다. 베포타스틴은 새로운 2세대 항히스타민 약물로서, 알레르기성 비염의 증상 발현을 억제할 뿐만 아니라, 혈액뇌관문을 통과하지 않아 기존의 1세대 항히스타민제가 가지는 졸림과 같은 부작용을 유발시키지 않는다. Bepotastine is a compound of formula (I) wherein the chemical name is (S) -4- [4- [(4-chlorophenyl) -2-pyridylmethoxy] piperidin- . BePotastine is a new second-generation antihistamine drug that not only inhibits the onset of symptoms of allergic rhinitis but also does not pass through the blood-brain barrier and does not cause side effects such as sleepiness that the first-generation antihistamines have.
<화학식 1>≪ Formula 1 >
베포타스틴은 베실산염 형태의 속방성 제제로 개발되어 '타리온'이라는 상품명으로 시판되고 있다. 상기 제제는 1일 2회 10mg씩 투여된다. 상기 제제는 식사와 관계없이 복용하고 있으나, 일본 PMDA 및 'Drugs' 2010년 (Volume 70, 페이지 1579-1591) ' Oral Bepotastine in allergic disorders'에 따르면 베포타스틴은 식사 후 약물을 복용하였을 때 공복시보다 체내흡수율이 저하되는 현상을 보인다고 알려져 있다. 또한, 베포타스틴의 pH 용액별 용해도를 비교하였을 때 pH가 높아질수록 용해성이 감소하는 특성을 보이는 것으로 알려져 있다. Bephotastine has been developed as an immediate release formulation in the form of a vesicular salt and is marketed under the trade name Tarion. The formulation is administered 10 mg twice a day. According to PMDA and 'Drugs' 2010 (Volume 70, pages 1579-1591) 'Oral Bepotastine in allergic disorders' in Japan PMDA and beverages do not take meals, but when the drug is taken after meals, It is known that the absorption rate in the body is lowered. Also, it is known that the solubility of bepotastine in pH solution is decreased and the solubility decreases with increasing pH.
환자 복약순응도를 높이기 위해 1일 1회 투여를 위한 베포타스틴-함유 방출제어 제제에 대한 연구가 다양하게 시도된 바 있다[예를 들어, 대한민국 특허공개 제2012-0083276호, 대한민국 특허등록 제10-1731078호, 대한민국 특허공개 제10-2014-0016260호(국제특허공개 제WO 2012/104818호), 대한민국 특허공개 제10-2015-0138104호 등]. 이들 종래의 베포타스틴-함유 방출제어 제제는 속방부 및 서방부를 서로 구분하여 제제화된 것으로, 예를 들어 서방부를 수불용성 중합체로 표면 도포된 형태를 갖거나(대한민국 특허공개 제2012-0083276호 등) 혹은 속방부와 서방부를 각각 별도의 층에 포함하는 이중층 정제 형태를 갖는다(대한민국 특허등록 제10-1731078호, 대한민국 특허공개 제10-2014-0016260호, 대한민국 특허공개 제10-2015-0138104호 등). 그러나, 이러한 종래의 제제들은 수불용성 중합체의 코팅 공정을 수행하여야 하거나 혹은 이중층 정제를 포함한 다층 구조의 형성을 위한 복수의 타정 공정을 수행하여야 하므로 제조가 복잡하여 생산현장에서 적용하기가 곤란한 문제점이 있다. 예를 들어, 대한민국 특허공개 제10-2014-0016260호는 일부의 베포타스틴 베실레이트를 함유하는 방출 조절 매트릭스층, 비활성 층, 방출 조절 코팅층, 베포타스틴 약물층 및 나머지 베포타스틴 베실레이트를 약물층을 포함하는 다층 정제; 베포타스틴 베실레이트를 함유하는 약물층, 생체 점착성 층(mucoadhesive layer), CR 코팅층, 및 활성 IR 코팅층을 포함하는 다층 정제를 개시하고 있으나, 다층 구조로 인한 복잡한 제조공정으로 인하여, 실제 생산 현장에서 적용하기 곤란한 문제점이 있다.Various studies have been made on the preparation of controlled release beportastine-containing release form for once-a-day administration in order to improve compliance with the patient's medication compliance [for example, Korean Patent Publication No. 2012-0083276, Korean Patent No. 10 -1731078, Korean Patent Laid-open Publication No. 10-2014-0016260 (International Patent Publication No. WO 2012/104818), Korean Patent Laid-open Publication No. 10-2015-0138104, etc.]. These conventional preparations of controlled release of bevetastin-containing preparation are prepared by separating the immediate-release part and the extended part. For example, they may have a form in which the extended part is surface-coated with a water-insoluble polymer (Korean Patent Publication No. 2008-0083276 ) Or a bilayer tablet form in which the inner and the outer portions are separately contained in separate layers (Korea Patent No. 10-1731078, Korean Patent Publication No. 10-2014-0016260, Korean Patent Publication No. 10-2015-0138104 Etc). However, such conventional preparations have a problem in that they are required to be coated with a water-insoluble polymer or to perform a plurality of tableting processes for forming a multi-layered structure including a double-layered tablet, . For example, Korean Patent Laid-open Publication No. 10-2014-0016260 discloses a pharmaceutical composition comprising a release-controlling matrix layer containing some bevapastastin besylate, an inactive layer, a release-controlled coating layer, a betapastin drug layer and the remaining betapastin besylate A multi-layered tablet comprising a drug layer; Layer tablet comprising a drug layer containing bevitalystine besylate, a mucoadhesive layer, a CR coating layer, and an active IR coating layer. However, due to the complicated manufacturing process due to the multi-layer structure, There is a problem that is difficult to apply.
한편, 상기한 바와 같이, 베포타스틴은 식사 후 약물을 복용하였을 때 공복시보다 체내흡수율이 저하되는 현상을 보이며, pH가 높아질수록 베포타스틴의 용해성이 감소하는 특성을 보이는 것으로 알려져 있다. 따라서, 속방성 제제는 식사에 의한 영향으로 용출율 저하 및 이로 인한 흡수 저하 현상을 나타낸다. 또한, 서방서 제제의 경우에도 식사에 대한 영향에 의해 약물 용출 양상이 변화하게 되어 경구투여 시 약물의 흡수 저하 및 개체 별 편차가 높게 나타나게 된다.On the other hand, as described above, it has been known that when the drug is taken after meals, the absorption rate of bepotastine in the body is lower than that in fasting, and that the higher the pH is, the lower the solubility of bepotastine is. Therefore, the immediate release preparation shows a phenomenon that the dissolution rate is lowered due to the effect of the meal and the absorption is lowered. In addition, even in the case of the sustained-release formulation, the dissolution profile of the drug changes due to the effect on the diet, resulting in a decrease in absorption of the drug and a high variation in the individual.
따라서, 복잡한 제제화 공정(예를 들어, 수불용성 중합체 코팅 공정, 다층 구조의 형성 공정 등)을 회피함과 동시에 위장관 환경 및/또는 음식물 등에 의한 위장관 pH의 변화에 따른 방출 변화(및 이로 이한 흡수편차)를 최소화할 수 할 수 있는 1일 1회 투여를 위한 방출제어 제제의 개발이 당업계에 요구되고 있다.Thus, it is desirable to avoid complicated formulation processes (e.g., water-insoluble polymer coating processes, formation processes of multi-layer structures, etc.) while avoiding emission changes due to changes in gastrointestinal environment and / Lt; RTI ID = 0.0 > 1 < / RTI >
본 발명자들은 1일 1회 투여되는 단일 매트릭스 정제 형태의 약학 조성물을 개발하기 위하여 다양한 연구를 수행하였다. 그 결과, 본 발명자들은 팽윤성 중합체 및 특정 방출조절제를 조합하여 방출제어 단일 매트릭스 정제(monolithic matrix tablet) 형태로 제제화할 경우, 초기에는 속방성 방출패턴을 나타내고 후기에는 지속성 방출패턴을 나타내면서 1일 1회 투여가 가능하고; 또한 위장관 환경 및/또는 음식물 등에 의한 위장관 pH의 변화에 따른 방출 변화(및 이로 이한 흡수편차)를 최소화할 수 있다는 것을 발견하였다. 또한, 직접타정법 또는 건식과립타정법에 따라 상기 단일 매트릭스 정제를 제조할 경우, 베포타스틴의 안정성을 효과적으로 유지할 수 있다는 것을 발견하였다.The present inventors have conducted various studies to develop a pharmaceutical composition in the form of a single matrix tablet once a day. As a result, the present inventors have found that when a swellable polymer and a specific release modifier are combined and formulated into a release-controlled monolithic matrix tablet, they exhibit an immediate release pattern at the beginning and a sustained release pattern at a later time Administration is possible; It has also been found that release changes (and thus absorption deviations) due to changes in gastrointestinal pH due to gastrointestinal environment and / or food or the like can be minimized. Further, it has been found that the stability of bevetastine can be effectively maintained when the single matrix tablet is prepared according to the direct tableting method or dry granule tableting method.
따라서, 본 발명은 베포타스틴 또는 이의 염을 팽윤성 중합체 및 특정 방출조절제의 조합을 사용하여 제제화하여 얻어지는 1일 1회 투여되는 방출제어 단일 매트릭스 정제를 제공하는 것을 목적으로 한다.Accordingly, it is an object of the present invention to provide a once-daily controlled release single matrix tablet obtained by formulating bevetastine or a salt thereof using a combination of a swelling polymer and a specific release modifying agent.
또한, 본 발명은 상기 방출제어 단일 매트릭스 정제의 제조방법을 제공하는 것을 목적으로 한다.It is another object of the present invention to provide a method for producing the above-mentioned release-controlled single matrix tablet.
본 발명의 일 태양에 따라, 베포타스틴 또는 이의 약학적으로 허용가능한 염; 팽윤성 중합체; 및 구연산, 숙신산, 주석산, 옥살산, 글루탐산, 아스코르브산, 말산, 말레인산, 젖산, 푸마르산, 개미산, 아세트산, 알긴산, 및 폴리아크릴산으로 이루어진 군으로부터 하나 이상 선택된 방출조절제를 포함하는, 1일 1회 투여를 위한 방출제어 단일 매트릭스 정제가 제공된다.According to one aspect of the present invention, beportastine or a pharmaceutically acceptable salt thereof; A swellable polymer; And one or more release regulators selected from the group consisting of citric acid, succinic acid, tartaric acid, oxalic acid, glutamic acid, ascorbic acid, malic acid, maleic acid, lactic acid, fumaric acid, formic acid, acetic acid, alginic acid, and polyacrylic acid. A controlled release single matrix tablet is provided.
본 발명의 다른 태양에 따라, (a) 베포타스틴 또는 이의 약학적으로 허용가능한 염; 팽윤성 중합체; 구연산, 숙신산, 주석산, 옥살산, 글루탐산, 아스코르브산, 말산, 말레인산, 젖산, 푸마르산, 개미산, 아세트산, 알긴산, 및 폴리아크릴산으로 이루어진 군으로부터 하나 이상 선택된 방출조절제; 및 희석제를 혼합하는 단계; 및 (b) 단계(a)에서 얻어진 혼합물을 활택제와 혼합한 다음, 얻어진 혼합물을 타정하는 단계를 포함하는, 1일 1회 투여를 위한 방출제어 단일 매트릭스 정제의 제조방법이 제공된다.According to another aspect of the present invention there is provided a pharmaceutical composition comprising: (a) bevitalastine or a pharmaceutically acceptable salt thereof; A swellable polymer; At least one release controlling agent selected from the group consisting of citric acid, succinic acid, tartaric acid, oxalic acid, glutamic acid, ascorbic acid, malic acid, maleic acid, lactic acid, fumaric acid, formic acid, acetic acid, alginic acid and polyacrylic acid; And a diluent; And (b) mixing the mixture obtained in step (a) with a lubricant, and then titrating the resulting mixture. The present invention also provides a process for preparing a release-controlled single matrix tablet for once-a-day administration.
본 발명의 또다른 태양에 따라, (a') 베포타스틴 또는 이의 약학적으로 허용가능한 염; 팽윤성 중합체; 구연산, 숙신산, 주석산, 옥살산, 글루탐산, 아스코르브산, 말산, 말레인산, 젖산, 푸마르산, 개미산, 아세트산, 알긴산, 및 폴리아크릴산으로 이루어진 군으로부터 하나 이상 선택된 방출조절제; 희석제; 및 활택제의 혼합물의 건식 과립을 제조하는 단계; 및 (b') 단계(a')에서 얻어진 건식 과립을 활택제와 혼합한 다음, 얻어진 혼합물을 타정하는 단계를 포함하는, 1일 1회 투여를 위한 방출제어 단일 매트릭스 정제의 제조방법이 제공된다.According to a further aspect of the present invention there is provided a pharmaceutical composition comprising (a ') bepotastine or a pharmaceutically acceptable salt thereof; A swellable polymer; At least one release controlling agent selected from the group consisting of citric acid, succinic acid, tartaric acid, oxalic acid, glutamic acid, ascorbic acid, malic acid, maleic acid, lactic acid, fumaric acid, formic acid, acetic acid, alginic acid and polyacrylic acid; diluent; Preparing a dry granulate of a mixture of a lubricant and a lubricant; And (b ') mixing the dry granules obtained in step (a ') with a lubricant, and then titrating the resultant mixture, wherein the release-controlled single matrix tablet is prepared for once- .
본 발명의 방출제어 단일 매트릭스 정제는 팽윤성 중합체 및 특정 방출조절제를 조합하여 제제화함으로써, 초기(약 6시간까지)에는 속방성 용출패턴을 나타내고 후기(약 6시간 이후)에는 지속적 용출패턴을 나타냄으로써 1일 1회 투여가 가능할 뿐만 아니라, 위장관 환경 및/또는 음식물 등에 의한 위장관 pH의 변화와 무관한 용출을 달성할 수 있으므로 흡수 편차를 최소화할 수 있다. 또한, 1일 1회 투여되는 본 발명의 방출제어 단일 매트릭스 정제는 종래의 1일 2회 투여되는 제제와 생물학적으로 동등하므로, 1일 1회 투여로 인한 환자의 복약순응도 향상을 도모할 수 있다. 또한, 본 발명의 제조방법에 따라 제조된 방출제어 단일 매트릭스 정제는 베포타스틴의 안정성을 효과적으로 유지할 수 있다.The release-controlled, single-matrix tablets of the present invention exhibit an immediate release pattern at the beginning (up to about 6 hours) and a continuous release pattern at a later stage (up to about 6 hours) by formulation with a combination of a swellable polymer and a specific release modifier It is possible not only to administer once a day but also to dissolve irrespective of changes in gastrointestinal pH due to the gastrointestinal tract environment and / or food or the like, so that the absorption deviation can be minimized. In addition, since the release-controlled single matrix tablet of the present invention administered once a day is biologically equivalent to the conventional twice-a-day formulation, it is possible to improve the patient's compliance with the medicament once administered once a day. In addition, the release-controlled single matrix tablets prepared according to the preparation method of the present invention can effectively maintain the stability of bevetastine.
도 1은 본 발명의 방출제어 단일 매트릭스 정제의 용출시험 결과를 나타낸다.
도 2는 방출조절제를 함유하지 않는 단일 매트릭스 정제(비교예 1)의 용출시험 결과를 나타낸다.
도 3은 본 발명의 방출제어 단일 매트릭스 정제(단회 투여) 및 대조제제(타리온정, 2회 투여)를 비글견에 각각 투여한 후 얻어진 혈장 중 농도 프로파일이다.Figure 1 shows the dissolution test results of the release-controlled single matrix tablets of the present invention.
Figure 2 shows the dissolution test results of a single matrix tablet (Comparative Example 1) containing no release modifier.
FIG. 3 is a plasma concentration profile obtained after administering the release-controlled single matrix tablets (single dose) and the control preparation (double-dose, two doses) of the present invention to beagle dogs, respectively.
본 발명은 베포타스틴 또는 이의 약학적으로 허용가능한 염; 팽윤성 중합체; 및 구연산, 숙신산, 주석산, 옥살산, 글루탐산, 아스코르브산, 말산, 말레인산, 젖산, 푸마르산, 개미산, 아세트산, 알긴산, 및 폴리아크릴산으로 이루어진 군으로부터 하나 이상 선택된 방출조절제를 포함하는, 1일 1회 투여를 위한 방출제어 단일 매트릭스 정제를 제공한다.The present invention relates to a pharmaceutical composition comprising bevetastine or a pharmaceutically acceptable salt thereof; A swellable polymer; And one or more release regulators selected from the group consisting of citric acid, succinic acid, tartaric acid, oxalic acid, glutamic acid, ascorbic acid, malic acid, maleic acid, lactic acid, fumaric acid, formic acid, acetic acid, alginic acid, and polyacrylic acid. ≪ / RTI > a single matrix tablet.
본 발명의 방출제어 단일 매트릭스 정제는 활성성분으로서 베포타스틴 또는 이의 약학적으로 허용가능한 염을 포함한다. 상기 베포타스틴의 약학적으로 허용가능한 염은 약리학적 또는 생리학적으로 허용되는 무기산, 유기산, 염기로부터 유도된 염을 제한 없이 포함한다. 상기 무기산 또는 유기산의 예는 염산, 브롬산, 브롬화수소산, 황산, 질산, 과염소산, 푸마르산, 말레산, 인산, 글리콜산, 락트산, 살리실산, 숙신산, 톨루엔-p-설폰산, 타르타르산, 아세트산, 시트르산, 메탄설폰산, 포름산, 벤조산, 말론산, 나프탈렌-2-설폰산, 벤젠설폰산 등을 포함한다. 상기 염기의 예는 알칼리 금속(예를 들어, 나트륨 또는 칼륨), 알칼리 토금속(예를 들어, 마그네슘) 등을 포함한다. 일 구현에에서, 베포타스틴의 약학적으로 허용가능한 염은 베포타스틴 베실산염일 수 있다. 베포타스틴 또는 이의 약학적으로 허용가능한 염은 치료학적으로 유효한 양(therapeutically effective amount)로 사용될 수 있으며, 예를 들어 단위 정제 당 10 mg ∼ 40 mg, 바람직하게는 15 mg ∼ 30 mg, 더욱 바람직하게는 약 20 mg의 베포타스틴 베실산염을 함유할 수 있다.The release-controlled single matrix tablets of the present invention comprise bevotastine or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutically acceptable salts of bevapastastin include, without limitation, salts derived from pharmacologically or physiologically acceptable inorganic acids, organic acids, bases. Examples of the inorganic acid or organic acid include hydrochloric acid, hydrobromic acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, Methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid and the like. Examples of such bases include alkali metals (e.g., sodium or potassium), alkaline earth metals (e.g., magnesium), and the like. In one embodiment, the pharmaceutically acceptable salt of bepotastine may be bepotastine bevacillate. Beptotastine or a pharmaceutically acceptable salt thereof may be used as a therapeutically effective amount, for example, from 10 mg to 40 mg, preferably from 15 mg to 30 mg, more preferably from 10 mg to 40 mg, Lt; RTI ID = 0.0 > mg / ml < / RTI >
본 발명의 방출제어 단일 매트릭스 정제에 있어서, 팽윤성 중합체는 베포타스틴 또는 이의 약학적으로 허용가능한 염의 지속적인 방출/용출을 가능하게 한다. 상기 팽윤성 중합체는 폴리비닐 알코올, 히드록시프로필 메틸셀룰로오스, 히드록시프로필 셀룰로오스, 히드록시에틸 셀룰로오스, 메틸셀룰로오스, 카르복메틸 셀룰로오스, 폴리에틸렌 옥사이드, 폴리비닐피롤리돈, 잔탄 검, 구아 검, 키토산, 카보머, 카라기난, 카르복시메틸 셀룰로오스, 및 알긴산 나트륨으로 이루어진 군으로부터 하나 이상 선택될 수 있다. 팽윤성 중합체의 특정 조합, 즉 히드록시프로필 메틸셀룰로오스와 폴리비닐 알코올의 조합을 사용할 경우 베포타스틴의 초기 용출(약 6시간까지의 용출)이 속방성 용출패턴을 나타냄과 동시에 추기 용출은 지속적인 용출패턴을 나타낸다는 것이 본 발명에 의해 밝혀졌다. 따라서, 상기 팽윤성 중합체로는 히드록시프로필 메틸셀룰로오스와 폴리비닐 알코올의 조합을 사용하는 것이 바람직하다. 상기 히드록시프로필 메틸셀룰로오스와 폴리비닐 알코올의 조합에 있어서, 히드록시프로필 메틸셀룰로오스와 폴리비닐 알코올의 중량비는 1 : 1∼2, 바람직하게는 약 1 : 1.5 일 수 있다. 상기 히드록시프로필 메틸셀룰로오스로는 50 mPa.S 내지 100,000 mPa.S의 점도, 더욱 바람직하게는 4,000 mPa.S 내지 100,000 mPa.S의 점도를 갖는 히드록시프로필 메틸셀룰로오스를 사용할 수 있다. 또한, 상기 폴리비닐 알코올은 20,000 내지 250,000의 중량평균분자량을 갖는 것이 바람직하다. 상기 팽윤성 중합체는 정제 총 중량에 대하여 20 ∼ 80 중량%의 양으로, 바람직하게는 30 ∼ 70 중량%의 양으로, 더욱 바람직하게는 약 50 중량%의 양으로 존재할 수 있다.In the release-controlled, single matrix tablet of the present invention, the swellable polymer enables sustained release / elution of the betapastin or a pharmaceutically acceptable salt thereof. The swelling polymer may be selected from the group consisting of polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, polyethylene oxide, polyvinylpyrrolidone, xanthan gum, guar gum, chitosan, Carrageenan, carboxymethylcellulose, and sodium alginate. When a specific combination of swellable polymers, that is, a combination of hydroxypropylmethylcellulose and polyvinyl alcohol is used, the initial elution of bevetastin (elution up to about 6 hours) shows a rapid elution pattern, and the additional elution pattern is a continuous elution pattern ≪ / RTI > is shown by the present invention. Therefore, it is preferable to use a combination of hydroxypropyl methylcellulose and polyvinyl alcohol as the swelling polymer. In the combination of hydroxypropyl methylcellulose and polyvinyl alcohol, the weight ratio of hydroxypropyl methylcellulose and polyvinyl alcohol may be 1: 1 to 2, preferably about 1: 1.5. As the hydroxypropylmethylcellulose, hydroxypropylmethylcellulose having a viscosity of 50 mPa.S to 100,000 mPa.S, more preferably 4,000 mPa.S to 100,000 mPa.S, may be used. The polyvinyl alcohol preferably has a weight average molecular weight of 20,000 to 250,000. The swellable polymer may be present in an amount of 20 to 80 wt.%, Preferably 30 to 70 wt.%, More preferably about 50 wt.%, Based on the total weight of the tablet.
본 발명의 방출제어 단일 매트릭스 정제에 있어서, 방출조절제는 베포타스틴과 팽윤성 중합체를 함유하는 제제가 체내 거동에 따라 위장관 환경에서 pH가 변하더라도 일정한 용출패턴을 나타날 수 있도록 한다. 일반적으로 위장는 약 pH 1.2, 십이지장은 약 pH 5부근, 공장은 약 pH 6, 회장은 약 pH 7의 pH를 나타내며, 제제가 머무르는 위치에 따라 용출율의 변화가 발생하고, 이에 따른 체내 흡수 패턴도 변화를 가져올 수 있다, 더욱이, 식사 후에는 음식물의 영향으로 위장의 pH가 3-5 사이로 증가하는 경우도 있으며, 통상의 서방성 중합체를 사용하여 제제화할 경우 방출이 저하되고, 초기의 용출 저하로 인한 체내 흡수의 저하를 가져올 가능성이 매우 높다. 본 발명에 따라 특정 방출조절제를 사용할 경우, 위장관 환경 및/또는 음식물 등에 의한 위장관 pH의 변화와 무관한 용출을 달성할 수 있으므로 흡수 편차를 최소화할 수 있다. 상기 방출조절제는 구연산, 숙신산, 주석산, 옥살산, 글루탐산, 아스코르브산, 말산, 말레인산, 젖산, 푸마르산, 개미산, 아세트산, 알긴산, 및 폴리아크릴산으로 이루어진 군으로부터 하나 이상 선택된다. 이들 방출조절제는 강한 산성을 띠지 않으면서 중성 이상의 조건에서 베포타스틴의 방출능력을 향상시킬 수 있다. 또한, 이들 방출조절제는 산성조건에서는 방출조절을 하는 약물의 용출에 큰 영향을 미치지 않으나 pH가 상승할수록 서방출 제형의 내부를 산성조건으로 만들어 베포타스틴의 방출을 증가시켜 pH 1.2액의 용출과 동일한 용출패턴을 나타내도록 한다. 상기 방출조절제로는 구연산, 푸마르산, 주석산, 숙신산, 말산, 및 알긴산으로 이루어진 군으로부터 하나 이상 선택된 방출조절제를 사용하는 것이 바람직하며, 더욱 바람직하게는 구연산을 사용하는 것이 바람직하다. 상기 방출조절제는 정제 총 중량에 대하여 5 ∼ 30 중량%의 양으로 존재하는 것이 바람직하며, 5 ∼ 25 중량%의 양으로 존재하는 것이 더욱 바람직하며, 7 ∼ 20 중량%의 양으로 존재하는 것이 더더욱 바람직하다. 방출조절제의 양이 5 중량% 미만일 경우 상기한 방출조절제로의 효과가 나타나지 않을 수 있으며, 방출조절제의 양이 30 중량%를 초과할 경우 광안정성을 포함한 안정성에 부정적인 영향을 미칠 수 있다.In the release-controlled, single-matrix tablet of the present invention, the release modifier allows the formulation containing beportastine and a swellable polymer to exhibit a constant release pattern, even when the pH changes in the gastrointestinal tract according to the behavior of the body. In general, the gastrointestinal pH is about 1.2, the duodenum is about
일 구현예에서, 용출매로서 정제수, pH1.2 액, pH4.0 액, pH6.8 액을 각각 900 ml씩 사용하여 100 rpm으로 12시간 동안 교반하면서 대한민국 약전 용출시험 제1법에 따라 용출시험을 수행하였을 때, 4시간 내지 12시간 사이의 임의의 시점에서 (i) pH 1.2 액에서의 용출율과 정제수에서의 용출율의 차이, (ii) pH 1.2 액에서의 용출율과 정제수에서의 용출율과 pH1.2 액에서의 용출율의 차이, (iii) pH 1.2 액에서의 용출율과 정제수에서의 용출율과 pH4.0 액에서의 용출율의 차이, 및 (iv) pH 1.2 액에서의 용출율과 정제수에서의 용출율과 pH6.8 액에서의 용출율의 차이가 10% 이하인 방출제어 단일 매트릭스 정제가 제공된다.In one embodiment, 900 ml of each of purified water, pH 1.2, pH 4.0, and pH 6.8 was used as an eluant, and the elution test was performed according to the Korean Pharmacopoeia dissolution test 1 method while stirring at 100 rpm for 12 hours (Ii) the dissolution rate in the pH 1.2 solution, the dissolution rate in the purified water, and the pH value in the pH 1 solution and the purified water, respectively, at any point between 4 hours and 12 hours. (Iii) a difference in dissolution rate in pH 1.2 solution, a purified water dissolution rate and a dissolution rate in pH 4.0 solution, and (iv) a dissolution rate in pH 1.2 solution and a dissolution rate in purified water and pH 6 A controlled release single matrix tablet is provided wherein the difference in dissolution rate in the .8 solution is 10% or less.
본 발명의 방출제어 단일 매트릭스 정제는 희석제, 계면활성제, 활택제, 착향제, 및 코팅제로 이루어진 군으로부터 하나 이상 선택된 약학적으로 허용가능한 첨가제를 추가로 포함할 수 있다.The controlled release single matrix tablets of the present invention may further comprise one or more pharmaceutically acceptable additives selected from the group consisting of diluents, surfactants, lubricants, flavors, and coatings.
상기 희석제의 예는 유당, 포도당, 미결정 셀룰로오스, 결정 셀룰로오스, 인산이수소칼슘 또는 이의 수화물(예를 들어 2수화물), 만니톨, 이소말트, 솔비톨, 전호화 전분, 자당, 전분, 락티톨, 자일리톨, 덱스트로스, 덱스트란, 베타시클로덱스트린, 셀락토스 TM(락토오즈와 셀룰로오스의 혼합물), 프로솔브 TM(실리카와 미결정 셀룰로오스의 혼합물), 말티톨, 옥수수 전분, 저치환 히드록시프로필셀룰로오스, 감자 전분 등을 포함하지만, 이에 제한되는 것은 아니다. Examples of the diluent include lactose, glucose, microcrystalline cellulose, crystalline cellulose, calcium dihydrogen phosphate or its hydrate (for example, dihydrate), mannitol, isomalt, sorbitol, pregelatinized starch, sucrose, starch, lactitol, xylitol, Dextrose, dextran, betacyclodextrin, cellulotose TM (a mixture of lactose and cellulose), prosolve TM (a mixture of silica and microcrystalline cellulose), maltitol, corn starch, low substituted hydroxypropyl cellulose, potato starch, and the like.
상기 계면활성제의 예는 소디움라우릴설페이트, 폴리소르베이트 80, 폴리소르베이트 60, 폴리소르베이트 40, 자당 지방산 에스테르, 크레모포어 RH 40TM 등을 포함하지만, 이에 제한되는 것은 아니다. Examples of such surfactants include, but are not limited to, sodium lauryl sulfate, polysorbate 80, polysorbate 60, polysorbate 40, sucrose fatty acid ester, cremophor RH 40 TM , and the like.
상기 활택제의 예는 스테아린산 또는 이의 염(예를 들어, 스테아린산 마그네슘, 스테아린산 칼슘 등), 스테아릴푸마르산 또는 이의 염(스테아릴푸마르산 나트륨 등), 경질 무수규산, 팔미트산, 활석, 카르나우바 왁스, 수소화 식물성 오일, 광유, 폴리에틸렌 글리콜 등을 포함하지만, 이에 제한되는 것은 아니다.Examples of the lubricant include stearic acid or a salt thereof (e.g., magnesium stearate, calcium stearate, etc.), stearyl fumaric acid or its salts (such as sodium stearyl fumarate), light silicic anhydride, palmitic acid, talc, Waxes, hydrogenated vegetable oils, mineral oils, polyethylene glycols, and the like.
본 발명은 또한 상기 방출제어 단일 매트릭스 정제의 제조방법을 제공한다. 즉, 본 발명은 직접타정법 또는 건식과립타정법을 통한 상기 방출제어 단일 매트릭스 정제의 제조방법을 제공하며, 본 발명의 제조방법에 따라 제조된 방출제어 단일 매트릭스 정제는 베포타스틴의 안정성을 효과적으로 유지할 수 있다.The present invention also provides a method of making the release-controlled single matrix tablet. That is, the present invention provides a method for producing the release-controlled single matrix tablet through a direct tableting method or a dry granule tabletting method, wherein the release-controlled single matrix tablet prepared according to the preparation method of the present invention effectively inhibits the stability of bevetastine .
일 태양에서, 본 발명은 (a) 베포타스틴 또는 이의 약학적으로 허용가능한 염; 팽윤성 중합체; 구연산, 숙신산, 주석산, 옥살산, 글루탐산, 아스코르브산, 말산, 말레인산, 젖산, 푸마르산, 개미산, 아세트산, 알긴산, 및 폴리아크릴산으로 이루어진 군으로부터 하나 이상 선택된 방출조절제; 및 희석제를 혼합하는 단계; 및 (b) 단계(a)에서 얻어진 혼합물을 활택제와 혼합한 다음, 얻어진 혼합물을 타정하는 단계를 포함하는, 1일 1회 투여를 위한 방출제어 단일 매트릭스 정제의 제조방법을 제공한다.In one aspect, the present invention provides a pharmaceutical composition comprising (a) bepotastine or a pharmaceutically acceptable salt thereof; A swellable polymer; At least one release controlling agent selected from the group consisting of citric acid, succinic acid, tartaric acid, oxalic acid, glutamic acid, ascorbic acid, malic acid, maleic acid, lactic acid, fumaric acid, formic acid, acetic acid, alginic acid and polyacrylic acid; And a diluent; And (b) mixing the mixture obtained in step (a) with a lubricant and then titrating the resulting mixture. The present invention also provides a process for preparing a controlled release single matrix tablet for once-a-day administration.
다른 태양에서, 본 발명은 (a') 베포타스틴 또는 이의 약학적으로 허용가능한 염; 팽윤성 중합체; 구연산, 숙신산, 주석산, 옥살산, 글루탐산, 아스코르브산, 말산, 말레인산, 젖산, 푸마르산, 개미산, 아세트산, 알긴산, 및 폴리아크릴산으로 이루어진 군으로부터 하나 이상 선택된 방출조절제; 희석제; 및 활택제의 혼합물의 건식 과립을 제조하는 단계; 및 (b') 단계(a')에서 얻어진 건식 과립을 활택제와 혼합한 다음, 얻어진 혼합물을 타정하는 단계를 포함하는, 1일 1회 투여를 위한 방출제어 단일 매트릭스 정제의 제조방법을 제공한다.In another aspect, the invention provides a pharmaceutical composition comprising (a ') bepotastine or a pharmaceutically acceptable salt thereof; A swellable polymer; At least one release controlling agent selected from the group consisting of citric acid, succinic acid, tartaric acid, oxalic acid, glutamic acid, ascorbic acid, malic acid, maleic acid, lactic acid, fumaric acid, formic acid, acetic acid, alginic acid and polyacrylic acid; diluent; Preparing a dry granulate of a mixture of a lubricant and a lubricant; And (b ') mixing the dry granules obtained in step (a') with a lubricant, and then titrating the resultant mixture, to prepare a release-controlled single matrix tablet for once-a-day administration .
본 발명의 제조방법에 있어서, 베포타스틴 또는 이의 약학적으로 허용가능한 염; 팽윤성 중합체; 방출조절제; 약학적으로 허용가능한 첨가제(예를 들어, 희석제, 활택제 등)는 상기에서 설명한 바와 같다. 이들 성분들은 적절한 메쉬 체(mesh screen), 예를 들면 400-700 ㎛ 메쉬 체를 사용하여 체질한 후 사용하는 것이 바람직하다. In the preparation method of the present invention, beportastine or a pharmaceutically acceptable salt thereof; A swellable polymer; Release modifiers; Pharmaceutically acceptable additives (for example, diluents, lubricants, etc.) are as described above. These components are preferably sieved using a suitable mesh screen, for example a 400-700 μm mesh sieve.
본 발명의 제조방법에 있어서, 상기 혼합은 제제학 분야에서 사용되는 통상의 방법에 따라 수행될 수 있다. 또한, 상기 건식 과립(dry granules)의 제조 또한 제제학 분야에서 사용되는 통상의 방법에 따라 수행될 수 있으며, 예를 들어 얻어진 혼합물을 롤러 컴팩터 등을 사용하여 압축함으로써 수행될 수 있다. 상기 타정 또한 제제학 분야에서 사용되는 통상의 방법에 따라 수행될 수 있다. 타정압은 약 7∼10 kp의 경도가 얻어지도록 적절히 조절될 수 있다.In the production process of the present invention, the mixing can be carried out according to a conventional method used in the pharmaceutical industry. The production of the dry granules may also be carried out according to the conventional methods used in the pharmaceutical industry, for example, by compressing the resulting mixture using a roller compactor or the like. The tableting may also be carried out according to conventional methods used in the field of medicine. The static pressure can be adjusted appropriately to obtain a hardness of about 7-10 kp.
본 발명의 방출제어 단일 매트릭스 정제는 나정 형태로 사용될 수 있으며, 필요할 경우 필름코팅층 등의 통상의 코팅층을 추가로 포함할 수 있다. 상기 필름코팅층은 폴리비닐 알코올, 히드록시프로필셀룰로오스, 잔탄검, 락토스, 히드록시프로필메틸셀룰로스, 트리아세틴, 폴리비닐피놀리돈, 폴리에틸렌글리콜, 프로필렌글리콜, 탈크, 티타늄 이산화물, 색소 등의 통상의 필름코팅 형성용 성분들을 포함할 수 있다. 필름코팅 형성은 통상의 방법에 따라 분무 코팅 등의 방법을 통하여 수행될 수 있다.The release-controlled single matrix tablets of the present invention can be used in an amorphous form and, if necessary, can additionally include conventional coating layers such as film coating layers. The film coating layer may be formed using a conventional film such as polyvinyl alcohol, hydroxypropylcellulose, xanthan gum, lactose, hydroxypropyl methylcellulose, triacetin, polyvinylpyrinolidone, polyethylene glycol, propylene glycol, talc, titanium dioxide, And may include components for forming a coating. Film coating formation can be carried out by a method such as spray coating according to a conventional method.
이하, 본 발명을 실시예 및 시험예를 통하여 더욱 상세히 설명한다. 그러나, 하기 실시예 및 시험예는 본 발명을 예시하기 위한 것으로, 본 발명이 이들에 의해 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples and test examples. However, the following examples and test examples are provided for illustrating the present invention, and the present invention is not limited thereto.
실시예Example 1. One. 직접타정법에In direct tattooing 의한 단일 매트릭스 정제의 제조 ≪ / RTI >
하기 표 1의 함량 및 조성에 따라 베포타스틴 베실산염을 함유하는 정제를 제조하였다. 표 1의 각 성분의 함량은 정제당 함량(mg)을 나타낸다. 베포타스틴 베실산염, 히드록시프로필 메틸셀룰로오스 2208(15,000 mPa.S, 제조원 shinetsu), 폴리비닐 알코올(EMPROVE 40-88 TM, 제조원 Merck), 미결정 셀룰로오스, 및 구연산을 각각 20메쉬 체망에 사과한 후 약 10분간 혼합하였다. 얻어진 혼합물에 40메쉬 체망에 사과한 스테아릴푸마르산 나트륨을 넣고 추가로 약 5분간 혼합하였다. 얻어진 혼합물을 압축타정기에서 압축하여 1정의 중량이 200 mg인 원형 정제를 제조하였다. 정제의 경도는 약 10 kp가 되도록 타정 압력을 조정하였다. Tablets containing beportastine bevacillate were prepared according to the contents and compositions of Table 1 below. The content of each component in Table 1 represents the refined sugar content (mg). Hydroxypropylmethylcellulose 2208 (15,000 mPa.S, shinetsu), polyvinyl alcohol (EMPROVE 40-88 TM , manufactured by Merck), microcrystalline cellulose, and citric acid were each ap- plied in a 20 mesh sieve and mixed for about 10 minutes. To the resulting mixture was added 40 ml of apple stearyl fumarate in a 40 mesh sieve, followed by mixing for about 5 minutes. The resulting mixture was compressed on a compression tablet machine to prepare a circular tablet having a weight of 200 mg per tablet. The tableting pressure was adjusted so that the hardness of the tablet was about 10 kp.
실시예Example 2. 2. 건식과립타정법에In dry granule tabletting method 의한 단일 매트릭스 정제의 제조 ≪ / RTI >
하기 표 2의 함량 및 조성에 따라 베포타스틴 베실산염을 함유하는 정제를 제조하였다. 표 2의 각 성분의 함량은 정제당 함량(mg)을 나타낸다. 베포타스틴 베실산염, 히드록시프로필 메틸셀룰로오스 2208(15,000 mPa.S, 제조원 shinetsu), 폴리비닐 알코올(EMPROVE 40-88 TM, 제조원 Merck), 미결정 셀룰로오스, 및 구연산을 각각 20메쉬 체망에 사과한 후 약 10분간 혼합하였다. 얻어진 혼합물에 40메쉬 체망에 사과한 스테아린산 마그네슘 및 콜로이드성 경질 무수규산을 추가로 약 5분간 혼합하였다. 얻어진 혼합물을 롤러 컴팩터에서 압축하여 건식과립을 제조한 후, 오실레이터에서 16메쉬 체망으로 사과하였다. 얻어진 과립에 40메쉬 체망에 사과한 스테아릴푸마르산 나트륨을 넣고 추가로 약 5분간 혼합하였다. 얻어진 혼합물을 압축타정기에서 압축하여 1정의 중량이 200 mg인 원형 정제를 제조하였다. 정제의 경도는 약 10 kp가 되도록 타정 압력을 조정하였다. Tablets containing beportastine bevacillate were prepared according to the contents and compositions in Table 2 below. The content of each component in Table 2 represents the refined sugar content (mg). Hydroxypropylmethylcellulose 2208 (15,000 mPa.S, shinetsu), polyvinyl alcohol (EMPROVE 40-88 TM , manufactured by Merck), microcrystalline cellulose, and citric acid were each ap- plied in a 20 mesh sieve and mixed for about 10 minutes. The obtained mixture was further mixed with magnesium stearate and colloidal hard anhydrous silicic acid in a 40-mesh sieve for about 5 minutes. The resulting mixture was compressed on a roller compactor to produce dry granules, which were then applicated in an oscillator with a 16 mesh sawmill. To the resulting granules was added 40 ml of apple stearyl fumarate in a 40 mesh sieve, followed by mixing for about 5 minutes. The resulting mixture was compressed on a compression tablet machine to prepare a circular tablet having a weight of 200 mg per tablet. The tableting pressure was adjusted so that the hardness of the tablet was about 10 kp.
실시예Example 3 내지 6. 단일 매트릭스 정제의 제조 3 to 6. Preparation of Single Matrix Tablets
하기 표 3의 함량 및 조성에 따라 베포타스틴 베실산염을 함유하는 정제를 제조하였다. 표 3의 각 성분의 함량은 정제당 함량(mg)을 나타낸다. 베포타스틴 베실산염, 히드록시프로필 메틸셀룰로오스 2208 (100,000 mPa.S, 제조원 shinetsu)/히드록시프로필 메틸셀룰로오스 2208 (15,000 mPa.S, 제조원 shinetsu)/히드록시프로필 메틸셀룰로오스 2910 (4,000 mPa.S, 제조원 shinetsu), 폴리비닐 알코올(EMPROVE 40-88 TM, 제조원 Merck), 미결정 셀룰로오스/D-만니톨/인산이수소칼슘, 및 구연산을 각각 20메쉬 체망에 사과한 후 약 10분간 혼합하였다. 얻어진 혼합물에 40메쉬 체망에 사과한 스테아린산 마그네슘/스테아릴푸마르산 나트륨을 넣고 추가로 약 5분간 혼합하였다. 얻어진 혼합물을 압축타정기에서 압축하여 1정의 중량이 200 mg인 원형 정제를 제조하였다. 정제의 경도는 약 10 kp가 되도록 타정 압력을 조정하였다.Tablets containing beportastine bevacillate were prepared according to the contents and compositions in Table 3 below. The content of each component in Table 3 represents the refined sugar content (mg). Hydroxypropylmethylcellulose 2208 (100,000 mPa.S, shinetsu) / hydroxypropylmethylcellulose 2208 (15,000 mPa.S, shinetsu) / hydroxypropylmethylcellulose 2910 (4,000 mPa.S., Shinetsu), polyvinyl alcohol (EMPROVE 40-88 TM , manufactured by Merck), microcrystalline cellulose / D-mannitol / calcium dihydrogenphosphate, and citric acid were each ap- plied to a 20-mesh sieve and mixed for about 10 minutes. To the obtained mixture, magnesium stearate / sodium stearyl fumarate in an amount of 40 mesh sieve was added and mixed for about 5 minutes. The resulting mixture was compressed on a compression tablet machine to prepare a circular tablet having a weight of 200 mg per tablet. The tableting pressure was adjusted so that the hardness of the tablet was about 10 kp.
실시예Example 7 내지 9. 단일 매트릭스 정제의 제조 7 to 9. Preparation of Single Matrix Tablets
하기 표 4의 함량 및 조성에 따라 베포타스틴 베실산염을 함유하는 정제를 제조하였다. 표 4의 각 성분의 함량은 정제당 함량(mg)을 나타낸다. 베포타스틴 베실산염, 히드록시프로필 메틸셀룰로오스 2208 (100,000 mPa.S, 제조원 shinetsu)/유드라짓 L100 55(Eudragit TM L100 55, 제조원 Evinik), 폴리에틸렌 옥사이드(Polyox303 TM, 제조원 Dow), 미결정 셀룰로오스/D-만니톨, 및 구연산을 각각 20메쉬 체망에 사과한 후 약 10분간 혼합하였다. 얻어진 혼합물에 40메쉬 체망에 사과한 스테아린산 마그네슘을 넣고 추가로 약 5분간 혼합하였다. 얻어진 혼합물을 압축타정기에서 압축하여 1정의 중량이 240 mg인 원형 정제를 제조하였다. 정제의 경도는 약 10 kp가 되도록 타정 압력을 조정하였다. Tablets containing beportastine besylate were prepared according to the contents and compositions in Table 4 below. The content of each component in Table 4 represents the content of refined sugar (mg). Hydroxypropylmethylcellulose 2208 (100,000 mPa.S, shinetsu) / Eudragit L100 55 (Eudragit) TM L100 55, manufactured by Evinik), polyethylene oxide (Polyox303 TM , manufactured by Dow), microcrystalline cellulose / D-mannitol, and citric acid were each ap- plied in a 20-mesh sieve and mixed for about 10 minutes. To the obtained mixture, magnesium stearate was added to a 40 mesh sieve, and the mixture was further mixed for about 5 minutes. The resultant mixture was compressed in a compression tablet machine to prepare a circular tablet having a weight of 240 mg. The tableting pressure was adjusted so that the hardness of the tablet was about 10 kp.
실시예Example 10 내지 14. 단일 매트릭스 정제의 제조 10 to 14. Preparation of Single Matrix Tablets
하기 표 5의 함량 및 조성에 따라 베포타스틴 베실산염을 함유하는 정제를 제조하였다. 표 5의 각 성분의 함량은 정제당 함량(mg)을 나타낸다. 베포타스틴 베실산염, 히드록시프로필 메틸셀룰로오스 2208(15,000 mPa.S, 제조원 shinetsu), 폴리비닐 알코올(EMPROVE 40-88 TM, 제조원 Merck), 미결정 셀룰로오스, 및 주석산/푸마르산/숙신산/말산/알긴산을 각각 20메쉬 체망에 사과한 후 약 10분간 혼합하였다. 얻어진 혼합물에 40메쉬 체망에 사과한 스테아릴푸마르산 나트륨을 넣고 추가로 약 5분간 혼합하였다. 얻어진 혼합물을 압축타정기에서 압축하여 1정의 중량이 200 mg인 원형 정제를 제조하였다. 정제의 경도는 약 10 kp가 되도록 타정 압력을 조정하였다. Tablets containing beportastine bevacillate were prepared according to the contents and compositions in Table 5 below. The content of each component in Table 5 represents the refined sugar content (mg). Hydroxypropylmethylcellulose 2208 (15,000 mPa.S, shinetsu), polyvinyl alcohol (EMPROVE 40-88 TM , manufactured by Merck), microcrystalline cellulose, and tartaric acid / fumaric acid / succinic acid / malic acid / alginic acid were each ap- plied in a 20 mesh sieve and mixed for about 10 minutes. To the resulting mixture was added 40 ml of apple stearyl fumarate in a 40 mesh sieve, followed by mixing for about 5 minutes. The resulting mixture was compressed on a compression tablet machine to prepare a circular tablet having a weight of 200 mg per tablet. The tableting pressure was adjusted so that the hardness of the tablet was about 10 kp.
(15,000 mPa.S)Hydroxypropylmethylcellulose 2208
(15,000 mPa.s)
실시예Example 15. 단일 매트릭스 정제의 제조 15. Preparation of single matrix tablets
필름코팅 기재(OPADRY 03B28796 WHITE, 칼라콘)를 70% 에탄올 용액에 분산시켜 코팅액을 제조하였다. 얻어진 코팅액을 이용하여 실시예 3에서 제조한 정제를 Se-Jong SFC-30FN 코팅 기기에서 약 3% 필름막을 형성시켜 필름코팅정을 제조하였다.The film-coated substrate (OPADRY 03B28796 WHITE, colorcon) was dispersed in a 70% ethanol solution to prepare a coating solution. Using the obtained coating solution, a film of about 3% was formed on the Se-Jong SFC-30FN coating apparatus using the tablets prepared in Example 3 to prepare film-coated tablets.
비교예Comparative Example 1. 단일 매트릭스 정제의 제조 1. Preparation of single matrix tablets
하기 표 6의 함량 및 조성에 따라, 구연산을 사용하지 않은 것을 제외하고는 실시예 3과 동일한 방법으로 단일 매트릭스 정제를 제조하였다.A single matrix tablet was prepared in the same manner as in Example 3, except that citric acid was not used, according to the content and composition of Table 6 below.
비교예Comparative Example 2. 2. 습식과립타정법에In the wet granulation method 의한 단일 매트릭스 정제의 제조 ≪ / RTI >
습식과립법에 따라 하기 표 7의 함량 및 조성에 따라 베포타스틴 베실산염을 함유하는 정제를 제조하였다. 표 7의 각 성분의 함량은 정제당 함량(mg)을 나타낸다. 베포타스틴 베실산염, 히드록시프로필 메틸셀룰로오스 2208(100,000 mPa.S, 제조원 shinetsu), 폴리비닐 알코올(EMPROVE 40-88 TM, 제조원 Merck), 미결정 셀룰로오스, 및 구연산을 각각 20메쉬 체망에 사과한 후, 고속 혼합기(High shear mixer)에 넣고 약 4분간 혼합하였다. 결합액으로 90% 에탄올(v/v) 40mL을 사용하여 고속 혼합기에 천천히 넣으면서 과립화하였다. 얻어진 과립을 90℃에서 10분간 건조감량을 측정하였을 때 2% 이하가 되도록 열풍건조기에서 약 4시간 동안 건조하였다. 건조 과립을 오실레이터에서 16메쉬 체망으로 사과하였다. 얻어진 과립에 40메쉬 체망에 사과한 스테아린산 마그네슘을 넣고 추가로 약 5분간 혼합하였다. 얻어진 혼합물을 압축타정기에서 압축하여 1정의 중량이 200 mg인 원형 정제를 제조하였다. 정제의 경도는 약 10 kp가 되도록 타정 압력을 조정하였다. Tablets containing bevapastastin beetle were prepared according to the content and composition of Table 7 according to the wet granulation method. The content of each component in Table 7 represents the content of refined sugar (mg). Hydroxypropylmethylcellulose 2208 (100,000 mPa.S, shinetsu), polyvinyl alcohol (EMPROVE 40-88 TM , manufactured by Merck), microcrystalline cellulose, and citric acid were each ap- plied in a 20-mesh sieve, followed by mixing in a high-shear mixer for about 4 minutes. And 40 mL of 90% ethanol (v / v) as a binding liquid was slowly added to the high-speed mixer and granulated. The obtained granules were dried for about 4 hours in a hot-air dryer so that the drying loss was measured at 90 ° C for 10 minutes to be not more than 2%. The dried granules were applicated in an oscillator with a 16 mesh saw blade. To the resulting granules, magnesium stearate was added to a 40 mesh sieve, and the mixture was further mixed for about 5 minutes. The resulting mixture was compressed on a compression tablet machine to prepare a circular tablet having a weight of 200 mg per tablet. The tableting pressure was adjusted so that the hardness of the tablet was about 10 kp.
시험예Test Example 1. 용출시험 1. Dissolution test
실시예 3의 정제 및 비교예 1의 정제에 대한 용출시험을 정제수, pH1.2 액, pH4.0 액, pH6.8 액을 용출매로 사용하여 대한민국약전 용출시험 제1법(회전검체통법, 100 rpm)에 따라 수행하였다. 각각 6정을 사용하여 용출매(900 mL)에서 37±0.5℃에서 용출시험을 수행하였으며, 소정의 시간에 샘플 10 mL을 취하여 0.45 ㎛ 실린지 필터로 여과하였다. 각 샘플 중 베포타스틴의 함량은 하기 조건하에서 고속액체크로마토그래피(HPLC)로 측정하였다. The elution test for the tablets of Example 3 and the tablets of Comparative Example 1 was performed using the purified water, pH 1.2, pH 4.0, and pH 6.8 as the eluant, 100 rpm). The elution test was performed at 37 ± 0.5 ° C in an eluent (900 mL) using 6 tablets each, and 10 mL of a sample was taken at a predetermined time and filtered through a 0.45 μm syringe filter. The content of bevetastatin in each sample was measured by high performance liquid chromatography (HPLC) under the following conditions.
<HPLC 조건><HPLC Conditions>
- 검출기: 자외부흡광광도계 (측정파장: 260 ㎚)- Detector: Ultraviolet absorptiometer (measuring wavelength: 260 nm)
- 컬럼: Kromasil C8 column, 150 x 4.6 mm, 5 ㎛ - Column: Kromasil C8 column, 150 x 4.6 mm, 5 탆
- 컬럼 온도: 약 40℃- Column temperature: about 40 ℃
- 유속: 1.0 mL/min- Flow rate: 1.0 mL / min
- 이동상: A : B (70 : 30) 혼합액에 1 g/L 펜탄술폰산 혼합액- mobile phase: 1 g / L pentane sulfonic acid mixture (A: B (70: 30)
이동상 A: 50 mM 인산이수소칼륨용액 (인산으로 pH 3.0 조정) Mobile phase A: 50 mM potassium dihydrogen phosphate solution (pH 3.0 adjusted with phosphoric acid)
이동상 B: 아세토니트릴 Mobile phase B: acetonitrile
실시예 3의 정제 및 비교예 1의 정제의 용출시험 결과는 각각 도 1 및 도 2와 같다. 실시예 3의 정제 및 비교예 1의 정제는 모두 초기, 즉 약 용출개시 후 약 6시간 동안 약 70%의 용출을 달성하였으며, 또한 이후 거의 0차 속도로 지속적으로 약물이 방출되는 방출제어 용출 프로파일(controlled-release dissolution profile)을 나타내었다. 그러나, 비교예 1의 정제는 용출매의 pH에 따라 용출율에 있어서 큰 차이를 나타낸 반면, 실시예 3의 정제는 용출매의 pH와 무관한 용출 프로파일을 나태었다. 실시예 3의 정제 및 비교예 1의 정제에 대한 pH 1.2 액에서의 용출율과 다른 pH 액에서의 용출율의 차이를 계산하면 각각 표 8 및 표 9와 같다. The results of the dissolution test of the tablet of Example 3 and the tablet of Comparative Example 1 are shown in Figs. 1 and 2, respectively. The tablets of Example 3 and the tablets of Comparative Example 1 both achieved an elution of about 70% for about 6 hours after initiation of drug elution, and thereafter release controlled elution profiles with sustained drug release at nearly zero order rate (controlled-release dissolution profile). However, the tablets of Comparative Example 1 showed a large difference in the elution rate according to the pH of the eluant, whereas the tablets of Example 3 exhibited an elution profile independent of the pH of the eluate. The difference between the dissolution rate in the pH 1.2 solution and the dissolution rate in the other pH solution for the tablets of Example 3 and the tablets of Comparative Example 1 are shown in Tables 8 and 9, respectively.
상기 도 1, 도 2, 표 8 및 표 9의 결과로부터, 본 발명에 따른 정제는 위장관 환경 및/또는 음식물 등에 의한 위장관 pH의 변화와 무관하게 방출조절 용출 프로파일을 나타냄을 알 수 있다.1, 2, 8 and 9, it can be seen that the tablets according to the present invention exhibit a controlled release profile regardless of changes in the gastrointestinal tract environment and / or the gastrointestinal tract pH due to food or the like.
시험예Test Example 2. 안정성 시험 2. Stability test
실시예 3의 정제 및 비교예 2의 정제를 각각 HDPE병에 넣고 40℃, 상대습도 75%의 가속조건에서 1개월 동안 안정성 시험을 수행하였다. 1개월 경과 후, 검체를 채취하여 다음과 같이 유연물질의 함량을 분석하였다. 즉, 검체 20정을 취하여 가루로 하고, 베포타스틴 베실산염 20 mg을 취하여 50 mL 플라스크에 넣고 아세토니트릴 10 mL을 넣어 10분간 초음파추출하고, 이동상으로 표선을 맞추어 하기 조건에 따라 액체크로마토그래피(HPLC)로 유연물질이 양을 분석하였다.The tablets of Example 3 and the tablets of Comparative Example 2 were each placed in an HDPE bottle and subjected to a stability test for one month at an acceleration condition of 40 DEG C and a relative humidity of 75%. After 1 month, samples were collected and analyzed for the contents of the following substances. 20 mg of the sample was taken as a powder, and 20 mg of bepotastine besylate was placed in a 50 mL flask, and 10 mL of acetonitrile was added thereto. The mixture was ultrasonically extracted for 10 minutes, and subjected to liquid chromatography HPLC). ≪ / RTI >
<HPLC 조건><HPLC Conditions>
- 검출기: 자외부흡광광도계 (측정파장: 220 ㎚)- Detector: Ultraviolet absorptiometer (measuring wavelength: 220 nm)
- 컬럼: Kromasil C8 column, 150 x 4.6 mm, 5 ㎛- Column: Kromasil C8 column, 150 x 4.6 mm, 5 탆
- 컬럼 온도: 약 40℃- Column temperature: about 40 ℃
- 유속: 1.0 mL/min- Flow rate: 1.0 mL / min
- 이동상: A : B (70 : 30) 혼합액에 1 g/L 펜탄술폰산 혼합액- mobile phase: 1 g / L pentane sulfonic acid mixture (A: B (70: 30)
이동상 A: 50 mM 인산이수소칼륨용액 (인산으로 pH 3.0 조정) Mobile phase A: 50 mM potassium dihydrogen phosphate solution (pH 3.0 adjusted with phosphoric acid)
이동상 B: 아세토니트릴 Mobile phase B: acetonitrile
상기와 같이 안정성 시험을 수행한 결과, 실시예 3의 정제는 유연물질이 정량한계 미만으로 검출되었으나. 비교예 2의 정제는 총 유연물질의 함량이 4.01%가 검출되어, 품질기준을 초과하였다. 따라서, 직접타정법 또는 건식과립타정법에 의해 정제의 제조를 수행하는 것이 우수한 안정성을 확보할 수 있는 반면, 습식과립타정법에 의한 정제의 제조는 안정성 확보가 곤란함을 알 수 있다.As a result of the stability test as described above, the tablets of Example 3 were found to be below the limit of the amount of the suppository. The tablets of Comparative Example 2 contained 4.01% of the total amount of the flexible material, exceeding the quality standard. Therefore, it is understood that preparation of the tablet by the direct tableting method or the dry granule tabletting method can secure excellent stability, while it is difficult to secure the stability of the tablet by the wet granule tableting method.
시험예Test Example 3. 약물동태시험( 3. Pharmacokinetics test ( pharmacokineticpharmacokinetic study) study)
대조제제로서 타리온정(동아제약, 베포타스틴 베실산염 10 mg/정, 1일 2회 투여)을 사용하여, 실시예 3의 정제의 1일 1회 투여와의 약물동태시험을 수행하였다. 비글견은(Canis familiaris, 1.5세령의 수컷)에 대조제제를 1차 투여 후 10시간 후에 2차 투여하여 1일 2회 투여하였고, 실시예 3의 정제는 1일 1회 투여하였다. 투여 후 30분, 1시간, 2시간, 3시간, 4시간, 5시간, 6시간, 8시간, 10시간, 11시간(대조제제만 채혈), 12시간, 13시간, 14시간, 16시간, 및 24시간 경과 후에 혈액 2 mL를 각각 채취하고, 혈장 중 베포타스틴의 농도를 분석하였다. 대조제제 및 실시예 3의 정제의 혈장 중 농도 프로파일은 도 3과 같으며, 이로부터 계산된 약물동태학적 파라미터(Cmax 및 AUC)는 표 10과 같다.A pharmacokinetic test with the once-a-day administration of the tablet of Example 3 was carried out using Tarionje (Dong-A Pharmaceutical, beportastine bevacillate 10 mg / tablet, twice a day) as a control preparation. The beagle dog (Canis familiaris, male of 1.5 years of age) was administered twice a day for 10 days after the first administration of the control preparation and twice a day, and the tablet of Example 3 was administered once a day. 12 hrs, 13 hrs, 14 hrs, 16 hrs, 10 hrs, 10 hrs, 11 hrs (collecting only the control preparation), 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, And 2 mL of blood after 24 hours, respectively, and the concentration of bepotastine in plasma was analyzed. The plasma concentration profiles of the control and the tablet of Example 3 are shown in FIG. 3, and the calculated pharmacokinetic parameters (Cmax and AUC) are shown in Table 10.
(실시예 3의 정제/대조제제)Ratio
(Tablet / control preparation of Example 3)
(ng/mL) 969.1 ± 275.8
(ng / mL)
(ng/mL)1091.2 + - 349.9
(ng / mL)
(ng.hr/mL)9720.4 ± 1590.9
(ng.hr / mL)
(ng.hr/mL)10048.6 + 708.8
(ng.hr / mL)
도 3 및 표 10의 결과로부터, 본 발명의 정제의 1일 1회 투여는 대조제제의 1일 2회 투여와 생물학적으로 동등함을 알 수 있다.From the results of FIG. 3 and Table 10, it can be seen that the once-daily administration of the tablet of the present invention is biologically equivalent to administration of the control preparation twice a day.
Claims (19)
(b) 단계(a)에서 얻어진 혼합물을 활택제와 혼합한 다음, 얻어진 혼합물을 타정하는 단계를 포함하는,
1일 1회 투여를 위한 방출제어 단일 매트릭스 정제의 제조방법.(a) bepotastine or a pharmaceutically acceptable salt thereof; A swellable polymer; At least one release controlling agent selected from the group consisting of citric acid, succinic acid, tartaric acid, oxalic acid, glutamic acid, ascorbic acid, malic acid, maleic acid, lactic acid, fumaric acid, formic acid, acetic acid, alginic acid and polyacrylic acid; And a diluent; And
(b) mixing the mixture obtained in step (a) with a lubricant, and then calibrating the resulting mixture.
A method for the preparation of a controlled release single matrix tablet for once-a-day dosing.
(b') 단계(a')에서 얻어진 건식 과립을 활택제와 혼합한 다음, 얻어진 혼합물을 타정하는 단계를 포함하는,
1일 1회 투여를 위한 방출제어 단일 매트릭스 정제의 제조방법.(a ') bepotastine or a pharmaceutically acceptable salt thereof; A swellable polymer; At least one release controlling agent selected from the group consisting of citric acid, succinic acid, tartaric acid, oxalic acid, glutamic acid, ascorbic acid, malic acid, maleic acid, lactic acid, fumaric acid, formic acid, acetic acid, alginic acid and polyacrylic acid; diluent; Preparing a dry granulate of a mixture of a lubricant and a lubricant; And
(b ') mixing the dry granules obtained in step (a') with a lubricant, and then calibrating the resulting mixture.
A method for the preparation of a controlled release single matrix tablet for once-a-day dosing.
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| PCT/KR2018/011923 WO2019088490A1 (en) | 2017-11-01 | 2018-10-11 | Controlled release single matrix tablet including bepotastine or pharmaceutically acceptable salt thereof, and method for producing same |
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