• Journal of Pharmaceutical Investigation
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• 제35권4호
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• pp.279-285
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• 2005

Ground CS-891 (N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5a-androst-1-ene-$17{\beta}$-carboxamide) of poorly water soluble drug was obtained using a Heiko Seisakusho model TI-100 vibration mill, and samples with different crystallinity were prepared at mixture ratios of 10:0, 7:3, 5:5, 3:7 and 0:10 (intact;ground CS-891). Physicochemical characterizations were obtained using qualitative and quantitative X-ray diffractometry, different scanning calorimetry (DSC), scanning electron microscopy (SEM), Quantasorb surface area analyzer, and controlled atmosphere microbalance. With increase of amorphous CS-891 in mixture ratios, the intensities of X-ray diffraction peaks of crystalline CS-891 were decreased, whereas surface area, water absorption, and exothermic peaks in DSC were increased. The apparent solubility of ground CS-891 was $4.4\;{\mu}g/ml$ and the solubility of intact CS-891 was $3.1\;{\mu}g/ml$ at $37{\pm}1^{\circ}C$. The apparent precipitation rates of CS-891 in a supersaturated solution during the solubility test were increased with an increase of amorphous CS-891, and a crystalline form of CS-891 transformed from amorphous CS-891 after the solubility test was found by X-ray diffraction analysis, DSC and SEM. The dissolution profiles of CS-891 with different crystallinity at $37{\pm}1^{\circ}C$ by the USP paddle method were investigated, and the apparent dissolution rate constant of ground CS-891 was about 5.9-fold higher than that of intact CS-891. A linear relationships between the crystallinity of CS-891 and the apparent dissolution rate constant (r>0.96) were obtained.

• 생명과학회지
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• 제31권5호
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• pp.502-510
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• 2021

자가 나노유화 약물전달시스템(SNEDDS)은 오일, 계면활성제, 공계면활성제의 균질한 혼합물로서 가벼운 교반에 의해도 에멀전 형성이 가능하고 분산 시 200 nm 이하 범위의 입자 크기를 갖는 나노 에멀전을 형성하는 약물 수송체를 말한다. SNEDDS는 난용성이며 생체이용률이 낮은 소수성약물의 흡수율을 높일 수 있는 뛰어난 가용화 방법으로 알려져 있다. 본 연구에서는 난용성인 티카그렐러에 대한 용해도가 높은 유상으로 MCT oil과, 계면활성제로 Tween 80, 공계면활성제로 Labrafil M1944CS를 사용하여 SNEDDS를 개발하고, 분무건조기술을 이용하여 다양한 다공성의 캐리어에 흡착시켜 고형의 SNEDDS를 제조하였다. 제조된 고형의 SNEDDS에 대하여 물리화학적 특성 및 분말특성을 평가한 후 용출시험을 진행하였다. 본 연구를 통해 얻어진 다공성의 캐리어에 흡착시켜 만들어진 다양한 고형 SNEDDS에서 티카그렐러의 결정형은 무정형으로 변환된 것을 확인할 수 있었다. 또한 제조된 고형의 SNEDDS 조성물들은 모두 원료에 비하여 우수한 용출양상을 나타내는 것을 확인할 수 있었다. 특히 이산화규소를 통해 얻어진 고형의 SNEDDS 조성물의 입자크기와 다분산지수가 제일 작았으며 흐름성과 압축성도 제일 우수하였다. 따라서 이산화규소를 통해 얻어진 고형의 SNEDDS 조성물은 난용성인 티카그렐러의 경구 고형제제화 연구에 적합한 약물 전달 시스템인 것을 확인할 수 있었다.

• Journal of Pharmaceutical Investigation
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• 제34권3호
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• pp.185-192
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• 2004

The objective of this study was to evaluate the effects of surfactant type and concentration upon dissolution rates of carbamazepine from an immediate-release tablet. The dissolution media used in this study were aqueous solutions containing 0.1-2% sodium lauryl sulfate, cetyltrimethylammonium bromide, or polysorbate 80. The solubility of carbamazepine in the dissolution media was determined at first. A dissolution study was then conducted by using the USP dissolution apparatus II (paddle method) with an agitation rate of 75 rpm. Aliquots of the dissolution media were taken at predetermined time intervals, and the amount of carbamazepine dissolved was measured spectrophotometrically at 285 nm. The dissolution data obtained were fitted into a biphasic exponential equation with four parameters. Excellent correlations were observed between the experimental data and the theoretical ones predicted by the equation. This equation permitted the calculation of $T_{50%}$ (the time required for dissolving 50% of carbamazepine) under various experimental conditions. Differentiation of the equation also led to the attainment of dissolution rates at dissolution time points. The addition of a surfactant to an aqueous solution led to increasing the solubility of carbamazepine by 3- to 12-folds, depending upon its type and concentration. This event also resulted in enhancing the magnitude of a sink condition during the dissolution study. As a result, the dissolution rate of carbamazepine was affected by the aqueous surfactant concentration in a proportional manner. Subsequently, $T_{50%}$ values declined rapidly, as the surfactant concentration increased. Such effects were observed in decreasing order of sodium lauryl sulfate, cetyltirmethylammonium bromide, and polysorbate 80. These results clearly demonstrated that it was possible to tailor a dissolution rate and $T_{50%}$ of carbamazepine by manipulating the type and concentration of a surfactant. Relevant information would be beneficial to setting up dissolution specifications for poorly water-soluble drug products.

• Journal of Pharmaceutical Investigation
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• 제41권3호
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• pp.125-142
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• 2011

Solid dispersion, defined as the dispersion of one or more active ingredient in a carrier or matrix at solid state, is an efficient strategy for improving dissolution of poorly water-soluble drugs for enhancement of their bioavailability. Compared to other conventional formulations such as tablets or capsules, solid dispersion which can be prepared by various methods has many advantages. However, despite numerous studies which have been carried out, limitations for commercializing these products remain to be solved. For example, during the manufacturing process or storage, amorphous form of solid dispersion can be converted into crystalline form. That is, the dissolution rate of solid dispersion would continuously decrease during storage, resulting in a product of no value. To resolve these problems, studies have been conducted on the effects of excipients. In fact, modification of the solid dispersions to overcome these disadvantages has progressed from the first generation to the recent third generation products. In this review, an overview on solid dispersions in general will be given with emphasis on the various manufacturing processes which include the use of polymers and on the stabilization strategies which include methods to prevent crystallization.

• KSBB Journal
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• 제24권6호
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• pp.533-540
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• 2009

본 연구에서는 난용성 약물인 5'-NIO의 가용화를 위해 초임계 유체 ASES 공정을 이용하여 PVP K-30과의 고체분산체를 제조하고 첨가제인 P188의 영향에 대해 고찰하였다. FE-SEM을 이용하여 초임계 유체 공정으로 제조된 고체분산체 미립자의 형상을 분석한 결과 100-200 nm 크기의 나노입자들이 응집된 형태를 나타내었으며, P188의 함량이 증가함에 따라 입자간의 응집이 증가하여 덩어리 형태로 전환되는 것을 확인할 수 있었다. XRD 분석 결과 5'-NIO 결정피크가 사라진 것을 확인하였으며, 이는 5'-NIO가 고분자 매질내에 분자 또는 나노 크기 수준으로 분산되었음을 의미한다. 또한 FT-IR 분석 결과 5'-NIO와 PVP K-30간에 수소결합과 같은 상호작용이 존재함을 학인할 수 있었다. 5'-NIO/PVP K-30 2성분계 고체분산체에 비이온성 계면활성제를 첨가한 경우 용출률이 현저히 향상되었으나, P188의 함량이 매우 큰 경우에는 오히려 용출률이 감소한 다는 것을 확인하였다. 본 연구를 통해 초임계 유체 공정이 기존의 고체분산체 제조 방법을 충분히 대체할 수 있다는 가능성을 확인할 수 있었다.

• 폴리머
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• 제32권3호
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• pp.193-198
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• 2008

시부트라민은 비만을 치료하기 위한 식욕억제제로서 높은 결정성을 갖는 난용성 약물이다. 이러한 난용성 약물의 용해도를 증가시키기 위하여 고체분산법을 바탕으로 한 분무건조기를 이용하여 미립구를 제조할 수 있었다. 제조된 미립구는 주사전자현미경을 이용하여 제조시 사용한 용매에 따른 미립구 형태차이를 확인할 수 있었으며 용매증발 속도가 빠를수록 구형을 이루는 것을 확인할 수 있었다. X선 회절기를 이용하여 제조된 미립구에서 시부트라민의 결정성이 10%이하로 감소되었음을 확인하였다. 제조된 미립구는 pH 1.2와 pH 6.8에서 방출을 실시하였으며 시부트라민이 pH에 따라서 용해도 차이가 크다는 것을 확인하였다. 또한, 경필 캡슐을 이용한 것이 정제형태보다 방출이 약 4배 정도 빠르다는 것을 확인할 수 있었다. 이러한 결과를 바탕으로 제형의 형태에 따라 방출거동이 조절될 수 있음을 확인하였다.

• Journal of Pharmaceutical Investigation
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• 제28권1호
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• pp.15-23
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• 1998

Extract of Centella asiatica(ECA), which is poorly water-soluble extract from the Centella asiatica is known to express excellent wound healing properties. $ECA-{\beta}-cyclodextrin$ $(asiaticoside-{\beta}-cyclodextrin\;and\;genin-{\beta}-cyc1odextrin)$ solid dispersion system, which was prepared by freezedrying method, was formulated as gels containing poloxamer 407 and propylene glycol, and evaluated with respect to their viscosity, stability, skin permeation and drug amount in the skin of hairless mouse. The average molar ratio $asiaticoside-{\beta}-CD$ and $genin-{\beta}-CD$ was 1:1.7 and 1:22, respectively. When the molar ratio of genin and ${\beta}-CD$ was 1:5, madecassic acid made 100% solid dispersion system and asiatic acid about 65%. In dissolution study, >99% of asiaticoside from $asiaticoside-{\beta}-CD$ was dissolved in 5 minutes, and >99% madecassic acid and >64% asiatic acid from $genin-{\beta}-CD$. The apparent viscosity of poloxamer 407 gels with $ECA-{\beta}-CD$ solid dispersion system increased in proportion to poloxamer 407 and propylene glycol concentration. In the accelerated stability test, all $ECA-{\beta}-CD$ poloxamer 407 gels showed that asiaticoside was most stable and madecassic acid stable and asiatic acid similar to stability of gel with free ECA. The permeation amount of asiaticoside in poloxamer gels through hairless mouse skin decreased as the concentration of poloxamer 407 increased. When propylene glycol was added at the level of 10%, the permeation amount of asiaticoside at poloxamer gels through hairless mouse skin increased but from 15% it decreased. The permeation of asiaticoside into the skin of hairless mouse was estimated to be about $0.10\;{\mu}g/cm^2$.