KR101855323B1 - Ｄｐｐ ｉｖ 억제제 제형 - Google Patents

Ｄｐｐ ｉｖ 억제제 제형 Download PDF

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KR101855323B1
KR101855323B1 KR1020167029877A KR20167029877A KR101855323B1 KR 101855323 B1 KR101855323 B1 KR 101855323B1 KR 1020167029877 A KR1020167029877 A KR 1020167029877A KR 20167029877 A KR20167029877 A KR 20167029877A KR 101855323 B1 KR101855323 B1 KR 101855323B1
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안야 콜라우쉬
패트릭 로머
게르트 자이페르트
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베링거 인겔하임 인터내셔날 게엠베하
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Abstract

본 발명은 아미노 그룹을 갖는 DPP IV 억제제로 이루어진 약제학적 조성물, 이의 제조방법, 및 진성 당뇨병의 치료를 위한 이의 용도에 관한 것이다.

Description

ＤＰＰ ＩＶ 억제제 제형 {DPP IV inhibitor formulations}
본 발명은 선택된 DPP IV 억제제로 이루어진 약제학적 조성물, 이의 제조방법, 및 선택된 의학적 상태의 치료를 위한 이의 용도에 관한 것이다.
CD26으로도 공지되어 있는 효소 DPP-IV (디펩티딜 펩티다아제 IV (dipeptidyl peptidase IV))는, N-말단에 프롤린 또는 알라닌 잔기를 갖는 다수의 단백질의 N-말단으로부터 디펩티드를 개열시키는 것으로 공지되어 있는, 세린 프로테아제이다. 이의 특성으로 인하여, 펩티트 GLP-1을 포함하는 생활성 펩티드의 혈장 농도를 간섭하는 DPP-IV 억제제가, 장래성 있는 진성 당뇨병 치료 약물인 것으로 간주된다.
선택된 DPP-IV 억제제의 약제학적 조성물을 제조하기 위한 시도에서, 1급 또는 2급 아미노 그룹을 갖는 DPP-IV 억제제는 미세결정질 셀룰로오스, 나트륨 전분 글리콜레이트, 크로스카멜로오스 나트륨, 타르타르산, 시트르산, 글루코오스, 프럭토오스, 사카로오스, 락토오스, 말토덱스트린과 같은 다수의 통상의 부형제와 비혼화성, 열화 문제, 또는 추출 문제를 나타내는 것으로 관찰되어 왔다. 화합물 자체가 매우 안정할지라도, 당해 화합물은, 고체 투여 제형에 사용되는 다수의 부형제와 반응하며, 특히 정제에서 제공되는 밀착 접촉 및 높은 부형제/약물 비율에서 부형제의 불순물과 반응한다. 아미노 그룹은 환원 당과 반응하고, 기타 반응성 카보닐 그룹과 반응하고, 예를 들면, 산화에 의해 미세결정질 셀룰로오스의 표면에 형성된 카복실산 작용기와 반응하는 것으로 보인다. 이러한 예측하지 못하는 어려움들은, 선택된 억제제의 놀라운 효능으로 인하여 요구되는 낮은 투여 범위에서 주로 관찰된다. 따라서, 선택된 DPP-IV 억제제 화합물의 예상치 못한 효능과 관련된 이들 기술적인 문제들을 해결하기 위한 약제학적 조성물이 요구된다.
본 발명에 따르는 약제학적 조성물은 1형 또는 2형 진성 당뇨병 환자의 혈당 조절을 달성하기 위한 치료를 위한 것이며, 활성 성분으로서의 아미노 그룹, 특히 유리 (free) 또는 1급 아미노 그룹을 갖는 DPP-IV 억제제, 제1 및 제2 희석제, 결합제, 붕해제 및 윤활제를 포함한다. 추가의 붕해제 및 추가의 활제 (glidant)는 추가의 선택 사항이다. 추가로, 당해 조성물은 류머티즘성 관절염, 비만증 및 골다공증의 치료 및 동종 이식 (allograft transplantation)의 지원에 사용될 수 있다.
본 발명에 따르는 약제학적 조성물에 적합한 희석제로는 셀룰로오스 분말, 2염기성 인산칼슘 무수물, 2염기성 인산칼슘 2수화물, 에리트리톨, 저치환된 하이드록시프로필 셀룰로오스, 만니톨, 프리젤라틴화 (pregelatinized) 전분 또는 자일리톨이 있다. 이들 희석제들 중에서, 만니톨 및 프리젤라틴화 전분이 바람직하다.
제2 희석제로서 바람직한 희석제로는, 추가의 결합제 특징을 갖는 위에서 언급된 희석제 프리젤라틴화 전분 및 저치환된 하이드록시프로필셀룰로오스 (L-HPC)가 있다.
본 발명에 따르는 약제학적 조성물에 적합한 윤활제로는 활석, 폴리에틸렌글리콜, 베헨산칼슘, 스테아르산칼슘, 수소화 피마자유 또는 스테아르산마그네슘이 있다. 바람직한 윤활제는 스테아르산마그네슘이다.
본 발명에 따르는 약제학적 조성물에 적합한 결합제로는 코포비돈 (비닐피롤리돈의 다른 비닐유도체와의 공중합물), 하이드록시프로필 메틸셀룰로오스 (HPMC), 하이드록시프로필셀룰로오스 (HPC), 폴리비닐피롤리돈 (포비돈), 프리젤라틴화 전분, 저치환된 하이드록시프로필셀룰로오스 (L-HPC)이 있으며, 코포비돈 및 프리젤라틴화 전분이 바람직하다.
위에서 언급된 결합제 프리젤라틴화 전분 및 L-HPC는 추가의 희석제 및 붕해제 특징을 나타내며, 제2 희석제 또는 붕해제로서 사용될 수도 있다.
본 발명에 따르는 약제학적 조성물에 적합한 붕해제로는 옥수수 전분, 크로스포비돈, 저치환된 하이드록시프로필셀룰로오스 (L-HPC) 또는 프리젤라틴화 전분이 있으며, 옥수수 전분이 바람직하다.
임의의 활제로서 콜로이드성 이산화규소가 사용될 수 있다.
본 발명에 따라는 예시적인 조성물은 희석제 만니톨, 추가의 결합제 특징을 갖는 희석제로서의 프리젤라틴화 전분, 결합제 코포비돈, 붕해제 옥수수 전분, 및 윤활제로서의 스테아르산마그네슘을 포함한다.
본 발명에 따르는 약제학적 조성물로 제조된 투여 제형은 활성 성분을 0.1 내지 100mg의 투여 범위로 함유한다. 바람직한 투여량은 0.5mg, 1mg, 2.5mg, 5mg 및 10mg이다.
통상의 약제학적 조성물은
활성 성분 0.5 내지 20중량%,
제1 희석제 40 내지 88중량%,
제2 희석제 3 내지 40중량%,
결합제 1 내지 5중량%,
붕해제 5 내지 15중량% 및
윤활제 0.1 내지 4중량%를 포함한다.
바람직한 약제학적 조성물은
활성 성분 0.5 내지 7중량%,
제1 희석제 50 내지 75중량%,
제2 희석제 5 내지 15중량%,
결합제 2 내지 4중량%,
붕해제 8 내지 12중량% 및
윤활제 0.5 내지 2중량%를 포함한다.
본 발명에 따르는 약제학적 조성물은 경구 사용을 위한 것이며, 캡슐제, 정제 또는 필름-피복 정제의 투여 제형으로 사용될 수 있다. 통상적으로, 필름 피복물은 당해 조성물 2 내지 4%, 바람직하게는 3%로 이루어지며, 필름-형성제, 가소제, 활제 및 임의로 하나 이상의 안료를 포함한다. 예시적인 피복 조성물은 하이드록시프로필메틸-셀룰로오스 (HPMC), 폴리에틸렌 글리콜 (PEG), 활석, 이산화티탄 및 임의로 산화철을 포함할 수 있다.
본 발명의 맥락에서 바람직한 활성 성분은 1급 아미노 그룹을 갖는 DPP-IV 억제제 및 이의 염, 예를 들면, 화학식 I 또는 화학식 II로 정의되는 임의의 DPP-IV 억제제 및 이의 염이다.
[화학식 I]
Figure 112016104036218-pat00001
[화학식 II]
Figure 112016104036218-pat00002
위의 화학식 I 및 화학식 II에서,
R1은 ([1,5]나프티리딘-2-일)메틸, (퀴나졸린-2-일)메틸], (퀴녹살린-6-일)메틸, (4-메틸-퀴나졸린-2-일)메틸, 2-시아노-벤질, (3-시아노-퀴놀린-2-일)메틸, (3-시아노-피리딘-2-일)메틸, (4-메틸-피리미딘-2-일)메틸 또는 (4,6-디메틸-피리미딘-2-일)메틸이고,
R2는 3-(R)-아미노-피페리딘-1-일, (2-아미노-2-메틸-프로필)-메틸아미노 또는 (2-(S)-아미노-프로필)-메틸아미노이다.
바람직한 DPP　IV 억제제 화합물은 다음의 화합물 및 이의 염이다.
ㆍ 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴(국제 공개공보 제WO 2004/018468호, 실시예 2(142)와 비교):
Figure 112016104036218-pat00003
ㆍ 1-[([1,5]나프티리딘-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-((R)-3-아미노-피페리딘-1-일)-크산틴(국제 공개공보 제WO 2004/018468호, 실시예 2(252)와 비교):
Figure 112016104036218-pat00004
ㆍ 1-[(퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-((R)-3-아미노-피페리딘-1-일)-크산틴(국제 공개공보 제WO 2004/018468호, 실시예 2(80)와 비교):
Figure 112016104036218-pat00005
ㆍ 2-((R)-3-아미노-피페리딘-1-일)-3-(부트-2-이닐)-5-(4-메틸-퀴나졸린-2-일메틸)-3,5-디하이드로-이미다조[4,5-d]피리다진-4-온(국제 공개공보 제WO 2004/050658호, 실시예 136와 비교):
Figure 112016104036218-pat00006
ㆍ 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부티인-1-일)-8-[(2-아미노-2-메틸-프로필)-메틸아미노]-크산틴(국제 공개공보 제WO 2006/029769호, 실시예 2(1)와 비교):
Figure 112016104036218-pat00007
ㆍ 1-[(3-시아노-퀴놀린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-((R)-3-아미노-피페리딘-1-일)-크산틴(국제 공개공보 제WO 2005/085246호, 실시예 1(30)와 비교):
Figure 112016104036218-pat00008
ㆍ 1-(2-시아노-벤질)-3-메틸-7-(2-부틴-1-일)-8-((R)-3-아미노-피페리딘-1-일)-크산틴(국제 공개공보 제WO 2005/085246호, 실시예 1(39)와 비교):
Figure 112016104036218-pat00009
ㆍ 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-[(S)-(2-아미노-프로필)-메틸아미노]-크산틴(국제 공개공보 제WO 2006/029769호, 실시예 2(4)와 비교):
Figure 112016104036218-pat00010
ㆍ 1-[(3-시아노-피리딘-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-((R)-3-아미노-피페리딘-1-일)-크산틴(국제 공개공보 제WO 2005/085246호, 실시예 1(52)와 비교):
Figure 112016104036218-pat00011
ㆍ 1-[(4-메틸-피리미딘-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-((R)-3-아미노-피페리딘-1-일)-크산틴(국제 공개공보 제WO 2005/085246호, 실시예 1(81)와 비교):
Figure 112016104036218-pat00012
ㆍ 1-[(4,6-디메틸-피리미딘-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-((R)-3-아미노-피페리딘-1-일)-크산틴(국제 공개공보 제WO 2005/085246호, 실시예 1(82)와 비교):
Figure 112016104036218-pat00013
ㆍ 1-[(퀴녹살린-6-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-((R)-3-아미노-피페리딘-1-일)-크산틴(국제 공개공보 제WO 2005/085246호, 실시예 1(83)와 비교):
Figure 112016104036218-pat00014
본 발명에 따르는 조성물을 제조하기 위해, 과립제를 습식 과립화 공정에 의해 제조할 수 있다. 액체 과립화는 동반한, 활성 성분 및 부형제의 또 다른 과립화 방법으로는, 유동층 과립화 또는 단일용기 (one-pot) 과립화가 있다.
습식 과립화 공정에서, 과립화 액체는 물, 에탄올, 메탄올, 이소프로판올, 아세톤, 바람직하게는 정제수와 같은 용매이며, 코포비돈과 같은 결합제를 함유한다. 당해 용매는, 최종 생성물에 남아있지 않는 휘발성 성분이다. 윤활제를 제외한 기타 부형제 및 활성 성분은 예비혼합되고, 고전단 과립화기를 사용하여 수성 과립화 액체와 함께 과립화된다. 습식 과립화 단계에 이어서, 임의의 습식 체질 (sieving) 단계, 건조 단계, 및 과립의 체질 단계가 수행된다. 예를 들면, 건조를 목적으로 유동층 건조기가 사용될 수 있다.
건조된 과립은 적절한 체 (sieve)를 통해 체질된다. 윤활제를 제외한 기타 부형제를 첨가한 후에, 당해 혼합물을 자유 낙하 블렌더 (free fall blender)와 같은 적합한 통상의 블렌더로 블렌딩하고, 이어서 스테아르산마그네슘과 같은 윤활제를 첨가하고, 블렌더로 최종 블렌딩한다.
따라서, 본 발명에 따르는 약제학적 조성물의 제조를 위한 예시적인 습식 과립화 공정은
a. 상온에서 코포비돈과 같은 결합제를 정제수와 같은 용매에 용해시켜, 과립화 액체를 제조하는 단계;
b. DPP-IV 억제제, 희석제 및 붕해제를 적합한 혼합기에서 블렌딩하여, 프리믹스 (premix)를 제조하는 단계;
c. 당해 프리믹스를 과립화 액체로 습윤시키고, 후속적으로 당해 습윤된 프리믹스를, 예를 들면, 고전단 믹서에서 과립화시키는 단계;
d. 당해 과립화된 프리믹스를 적어도 1.0mm, 바람직하게는 3mm의 메쉬 크기를 갖는 체를 통해 임의로 체질하는 단계;
e. 당해 과립제를, 약 40 내지 75℃, 바람직하게는 55 내지 65℃의 불활성 공기 온도에서, 예를 들면, 유동층 건조기에서, 1 내지 5% 범위의 목적하는 건조 감량이 수득될 때까지 건조시키는 단계;
f. 당해 건조된 과립제를, 예를 들면, 0.6 내지 1.6mm, 바람직하게는 1.0mm의 메쉬 크기를 갖는 체를 통해 체질함으로써 덩어리를 잘게 부수는 단계; 및
g. 바람직하게 체질된 윤활제를 당해 과립제에 첨가하여, 예를 들면, 큐브 믹서에서 최종 블렌딩하는 단계를 포함한다.
또 다른 공정에서, 단계 (g)에서 최종 블렌딩하기 전에, 붕해제 (예를 들면, 옥수수 전분) 또는 희석제 (예를 들면, 프리젤라틴화 전분) 또는 추가의 붕해제 (크로스포비돈)의 일부와 같은 부형제의 일부를 과립외 (extragranular)에 첨가할 수 있다.
또 다른 버전의 공정에서, 단계 (a) 내지 단계 (e)에서 제조된 과립제를 단일용기 고전단 과립화 공정에서 제조하고 후속적으로 단일용기 과립화기에서 건조시킬 수 있다.
캡슐제의 제조를 위해, 당해 최종 블렌드를 캡슐제 속에 추가로 충전시킨다.
정제 또는 정제 코어를 제조하기 위해, 당해 최종 블렌드를, 적절한 정제 프레스를 사용하여, 적절한 크기 및 파쇄 강도 (crushing strength)를 갖는 목적하는 정제 코어 중량의 정제로 추가로 압착시킨다.
필름-피복 정제를 제조하기 위해, 피복 현탁액을 제조하고, 압착된 정제 코어를, 중량이 약 2 내지 4%, 바람직하게는 약 3% 증가하도록, 표준 필름 피복기를 사용하여 피복 현탁액으로 피복한다. 필름 피복 용매는 휘발성 성분이며, 이는 최종 생성물 중에 잔류하지 않는다. 정제 중의 윤활제의 필요량을 감소시키기 위해, 임의로 외부 윤활 시스템을 사용한다.
실시예 1 - 직접 압착용 제형
스테아르산마그네슘을 제외한 모든 기타 부형제 및 1급 아미노 그룹을 갖는 활성 DPP IV 억제제 성분을 고전단 블렌더에서 블렌딩한다. 당해 프리믹스를 1mm 체를 통해 체질한다. 스테아르산마그네슘을 첨가한 후에, 당해 프리믹스를 자유 낙하 블렌더로 블렌딩하여 최종 블렌드를 수득한다. 당해 최종 블렌드를 적합한 정제 프레스를 사용하여 정제로 압착한다. 다음의 조성물을 수득할 수 있다.
Figure 112016104036218-pat00015
Figure 112016104036218-pat00016
실시예 2 - 또 다른 직접 압착용 제형
스테아르산마그네슘을 제외한 모든 기타 부형제 및 1급 아미노 그룹을 갖는 활성 DPP IV 억제제 성분을 고전단 블렌더에서 블렌딩한다. 당해 프리믹스를 1mm 체를 통해 체질한다. 스테아르산마그네슘을 첨가한 후에, 당해 프리믹스를 자유 낙하 블렌더로 블렌딩하여 최종 블렌드를 수득한다. 당해 최종 블렌드를 적합한 정제 프레스를 사용하여 정제로 압착한다. 다음의 조성물을 수득할 수 있다.
Figure 112016104036218-pat00017
Figure 112016104036218-pat00018
실시예 3 - 정제 제형
코포비돈을 상온에서 정제수에 용해시켜, 과립화 액체를 제조한다. 1급 아미노 그룹을 갖는 활성 DPP IV 억제제 성분, 만니톨 및 일부의 프리젤라틴화 전분을 적합한 믹서에서 블렌딩하여, 프리믹스를 제조한다. 당해 프리믹스를 과립화 액체로 습윤시키고 후속적으로 과립화시킨다. 당해 습윤 과립제를 1.6 내지 3.0mm의 메쉬 크기를 갖는 체를 통해 임의로 체질한다. 당해 과립제를, 적합한 건조기에서 약 55℃에서, 건조시 잔류 수분 함량이 2 내지 5% 줄어들 정도로 건조시킨다. 당해 건조된 과립제를 1.0mm의 메쉬 크기를 갖는 체를 통해 임의로 체질한다. 당해 과립제를 적합한 믹서에서 일부의 프리젤라틴화 전분과 블렌딩한다. 디럼핑을 위해 1.0mm 체를 통과시킨 후, 당해 블렌드에 스테아르산마그네슘을 첨가한다. 후속적으로 당해 최종 블렌드를 적합한 믹서에서 최종 블렌딩하여 제조하고, 정제로 압착한다. 다음의 정제 조성물을 수득할 수 있다.
Figure 112016104036218-pat00019
실시예 4 - 피복된 정제 제형
코포비돈을 상온에서 정제수에 용해시켜, 과립화 액체를 제조한다. 1급 아미노 그룹을 갖는 활성 DPP IV 억제제 성분, 만니톨, 프리젤라틴화 전분 및 옥수수 전분을 적합한 믹서에서 블렌딩하여, 프리믹스를 제조한다. 당해 프리믹스를 과립화 액체로 습윤시키고 후속적으로 과립화시킨다 고전단 믹서를 사용하여. 당해 습윤 과립제를 1.6 내지 3.0mm의 메쉬 크기를 갖는 체를 통해 임의로 체질한다. 당해 과립제를 유동층 건조기에서 약 60℃에서, 2 내지 4%의 목적하는 건조 감량이 수득될 때까지 건조시킨다. 당해 최종 블렌드를 정제 코어로 압착한다.
하이드록시프로필 메틸셀룰로오스, 폴리에틸렌 글리콜, 활석, 이산화티탄 및산화철을 적합한 믹서에서 상온에서 정제수에 현탁시켜, 피복 현탁액을 제조한다. 당해 정제 코어를 중량이 약 3% 증가하도록 피복 현탁액으로 피복하여, 필름-피복 정제를 제조한다. 다음의 정제 조성물을 수득할 수 있다.
Figure 112016104036218-pat00020
실시예 5 - 정제 제형
코포비돈을 상온에서 정제수에 용해시켜, 과립화 액체를 제조한다. 1급 아미노 그룹을 갖는 활성 DPP IV 억제제 성분, 만니톨 및 프리젤라틴화 전분을 적합한 믹서에서 블렌딩하여, 프리믹스를 제조한다. 당해 프리믹스를 과립화 액체로 습윤시키고 후속적으로 과립화시킨다. 당해 습윤 과립제를 적합한 체를 통해 임의로 체질한다. 당해 과립제를 적합한 건조기에서 약 50℃에서, 3 내지 5%의 목적하는 건조 감량이 수득될 때까지 건조시킨다. 당해 건조된 과립제를 1.0mm의 메쉬 크기를 갖는 체를 통해 임의로 체질한다.
스테아르산마그네슘을 1.0mm 체를 통과시키고, 과립제를 첨가한다. 후속적으로, 적합한 블렌더에서 최종적으로 블렌딩하여 최종 블렌드를 수득하고, 당해 최종 블렌드를 정제로 압착한다. 다음의 정제 조성물을 수득할 수 있다.
Figure 112016104036218-pat00021
실시예 6 - 정제 제형 변형체
코포비돈을 상온에서 정제수에 용해시켜, 과립화 액체를 제조한다. 1급 아미노 그룹을 갖는 활성 DPP IV 억제제 성분 및 일부의 만니톨, 프리젤라틴화 전분 및 옥수수 전분을 적합한 믹서에서 블렌딩하여, 프리믹스를 제조한다. 당해 프리믹스를 과립화 액체로 습윤시키고 후속적으로 과립화시킨다. 당해 습윤 과립제를 적합한 체를 통해 임의로 체질한다. 당해 과립제를 유동층 건조기에서 약 60℃ 불활성 공기 온도에서, 1 내지 4%의 목적하는 건조 감량이 수득될 때까지 건조시킨다. 당해 건조된 과립제를 1.0mm의 메쉬 크기를 갖는 체를 통해 임의로 체질한다.
스테아르산마그네슘 덩어리를 잘게 부수기 위해 체를 통과시킨 후, 당해 과립제에 첨가한다. 추가로, 당해 공정 단계에서 잔류하는 일부의 부형제를 과립 상태 이후에 첨가한다. 후속적으로, 적합한 블렌더에서 최종 블렌딩하에 최종 블렌드를 제조하고, 정제 코어로 압착한다.
하이드록시프로필 메틸셀룰로오스, 폴리에틸렌 글리콜, 활석, 이산화티탄 및산화철을 적합한 믹서에서 상온에서 정제수에 현탁시켜, 피복 현탁액을 제조한다. 중량이 약 3% 증가하도록 당해 정제 코어를 피복 현탁액으로 피복하여, 필름-피복 정제를 제조한다. 다음의 제형 변형체를 수득할 수 있다.
실시예 6.1 - 과립 상태 이후에 부형제를 갖는 제형 변형체
Figure 112016104036218-pat00022
실시예 6.2 - 추가의 과립 상태 이후에 붕해제를 갖는 제형 변형체
Figure 112016104036218-pat00023
실시예 6.3 - 고용량 제형 D
Figure 112016104036218-pat00024

Claims (24)

  1. 활성 성분으로서 유리 또는 1급 아미노 그룹을 갖는 DPP IV (dipeptidyl peptidase IV) 억제제 화합물 또는 이의 염, 제1 희석제, 제2 희석제, 결합제, 붕해제 및 윤활제를 포함하는 약제학적 조성물로서,
    상기 DPP IV 억제제가 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴이고,
    상기 약제학적 조성물이 0.5 내지 20 중량%의 활성 성분, 40 내지 88 중량%의 제1 희석제, 3 내지 40 중량%의 제2 희석제, 1 내지 5 중량%의 결합제, 5 내지 15 중량%의 붕해제 및 0.1 내지 4 중량%의 윤활제를 포함하고,
    상기 약제학적 조성물이 정제 또는 필름-피복 정제의 투여 제형이고,
    상기 DPP IV 억제제가 0.5mg 내지 10mg의 투여량으로 존재하고,
    상기 제1 및 제2 희석제가 셀룰로오스 분말, 2염기성 인산칼슘 무수물, 2염기성 인산칼슘 2수화물, 에리트리톨, 저치환된 하이드록시프로필 셀룰로오스, 만니톨, 프리젤라틴화 전분 및 자일리톨 중에서 선택되고,
    상기 결합제가 코포비돈 (비닐피롤리돈의 다른 비닐유도체와의 공중합물), 하이드록시프로필 메틸셀룰로오스 (HPMC), 하이드록시프로필셀룰로오스 (HPC), 폴리비닐피롤리돈 (포비돈), 프리젤라틴화 전분 및 저치환된 하이드록시프로필 셀룰로오스 (L-HPC) 중에서 선택되고,
    상기 붕해제가 옥수수 전분, 크로스포비돈, 저치환된 하이드록시프로필 셀룰로오스 (L-HPC) 및 프리젤라틴화 전분 중에서 선택되고,
    상기 윤활제가 활석, 폴리에틸렌글리콜, 베헨산칼슘, 스테아르산칼슘, 수소화 피마자유 및 스테아르산마그네슘 중에서 선택되고,
    상기 DPP IV 억제제가, 제1 희석제, 제2 희석제, 결합제, 붕해제 및 윤활제와 밀착 접촉되어 있는, 약제학적 조성물.
  2. 제1항에 있어서, 추가의 붕해제를 포함하는, 약제학적 조성물.
  3. 제1항에 있어서, 추가의 활제를 포함하는, 약제학적 조성물.
  4. 제1항에 있어서, 제1 및 제2 희석제가 셀룰로오스 분말, 2염기성 인산칼슘 무수물, 이염기성 인산칼슘 2수화물, 저치환된 하이드록시프로필 셀룰로오스, 만니톨 및 프리젤라틴화 전분 중에서 선택되는, 약제학적 조성물.
  5. 제1항에 있어서, 윤활제가 활석, 폴리에틸렌글리콜, 베헨산칼슘, 스테아르산칼슘, 수소화 피마자유 또는 스테아르산마그네슘인, 약제학적 조성물.
  6. 제1항에 있어서, 결합제가 코포비돈 (비닐피롤리돈의 다른 비닐유도체와의 공중합물), 하이드록시프로필 메틸셀룰로오스 (HPMC), 하이드록시프로필셀룰로오스 (HPC) 또는 폴리비닐피롤리돈 (포비돈)인, 약제학적 조성물.
  7. 제1항에 있어서, 붕해제가 옥수수 전분인, 약제학적 조성물.
  8. 제2항에 있어서, 추가의 붕해제가 크로스포비돈인, 약제학적 조성물.
  9. 제3항에 있어서, 추가의 활제가 콜로이드성 이산화규소인, 약제학적 조성물.
  10. 제1항에 있어서, 제1 희석제가 만니톨이고, 제2 희석제가 프리젤라틴화 전분이고, 결합제가 코포비돈이고, 붕해제가 옥수수 전분이고, 윤활제가 스테아르산마그네슘인, 약제학적 조성물.
  11. 제1항에 있어서, DPP IV 억제제 화합물, 제1 희석제, 제2 희석제, 결합제, 붕해제 및 윤활제의 총 중량을 기준으로 하여, 0.5 내지 7 중량%의 활성 성분, 50 내지 75 중량%의 제1 희석제, 5 내지 15 중량%의 제2 희석제, 2 내지 4 중량%의 결합제, 8 내지 12 중량%의 붕해제 및 0.5 내지 2 중량%의 윤활제를 포함하는, 약제학적 조성물.
  12. 제1항에 있어서, 필름-피복 정제의 투여 제형인, 약제학적 조성물.
  13. 제12항에 있어서, 2 내지 4 중량%의 필름 피복물을 포함하는, 약제학적 조성물.
  14. 제13항에 있어서, 필름 피복물이 필름-형성제, 가소제, 활제 및 임의로 하나 이상의 안료를 포함하는, 약제학적 조성물.
  15. 제14항에 있어서, 필름 피복물이 하이드록시프로필메틸셀룰로오스 (HPMC), 폴리에틸렌 글리콜 (PEG), 활석, 이산화티탄 및 산화철을 포함하는, 약제학적 조성물.
  16. 제1항 내지 제15항 중의 어느 한 항에 있어서, 필름-피복 정제의 투여 제형이고, 여기서 DPP IV 억제제 화합물, 희석제, 붕해제 및 윤활제가 정제 코어에 존재하는, 약제학적 조성물.
  17. a. 결합제를 용매에 용해시켜, 과립화 액체를 제조하는 단계;
    b. DPP IV 억제제, 희석제 및 붕해제를 블렌딩하여, 프리믹스(pre-mix)를 제조하는 단계;
    c. 상기 프리믹스를 과립화 액체로 습윤시키고, 후속적으로 상기 습윤된 프리믹스를 과립화시는 단계;
    d. 상기 과립화된 프리믹스를 1.0mm 이상의 메쉬 크기를 갖는 체(sieve)를 통해 임의로 체질하는 단계;
    e. 상기 과립제를 40 내지 75℃에서, 1 내지 5% 범위의 목적하는 건조 감량이 수득될 때까지 건조시키는 단계;
    f. 상기 건조된 과립제를 0.6mm 이상의 메쉬 크기를 갖는 체를 통해 체질하는 단계; 및
    g. 윤활제를 상기 과립제에 첨가하여 최종 블렌딩하는 단계
    를 포함하는, 제1항에 따르는 약제학적 조성물의 제조방법.
  18. 제17항에 있어서,
    h. 상기 최종 블렌드를 정제 코어로 압착하는 단계;
    i. 피복 현탁액을 제조하는 단계; 및
    j. 중량이 2 내지 4% 증가하도록 상기 정제 코어를 피복 현탁액으로 피복하여 필름-피복 정제를 제조하는 단계
    를 추가로 포함하는, 제조방법.
  19. 제17항에 있어서, 단계 g의 최종 블렌딩 이전에, 일부의 부형제가 과립외(extragranular)에 첨가되는, 제조방법.
  20. 제17항에 있어서, 단계 a 내지 단계 e에서 제조된 과립제가 단일용기 고전단 과립화 공정(one pot high shear granulation process)에서 제조되고, 후속적으로 단일용기 과립화기(one pot granulator)에서 건조되는, 제조방법.
  21. 필름-피복 정제의 투여 제형인 약제학적 조성물로서, 상기 필름-피복 정제가 정제 코어를 포함하고, 상기 정제 코어는 0.5 내지 7 중량%의 유리 또는 1급 아미노 그룹을 갖는 DPP IV 억제제 화합물, 50 내지 75 중량%의 제1 희석제, 5 내지 15 중량%의 제2 희석제, 2 내지 4 중량%의 결합제, 8 내지 12 중량%의 붕해제 및 0.5 내지 2 중량%의 윤활제를 포함하고,
    여기서 상기 DPP IV 억제제가 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴이고,
    상기 제1 및 제2 희석제가 셀룰로오스 분말, 2염기성 인산칼슘 무수물, 2염기성 인산칼슘 2수화물, 에리트리톨, 저치환된 하이드록시프로필 셀룰로오스, 만니톨, 프리젤라틴화 전분 및 자일리톨 중에서 선택되고,
    상기 결합제가 코포비돈 (비닐피롤리돈의 다른 비닐유도체와의 공중합물), 하이드록시프로필 메틸셀룰로오스 (HPMC), 하이드록시프로필셀룰로오스 (HPC), 폴리비닐피롤리돈 (포비돈), 프리젤라틴화 전분 및 저치환된 하이드록시프로필 셀룰로오스 (L-HPC) 중에서 선택되고,
    상기 붕해제가 옥수수 전분, 크로스포비돈, 저치환된 하이드록시프로필 셀룰로오스 (L-HPC) 및 프리젤라틴화 전분 중에서 선택되고,
    상기 윤활제가 활석, 폴리에틸렌글리콜, 베헨산칼슘, 스테아르산칼슘, 수소화 피마자유 및 스테아르산마그네슘 중에서 선택되고,
    상기 DPP IV 억제제가 0.5mg 내지 10mg의 투여량으로 함유되는, 약제학적 조성물.
  22. 삭제
  23. 제1항 내지 제15항 및 제21항 중의 어느 한 항에 있어서, DPP IV 억제제가 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴이고 5mg의 투여량인, 약제학적 조성물.
  24. 유리 또는 1급 아미노 그룹을 갖는 DPP IV 억제제 화합물 또는 이의 염, 희석제, 결합제 및 붕해제를 포함하는 습식 과립화에 의해 제조된 과립제로서,
    상기 DPP IV 억제제가 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)-크산틴이고,
    상기 희석제는 셀룰로오스 분말, 2염기성 인산칼슘 무수물, 2염기성 인산칼슘 2수화물, 에리트리톨, 저치환된 하이드록시프로필 셀룰로오스, 만니톨, 프리젤라틴화 전분 및 자일리톨 중에서 선택되고,
    상기 결합제가 코포비돈 (비닐피롤리돈의 다른 비닐유도체와의 공중합물), 하이드록시프로필 메틸셀룰로오스 (HPMC), 하이드록시프로필셀룰로오스 (HPC), 폴리비닐피롤리돈 (포비돈), 프리젤라틴화 전분 및 저치환된 하이드록시프로필 셀룰로오스 (L-HPC) 중에서 선택되고,
    상기 붕해제가 옥수수 전분, 크로스포비돈, 저치환된 하이드록시프로필 셀룰로오스 (L-HPC) 및 프리젤라틴화 전분 중에서 선택되고,
    상기 DPP IV 억제제가 0.5mg 내지 10mg의 투여량으로 존재하고,
    상기 DPP IV 억제제가, 희석제, 결합제 및 붕해제와 밀착 접촉되어 있는, 과립제.
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