본 연구에서는 입자 크기 뿐만 아니라 베지클 멤브레인의 변형도를 조절할 수 있는 에토좀을 통해 약물의 경피흡수능을 향상시킬 수 있는 새로운 접근을 소개한다. 이를 위해 신규 육모효능성분인 Triaminodil을 포집한 에토좀을 제조하였고 입자 제조 후 추가적인 에너지를 가함으로써 입자의 크기를 조절하였다. 광산란법, 투과전자현미경, 멤브레인 변형도 측정 등을 통해 입자의 변형도가 입자 크기에 의존하는 것을 확인하였다. 또한 in vitro 피부흡수시험과 전임상 성장기 유도평가를 통해 베지클 멤브레인의 변형도가 Triaminodil의 피부 전달효능에 크게 영향을 미치는 것을 확인하였다. 이러한 결과로부터 담지 된 약물의 전달효능을 극대화 시킬 수 있는 최적 크기의 전달체 영역이 존재함을 확인하였고 이는 입자의 크기와 멤브레인 특성에 큰 영향을 받기 때문에 전달체를 설계하는데 있어 이 두 가지 요인을 고려해야 한다.
본 연구에서는 입자 크기 뿐만 아니라 베지클 멤브레인의 변형도를 조절할 수 있는 에토좀을 통해 약물의 경피흡수능을 향상시킬 수 있는 새로운 접근을 소개한다. 이를 위해 신규 육모효능성분인 Triaminodil을 포집한 에토좀을 제조하였고 입자 제조 후 추가적인 에너지를 가함으로써 입자의 크기를 조절하였다. 광산란법, 투과전자현미경, 멤브레인 변형도 측정 등을 통해 입자의 변형도가 입자 크기에 의존하는 것을 확인하였다. 또한 in vitro 피부흡수시험과 전임상 성장기 유도평가를 통해 베지클 멤브레인의 변형도가 Triaminodil의 피부 전달효능에 크게 영향을 미치는 것을 확인하였다. 이러한 결과로부터 담지 된 약물의 전달효능을 극대화 시킬 수 있는 최적 크기의 전달체 영역이 존재함을 확인하였고 이는 입자의 크기와 멤브레인 특성에 큰 영향을 받기 때문에 전달체를 설계하는데 있어 이 두 가지 요인을 고려해야 한다.
This study introduces a flexible approach to enhance skin permeation by using ethosomes with deformable lipid membranes as well as controllable sizes. To demonstrate this, a set of ethosomes encapsulating an anti-hair loss ingredient, Triaminodil$^{TM}$, as a model drug, were fabricated w...
This study introduces a flexible approach to enhance skin permeation by using ethosomes with deformable lipid membranes as well as controllable sizes. To demonstrate this, a set of ethosomes encapsulating an anti-hair loss ingredient, Triaminodil$^{TM}$, as a model drug, were fabricated with varying their size, which was achieved by solely applying the different level of mechanical energy, while maintaining their chemical composition. After characterization of the ethosomes with dynamic light scattering, transmission electron microscopy, and deformability measurements, it was found that their membrane deformability depended on the particle size. Moreover, studies on in vitro skin permeation and murine anagen induction allowed us to figure out that the membrane deformability of ethosomes essentially affects delivery efficiency of Triaminodil$^{TM}$ through the skin. It was noticeable in our study that there existed an optimum particle size that can not only maximize the delivery of the drug through the skin, but also increase its actual dermatological activity. These findings offer a useful basis for understanding how ethosomes should be designed to improve delivery efficiency of encapsulated drugs therein in the aspects of changing their length scales and membrane properties.
This study introduces a flexible approach to enhance skin permeation by using ethosomes with deformable lipid membranes as well as controllable sizes. To demonstrate this, a set of ethosomes encapsulating an anti-hair loss ingredient, Triaminodil$^{TM}$, as a model drug, were fabricated with varying their size, which was achieved by solely applying the different level of mechanical energy, while maintaining their chemical composition. After characterization of the ethosomes with dynamic light scattering, transmission electron microscopy, and deformability measurements, it was found that their membrane deformability depended on the particle size. Moreover, studies on in vitro skin permeation and murine anagen induction allowed us to figure out that the membrane deformability of ethosomes essentially affects delivery efficiency of Triaminodil$^{TM}$ through the skin. It was noticeable in our study that there existed an optimum particle size that can not only maximize the delivery of the drug through the skin, but also increase its actual dermatological activity. These findings offer a useful basis for understanding how ethosomes should be designed to improve delivery efficiency of encapsulated drugs therein in the aspects of changing their length scales and membrane properties.
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가설 설정
Apparent hair growth in mice samples is shown in Figure 4. The reclipped hair weight for each test group was also determined and shown in Figure 5. The control group that was treated with hydroetnanolic solution alone showed little hair growth. Whereas, topical application of the ethosomes containing TAD to the clipped dorsal area of telogen phase C57BL/6 mouse significantly helped hairs grow.
제안 방법
From the standpoint of performance and applicability, there is a need for methods to fabricate carriers that can stabilize TAD and promote its dermal delivery. In this study, by using the ethosomes having controllable size and deformability, we try to demonstrate that they are indeed useful for enhancing the transport of TAD, which is characterized by using in vitro skin permeation study.
In this study, we fabricate a representative set of ethosomes that have different deformability, which is done by simply changing their particle size. Our ethosomes can not only solubilize insoluble active drugs in their core or lipid bilayers, but also improve the delivery efficiency through the skin.
Each group had 7 mice. Six types of formulations were prepared for animal study: a hydroethanolic solution as a vehicle, 0.5 wt% TAD dissolved in the vehicle solution, Ethosome230, Ethosomes100, Ethosome60, and a commercial ointment containing 2 wt% TAD as a positive control. The test formulation was topically applied to the clipped dorsal area twice a day for 3 week.
5 wt% TAD dissolved in the vehicle solution, Ethosome230, Ethosomes100, Ethosome60, and a commercial ointment containing 2 wt% TAD as a positive control. The test formulation was topically applied to the clipped dorsal area twice a day for 3 week. The dorsal skin was photographed when the test was finished.
After sampling, the receptor solution was completely removed and replaced with a fresh PBS solution. Then, the TAD concentration in the receptor solution was determined with HPLC measurements.
The degree of hair growth was evaluated by measuring the hair weights after treatment of test animals for given time. Treatments of TAD to the test animals was carried out every twice per day for 3 week.
대상 데이터
Employed stationary phase was RP 18 (250 × 4 mm ; 5 m). An UV detector was employed at the wavelength of 230 nm. The standard solution was prepared by dissolving TAD in a range of 0.
Then, mice were randomly divided into 6 groups. Each group had 7 mice. Six types of formulations were prepared for animal study: a hydroethanolic solution as a vehicle, 0.
데이터처리
The evaluation of statistical significance was performed by the two sample t-test.
(n ≥ 4, n is the repeating number of experiment). The evaluation of statistical significance was conducted by a one-way analysis of variance (ANOVA). Statistical significance is expressed as p < 0.
이론/모형
Transmission electron microscope images of the ethosomes down-sized by using different mechanical stirring methods. For this observation, we used a cryo-technique. (A) Ethosome230, (B) Ethosomes100, and (C) Ethosome60.
The deformability of ethosomal membranes was determined by the extrusion method[27]. The ethosomal suspensions were extruded through a polycarbonate filter membrane (Whatman Nuclepore Track-Etched Membranes, pore diameter 50 nm, UK).
The large-sized ethosome particles, Ethosome230, were prepared using Touitou's method[19].
The size and zeta potential values of ethosomes were determined by using a dynamic light scattering method (Malvern Zetasizer). To measure them, the test suspension was diluted by adding the ethanol solution that had the same ethanol content as the ethosomal suspension[19].
성능/효과
Among the ethosomes, Ethosome100 resulted in the highest hair growth by 36.0 ± 12.0 mg, which was statistically significant (p = 0.02).
The long-term storage stability of the ethosomes was observed by measuring the size changes (see Table 2). From the result that there was no significant size increment for several months, it was reasonable to say that the ethosomes prepared in this study had good dispersion stability without any serious coalescence or coagulation, regardless of the particle size. This attributes to the fact that, as reported previously, ethanol has the ability to prevent aggregation of vesicles, due to a net negative surface charge[20].
The former was supported by visualizing the intact liposomes in the dermis layer by using the electron microscope[8]. Further studies also demonstrated that unilamellar vesicles with smaller particle sizes showed the better ability to permeate into the deeper skin strata, compared with larger multi-lamellar vesicles. This supports the idea that the size of liposomes affects the level of their skin deposition[9,10].
This paper experimentally demonstrated that ethosomes could have an optimum size that provides enhanced transdermal delivery of drug compounds. This was possible by fabricating a set of ethosomes with membrane deformability as well as different particle sizes.
후속연구
[19]. Although further studies should be carried out to clarify how ethosomes work on enhancing the skin permeation, the synergetic effect coming from chemical enhancing of ethanol and flexible membrane characteristics is known to be responsible for it. Basically, fine control over several key parameters, such as the concentration of ethanol and the type of lipids enables manipulation of particle size, entrapment efficiency of drugs, and flexibility of membrane[20-23].
참고문헌 (32)
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