KR101200147B1 - Composition of extended release tablet containing tacrolimus - Google Patents
Composition of extended release tablet containing tacrolimus Download PDFInfo
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Abstract
본 발명은, 약효성분이 지속적으로 방출되어 1일1회 투여가 가능한 타크로리무스 함유 서방성 경구투여용 조성물에 관한 것이다. 구체적으로, 약효성분으로서 타크로리무스; 고체분산체 형성용 부형제로서 히드록시프로필베타사이클로덱스트린과 다이옥틸설포석시네이트와의 혼합물; 그리고 서방용 부형제로서 히드록시프로필메틸셀룰로스와 에틸셀룰로스와의 혼합물을 포함하는 타크로리무스 함유 서방성 경구투여용 조성물에 관한 것이다.The present invention relates to a tacrolimus-containing sustained release oral composition which can be administered once a day by continuously releasing the active ingredient. Specifically, tacrolimus as an active ingredient; Mixtures of hydroxypropylbetacyclodextrin and dioctylsulfosuccinate as excipients for forming solid dispersions; And it relates to a tacrolimus-containing sustained release oral composition comprising a mixture of hydroxypropyl methyl cellulose and ethyl cellulose as a sustained release excipient.
Description
본 발명은, 약효성분이 지속적으로 방출되어 1일1회 투여가 가능한 타크로리무스 함유 서방성 경구투여용 조성물에 관한 것이다.The present invention relates to a tacrolimus-containing sustained release oral composition which can be administered once a day by continuously releasing the active ingredient.
타크로리무스는 면역 억제 효과를 가지고 있는 마크롤라이드계 항생물질이다. 현재 널리 사용되는 면역억제제인 사이크로스포린 에이(Cyclosporin A)와 구조적으로는 다르지만, 그 작용 기전은 유사한 것으로 알려져 있다. 타크로리무스는 신장이나 간이식 수술시 나타나는 조직거부 반응에 대한 일차요법 또는 완화요법에 사용하고 있으며, 급성 조직거부 반응을 예방하거나 코르티코스테로이드(Corticosteroid)의 사용량을 줄이기 위한 일차적인 요법에 사용하는 경우 사이크로스포린 에이에 비해 효능이 높은 것으로 평가받고 있다. Tacrolimus is a macrolide antibiotic with immunosuppressive effects. Although structurally different from Cyclosporin A, an immunosuppressive agent currently widely used, its mechanism of action is known to be similar. Tacrolimus is used as a first-line or palliative therapy for tissue rejection reactions during kidney or liver transplantation, and when used as a primary therapy to prevent acute tissue rejection or to reduce the use of corticosteroids. It is evaluated to have higher efficacy than Porin A.
활성 화합물이 제어 방출되는 제제를 제조하기 위하여 대체로 다양한 기술이 공지되어 있다. 특히 위에서의 체류 시간을 연장시키기 위한 제제의 밀도증가(EP-A 265 061)이나 크게 공간 팽창되는 제제의 사용(EP-A 235 718)등이 그 예이다. 그러나 이러한 기술들은 단점을 갖고 있는데, 구체적으로는 비싸고 복잡한 제조 방법이거나, 개인간 및 개인내 차이가 있다는 것이다. Generally a variety of techniques are known for preparing formulations in which the active compound is controlled release. For example, an increase in the density of the preparation (EP-A 265 061) or the use of a highly spaced preparation (EP-A 235 718) to extend the residence time in the stomach. However, these techniques have disadvantages, specifically, expensive and complex manufacturing methods, or there are differences between individuals and within individuals.
이에, 본 발명의 목적은 저렴하고 용이한 제조방법으로 1일1회 투여를 가능케 하는 타크로리무스의 서방형 제제를 제공하는 것이다. Accordingly, it is an object of the present invention to provide a sustained release formulation of tacrolimus that enables administration once a day in an inexpensive and easy manufacturing method.
하기와 같은 본 발명의 구체적인 양태를 통하여 상기의 목적을 달성할 수 있었다:Through the following specific aspects of the present invention it was possible to achieve the above object:
(가) (1) 약효성분으로서 타크로리무스; (A) (1) tacrolimus as an active ingredient;
(2) 고체분산체 형성용 부형제로서 히드록시프로필베타사이클로덱스트린과 다이옥틸설포석시네이트와의 혼합물; 그리고 (2) a mixture of hydroxypropylbetacyclodextrin and dioctylsulfosuccinate as an excipient for solid dispersion formation; And
(3) 서방용 부형제로서 히드록시프로필메틸셀룰로스와 에틸셀룰로스와의 혼합물을 포함하는 타크로리무스 함유 서방성 경구투여용 조성물;
(3) Tacrolimus-containing sustained release oral composition comprising a mixture of hydroxypropylmethylcellulose and ethylcellulose as a sustained-release excipient;
(나) 상기 (가)에 있어서, 상기 히드록시프로필베타사이클로덱스트린은 타크로리무스 1 중량부에 대하여 1~10 중량부로 포함되며, 상기 다이옥틸설포석시네이트은 타크로리무스 1 중량부에 대하여 0.5~1.0 중량부로 포함되는 것인 조성물; 또는
(B) In the above (a), the hydroxypropyl beta cyclodextrin is included in 1 to 10 parts by weight based on 1 part by weight of tacrolimus, the dioctylsulfosuccinate is contained in 0.5 to 1.0 parts by weight based on 1 part by weight of tacrolimus. Composition to be; or
(다) 상기 (가)에 있어서, 상기 히드록시프로필메틸셀룰로스와 에틸셀룰로스와의 혼합물이, 타크로리무스 및 고체 분산체 형성용 부형제 총중량으로 1 중량부에 대하여 5~10 중량부로 함유되며, 여기에서 히드록시프로필메틸셀룰로스와 에틸셀룰로스의 중량비는 1: 1.6~2 인 것인 조성물.(C) In the above (a), the mixture of hydroxypropylmethylcellulose and ethyl cellulose is contained in an amount of 5 to 10 parts by weight based on 1 part by weight of the total weight of the excipient for forming tacrolimus and a solid dispersion, wherein The weight ratio of oxypropylmethyl cellulose and ethyl cellulose is 1: 1.6 to 2.
본 발명은, 약효성분이 최소 14시간 이상 동안 지속적으로 방출되어 1일1회 투여를 가능케 하는 타크로리무스 함유 서방성 경구투여용 조성물을 제공하며, 그의 제조방법이 용이하며 비용면에서도 저렴하여 그의 유용성이 크게 기대된다.The present invention provides a tacrolimus-containing sustained-release orally administered composition in which the active ingredient is continuously released for at least 14 hours or more, so that once-daily administration is possible. It is greatly expected.
도 1은 히드록시프로필메틸셀룰로스와 에틸셀룰로스의 비율에 따른 효과를 고찰한 것으로서 비교예 3 (●), 비교예 4 (○), 실시예 1 (▼), 실시예 2 (△) 및 비교예 5 (■)의 조성물로부터의 타크로리무스 용출곡선을 나타낸 것이다.
도 2는 비교예 1 (●) 및 비교예 2 (○)의 조성물로부터의 타크로리무스 용출곡선을 나타낸 것이다.1 is a view of the effects of the ratio of hydroxypropylmethylcellulose and ethyl cellulose, Comparative Example 3 (●), Comparative Example 4 (○), Example 1 (▼), Example 2 (△) and Comparative Examples The tacrolimus elution curve from the composition of 5 (■) is shown.
Fig. 2 shows tacrolimus elution curves from the compositions of Comparative Example 1 (●) and Comparative Example 2 (○).
상기 목적에 따라, 본 발명에서는 활성성분인 타크로리무스와, 고체 분산체를 만들기 위한 부형제인 히드록시프로필베타사이클로덱스트린 및 다이옥틸설포석시네이트 그리고 서방형 제제를 만들기 위한 부형제인 히드록시프로필메틸셀룰로스 및 에틸셀룰로스를 포함하는 타크로리무스 함유 경구용 서방형 제제 조성물을 제공한다.
In accordance with the above object, in the present invention, tacrolimus as an active ingredient, hydroxypropylbetacyclodextrin and dioctylsulfosuccinate as excipients for making solid dispersions, and hydroxypropylmethylcellulose and ethyl as excipients for making sustained-release preparations It provides a tacrolimus-containing oral sustained release formulation composition comprising cellulose.
이와 같은 본 발명을 더욱 상세히 설명하면 다음과 같다. Hereinafter, the present invention will be described in detail.
(ⅰ) 활성 성분(Iv) active ingredients
타크로리무스 (Tacrolimus)는 장기이식 시 사용하는 잘 알려진 면역억제제이다. 그러나 이 약물은 매우 지용성이기 때문에 물에 잘 녹지 않으며, 담즙의 존재에 따라 위장관 에서의 흡수가 결정된다. 경구 투여 시 사람에서의 생체이용률은 평균 29% 정도이며, 보통 0.5~67%의 범위를 보인다. 이 약물의 분포는 몸 전체를 걸쳐 이루어지며, 특히 간, 비장, 심장, 신장에서 높은 농도로 분포한다.
Tacrolimus is a well-known immunosuppressant for organ transplantation. However, because the drug is very fat-soluble, it is insoluble in water, and the presence of bile determines its absorption in the gastrointestinal tract. The average bioavailability in humans after oral administration is about 29%, usually in the range of 0.5-67%. The drug is distributed throughout the body, especially at high concentrations in the liver, spleen, heart and kidneys.
(ⅱ) 고체 분산체를 위한 부형제(Ii) excipients for solid dispersions
히드록시프로필베타사이클로덱스트린은 베타사이클로덱스트린의 일종으로 일반적인 β-cyclodextrin의 용도와 유사하게 사용된다. 하지만 신장독성이 적은 장점이 있어 경구나 비경구적인 제형을 만들 때 유용하게 사용되는 부형제이다. 히드록시프로필베타사이클로덱스트린은 본 발명의 타크로리무스 경구용 고형제제 조성물 중에서 타크로리무스 중량에 대하여 1~10 배를 첨가하는 것이 바람직하며 더욱 바람직하게는 7~9 배를 첨가하는 것이다. Hydroxypropylbetacyclodextrin is a kind of betacyclodextrin and is used similarly to the general β-cyclodextrin. However, it has the advantage of low nephrotoxicity, which makes it an useful excipient when preparing oral or parenteral formulations. The hydroxypropyl betacyclodextrin is preferably added 1 to 10 times by weight of tacrolimus in the tacrolimus oral solid preparation composition of the present invention, and more preferably 7 to 9 times.
다이옥틸설포석시네이트는 도큐세이트소듐이라고도 한다. 제형을 만드는 데 있어서 음이온 계면활성제로 작용하며, 주로 캡슐 제제와 다이렉트 컴프레션 정제(direct compression tablet)를 만들 때 습윤과 용출을 돕기 위해 사용된다. 또한 경구제제를 만들 때 사용되어 완하제의 역할을 하기도 한다. 다이옥틸설포석시네이트은 본 발명의 타크로리무스 경구용 고형제제 조성물 중에서 타크로리무스 중량에 대하여 0.5~1.0 배를 첨가하는 것이 바람직하며 더욱 바람직하게는 0.7~0.9 배를 첨가하는 것이다.
Dioctylsulfosuccinate is also called docuate sodium. It acts as an anionic surfactant in formulating formulations and is primarily used to aid wetting and dissolution when making capsule formulations and direct compression tablets. It is also used as a laxative to make oral preparations. The dioctylsulfosuccinate preferably adds 0.5 to 1.0 times the tacrolimus weight in the tacrolimus oral solid preparation composition of the present invention, and more preferably adds 0.7 to 0.9 times.
(ⅲ) 서방형 제제를 만들기 위한 부형제(Iii) excipients for making sustained release preparations;
히드록시프로필메틸셀룰로스는 가장 널리 사용되고 있는 셀룰로오스 계열의 고분자로 평균 분자량, 메틸기와 프로필기의 성분 비율에 의해 특성도 달라진다. 또한 이에 따라 각 제제에서 사용되는 용도도 달라지는데, 일반적으로 경구제제에서 정제나 과립의 제조 시 결합제나 필름형성제로 가장 많이 이용되고 있다. Hydroxypropylmethylcellulose is the most widely used cellulose-based polymer, and its properties vary depending on the average molecular weight, the proportion of methyl groups and propyl groups. In addition, according to the use of each formulation is also different, generally used in the preparation of tablets or granules in oral preparations are most commonly used as a binder or film forming agent.
에틸셀룰로스는 정제나 과립과 같은 경구용 제제의 소수성 코팅을 위해서 주로 사용된다. 이러한 코팅은 약물의 방출을 변형시키기 위한 용도이며 또한 맛을 좋게 하거나 제형의 안정성을 향상시키기 위한 것이기도 하다. 예를 들어 에틸셀룰로스로 코팅한 과립의 경우 공기 중에 산화되는 것을 방지할 수 있다. Ethylcellulose is mainly used for hydrophobic coating of oral preparations such as tablets and granules. Such coatings are intended to modify the release of the drug and also to improve taste or improve the stability of the formulation. For example, the granules coated with ethyl cellulose can be prevented from being oxidized in the air.
히드록시프로필메틸셀룰로스와 에틸셀룰로스는 그 혼합중량이, 타크로리무스 및 고체 분산체 형성용 부형제 총중량에 대하여 5~10배에 해당하도록 첨가하는 것이 바람직하며 더욱 바람직하게는 8~10 배를 첨가하는 것이다. 한편 히드록시프로필메틸셀룰로스와 에틸셀룰로스의 비율은 1: 1.6~2 가 바람직하다.
Hydroxypropylmethylcellulose and ethylcellulose are preferably added so that the mixed weight thereof is 5 to 10 times the total weight of the excipient for forming tacrolimus and solid dispersion, and more preferably 8 to 10 times. On the other hand, the ratio of hydroxypropylmethylcellulose and ethyl cellulose is preferably 1: 1.6 to 2.
본 발명의 조성물은 통상의 제제의 제조시 필요한 부형제 및 첨가제를 더 포함할 수 있다.
The compositions of the present invention may further comprise excipients and additives necessary for the preparation of conventional formulations.
비교예Comparative example 1~5 및 1 to 5 and 실시예Example 1 ~2 1 to 2
하기 표 1의 조성에 따라, 타크로리무스와 함께 히드록시프로필베타사이클로덱스트린 및 다이옥틸설포석시네이트를 에탄올과 메틸렌 클로라이드의 혼합용액에 녹인 후 분무건조 하여 얻은 분말에 히드록시프로필메틸셀룰로스와 에틸셀룰로스를 첨가하여 단말타정기를 이용하여 제제화 하였다.
According to the composition of Table 1 below, hydroxypropyl betacyclodextrin and dioctylsulfosuccinate together with tacrolimus were dissolved in a mixed solution of ethanol and methylene chloride, and then hydroxypropylmethylcellulose and ethylcellulose were added to the powder obtained by spray drying. It was formulated using a terminal tablet machine.
분무 건조 조건은 아래와 같다.Spray drying conditions are as follows.
- 분무건조기: BUCHI mini spray dryer B-191 Spray dryer: BUCHI mini spray dryer B-191
- 펌프속도: pump speed - 5ml/min Pump speed: pump speed-5ml / min
- 공기유속 (air flow rate): 600 NI/h Air flow rate: 600 NI / h
- 주입구 공기온도 (inlet air temperature) : 80℃ Inlet air temperature: 80 ℃
- 배출구 공기온도 (outlet air temperature): 55-60℃.Outlet air temperature: 55-60 ° C.
- 용매 --- 메틸렌클로라이드:에탄올= 1:2의 부피비율로 혼합한 것을 타크로리무스 0.25g 당 75ml 사용한다.
75 ml of 0.25 g of tacrolimus is used as a mixture in a volume ratio of solvent-methylene chloride: ethanol = 1: 2.
실험예Experimental Example 1 : 용출 시험 1: dissolution test
비교예 1~5 및 실시예 1~2에서 제조된 제제에 대하여 대한약전 일반시험법중 용출시험 제 2 법(패들법)에 따라 용출시험을 수행하고, 30분, 1시간, 2시간, 4시간, 6시간, 12시간 및 24시간 동안 용출된 타크로리무스의 양을 하기와 같은 분석법에 따라 측정하였다. 용출액은, 증류수에 히드록시프로필 셀룰로오스(HPC)를 0.005%가 되도록 녹이고 포스포릭에이시드(Phosphoric acid)로 pH가 4.5가 되도록 조절한 용액 500ml을 사용하였다. 용출액의 온도는 37±0.5℃로 하여 회전속도 100 rpm를 유지하였다. 결과는 도 1 및 2에 나타내었다.The dissolution test was performed on the formulations prepared in Comparative Examples 1 to 5 and Examples 1 to 2 according to the Dissolution Test No. 2 method (paddle method) of the Korean Pharmacopoeia General Test Method, and were used for 30 minutes, 1 hour, 2 hours, and 4 hours. The amount of tacrolimus eluted for hours, 6 hours, 12 hours and 24 hours was measured according to the following assay. As the eluate, 500 ml of a solution in which hydroxypropyl cellulose (HPC) was dissolved to 0.005% in distilled water and adjusted to pH 4.5 with phosphoic acid was used. The temperature of the eluate was 37 ± 0.5 ° C. and the rotation speed was maintained at 100 rpm. The results are shown in FIGS. 1 and 2.
분석법 : 액체 Method: liquid 크로마토그라피법Chromatography
칼럼 : ODS-2(5um, 4.6mm x 250mm) Column: ODS-2 (5um, 4.6mm x 250mm)
이동상 : H2O:AcCN=25:75Mobile phase: H 2 O: AcCN = 25: 75
유속 : 1.0 ml/min Flow rate: 1.0 ml / min
검출기 : L-2130, HITACHI Detector: L-2130, HITACHI
파장 : 210 nmWavelength: 210 nm
주입량 : 50μlInjection volume: 50μl
Claims (3)
(2) 고체분산체 형성용 부형제로서 히드록시프로필베타사이클로덱스트린과 다이옥틸설포석시네이트와의 혼합물; 그리고
(3) 서방용 부형제로서 히드록시프로필메틸셀룰로스와 에틸셀룰로스와의 혼합물을 포함하며,
상기 히드록시프로필베타사이클로덱스트린은 타크로리무스 1 중량부에 대하여 1~10 중량부로 포함되며, 상기 다이옥틸설포석시네이트은 타크로리무스 1 중량부에 대하여 0.5~1.0 중량부로 포함되며,
상기 히드록시프로필메틸셀룰로스와 에틸셀룰로스와의 혼합물이, 타크로리무스 및 고체 분산체 형성용 부형제 총중량으로 1 중량부에 대하여 5~10 중량부로 함유되며, 여기에서 히드록시프로필메틸셀룰로스와 에틸셀룰로스의 중량비는 1: 1.6~2 인 것인 타크로리무스 함유 서방성 경구투여용 조성물.
(1) tacrolimus as an active ingredient;
(2) a mixture of hydroxypropylbetacyclodextrin and dioctylsulfosuccinate as an excipient for solid dispersion formation; And
(3) a sustained release excipient comprising a mixture of hydroxypropylmethylcellulose and ethylcellulose,
The hydroxypropyl beta cyclodextrin is included in 1 to 10 parts by weight based on 1 part by weight of tacrolimus, the dioctylsulfosuccinate is included in 0.5 to 1.0 parts by weight based on 1 part by weight of tacrolimus,
The mixture of the hydroxypropyl methyl cellulose and ethyl cellulose is contained in 5 to 10 parts by weight with respect to 1 part by weight of the total weight of the excipient for forming tacrolimus and solid dispersion, wherein the weight ratio of hydroxypropyl methyl cellulose and ethyl cellulose 1: Tacrolimus-containing sustained release oral composition which is 1.6-2.
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