KR19980066583A - A composition for transdermal absorption of a steroidal drug and a formulation for transdermal absorption containing the same - Google Patents
A composition for transdermal absorption of a steroidal drug and a formulation for transdermal absorption containing the same Download PDFInfo
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Abstract
본 발명은 경피흡수될 스테로이드계 약물, 디에틸렌글리콜 에테르 및 소르비탄 에스테르를 포함하는 경피흡수촉진제, 및 점착성 기질을 포함하는 경피흡수투여용 조성물, 및 이를 포함하는 경피흡수투여용 제형에 관한 것이다.The present invention relates to a transdermal absorption accelerator comprising a steroidal drug to be transdermally absorbed, a diethylene glycol ether and a sorbitan ester, and an adhesive substrate, and a transdermal absorption composition comprising the same.
경피흡수촉진제의 두성분 디에틸렌글리콜 에테르 및 소르비탄 에스테르는 상승적으로 작용하여 스테로이드계 약물의 피부를 통한 흡수를 현저히 촉진하는 상승효과를 가져올 뿐만 아니라 조성물내에서 약물의 결정형성을 억제하여 단일 기질형 경피흡수투여용 제형에서도 지속적으로 균일한 약물흡수속도를 보장하는 예기치 않은 효과를 가져온다.The two-component diethylene glycol ethers and sorbitan esters of transdermal absorption accelerators act synergistically, resulting in a synergistic effect that significantly promotes the absorption of steroid drugs through the skin, as well as inhibiting the crystal formation of drugs in the composition, resulting in a single substrate type. Even in transdermal absorption formulations, there is an unexpected effect of ensuring a consistently uniform drug absorption rate.
Description
본 발명은 경피흡수될 스테로이드계 약물, 디에틸렌글리콜 에테르 및 소르비탄 에스테르를 포함하는 경피흡수촉진제 및 점착성 기질을 포함하는 경피흡수투여용 조성물, 및 경피흡수투여용 제형에 관한 것이다.The present invention relates to a transdermal absorption composition comprising a steroidal drug to be transdermally absorbed, a transdermal absorption accelerator including diethylene glycol ether and a sorbitan ester, and an adhesive substrate, and a transdermal absorption formulation.
피부를 통한 약물의 전달방법은 경구투여에 의해 쉽게 흡수되지 않는 약물의 대체 투여경로로써 편리한 방법이다. 이 방법을 사용하면 경구 투여시 일어나는 흡수와 대사의 여러 단계를 피할 수 있고, 그 결과 약물의 생체내 이용률(bioavailability)이 높아져 대사물에 의한 부작용 없이 낮은 투여 용량과 적은 투여 빈도로도 원하는 약물 치료 효과를 얻을 수 있다. 또한 약제학적 농도를 일정하게 유지함으로써 약제학적 효과도 높일 수 있다.Drug delivery through the skin is a convenient route for alternative administration of drugs that are not readily absorbed by oral administration. This method avoids the various steps of absorption and metabolism that occur during oral administration, resulting in higher bioavailability of the drug, resulting in desired drug treatment at lower doses and at lower doses without adverse effects from metabolites. The effect can be obtained. In addition, the pharmaceutical effect can be enhanced by keeping the pharmaceutical concentration constant.
피부 각질층의 세포들은 고도로 케라틴(keratin)화되어 있어 약물이 체내에 침투하는데에 있어서 실질적인 장벽으로 작용하고 있다. 따라서 이를 개선하여 약물의 피부 흡수를 증가시키기 위해 많은 흡수 촉진제를 사용하여 왔다. 예를 들어 미합중국 특허 제 4,006,218 호, 제 3,551,554 호, 제 4,568,343 호, 4,746,515 호, 제 4,379,454 호, 제 4,906,463 호, 제 4,440,777 호, 4,783,450 호 및 5,212,199 호에는 각각 피부흡수 촉진제로 디메틸설폭사이드(DMSO), 디메틸포름아미드, 폴리에틸렌글리콜 모노라우레이트, 글리세롤 모노라우레이트, 에탄올, 프로필렌글리콜 모노라우레이트, 유칼립톨, 레시틴, 소르비탄 에스테르가 개시되어 있다. 디에틸렌글리콜 모노에틸에테르는 나프록센, 니트로글리세린, 페닐부타존, 프라제팜 등의 국소도포 제형에서 용해 보조제로 사용되어 왔으나, 문헌(Touitou, E., et al., International Journal of Pharmaceutics, 70, 159-166(1991))과 문헌(Watkinson, A., et al., ibid, 74, 229-236(1991))에서는 각각 테오필린과 프로스타글란딘 E2의 경피투여에서 디에틸렌글리콜 모노에틸에테르가 약물의 피부흡수 촉진효과를 나타낸다고 밝혔다. 또한, 두가지 물질로 구성된 피부흡수 촉진제로써 유럽 특허공고 제 261429 호에서는 리놀레인산과 프로필렌글리콜이 개시되어 있고, 미합중국 특허 제 4,537,776 호, 제 4,764,379 호 및 제 4,973,468 호에는 각각 N-(히드록시에틸)피롤리딘과 메틸 라우레이트, 에탄올과 글리세롤 모노라우레이트, 디에틸렌글리콜 모노에틸에테르와 프로필렌글리콜 모노라우레이트가 개시되어 있다.The cells of the stratum corneum are highly keratinized, acting as a real barrier to the penetration of drugs into the body. Therefore, many absorption accelerators have been used to improve this and increase the skin absorption of the drug. For example, U.S. Pat. Dimethylformamide, polyethylene glycol monolaurate, glycerol monolaurate, ethanol, propylene glycol monolaurate, eucalyptol, lecithin, sorbitan esters are disclosed. Diethylene glycol monoethyl ether has been used as a dissolution aid in topical coating formulations such as naproxen, nitroglycerin, phenylbutazone and prazepam, but it is described in Touitou, E., et al., International Journal of Pharmaceutics, 70, 159. -166 (1991) and Watkinson, A., et al., Ibid, 74, 229-236 (1991), respectively, showed that diethylene glycol monoethyl ether was used as a skin absorber for transdermal administration of theophylline and prostaglandin E2. It has a promoting effect. In addition, European Patent Publication No. 261429 discloses linoleic acid and propylene glycol as a skin absorption promoter composed of two substances, and US Pat. Nos. 4,537,776, 4,764,379, and 4,973,468 each disclose N- (hydroxyethyl) pi Lolidine and methyl laurate, ethanol and glycerol monolaurate, diethylene glycol monoethyl ether and propylene glycol monolaurate are disclosed.
경피투여 제형은 크게 저장형, 단순 기질형 및 적층형으로 구분되는데, 특히 단순 기질형 경피흡수 제형은 약물이 압력민감형 접착제의 기질층에 분산되어 있는 형태로써 미합중국 특허 제 4,314,577 호, 제 4,438,139 호 및 제 4,839,174 호 등에 개시된 바 있다. 이 제형은 낮은 생산단가로 간편하게 제조할 수 있으나, 약물 방출속도가 시간의 제곱근에 반비례하므로 방출속도가 초기에는 높지만 시간이 경과함에 따라 급격히 감소되는 단점이 있다. 또한 체내에 원하는 치료량을 투여하기 위해서는 약물이 과포화된 상태가 바람직한데, 이 경우 열역학적으로 불안정해지며 과포화된 약물은 결정을 형성하려는 경향이 있어, 결과적으로 약물의 피부 흡수율이 감소하게 된다. 즉, 약물의 결정생성 억제기작은 경피흡수 제형의 효율과 질을 향상시킬 수 있는 매우 중요한 요소가 된다. 이에 문헌(Ma, X., et al,. ibid, 142, 115-119(1996))에서는 결정 생성의 억제제로써 폴리비닐피롤리돈, 폴리비닐피롤리돈 비닐아세테이트 공중합체 등을 제시한 바 있다.Transdermal formulations are broadly divided into storage, simple matrix, and lamination, in particular, simple matrix transdermal formulations in which the drug is dispersed in the substrate layer of the pressure sensitive adhesive, US Pat. Nos. 4,314,577, 4,438,139 and 4,839,174 and the like. This formulation can be easily produced at a low production cost, but since the drug release rate is inversely proportional to the square root of time, the release rate is initially high, but has a disadvantage of rapidly decreasing with time. In addition, the drug is supersaturated in order to administer the desired therapeutic amount into the body, in which case it becomes thermodynamically unstable and the supersaturated drug tends to form crystals, resulting in decreased skin absorption of the drug. In other words, the drug crystallization inhibitory mechanism is a very important factor that can improve the efficiency and quality of transdermal absorption formulations. Thus, Ma, X., et al., Ibid, 142, 115-119 (1996) have suggested polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate copolymers, etc. as inhibitors of crystal formation. .
본 발명자들은 단순 기질형 경피투여 제형의 단점인 약물방출 속도의 저하를 개선하고, 피부 흡수율이 지속적으로 유지되는 제형을 개발하고자 계속 연구진행한 결과, 단독 사용시 피부 흡수율이 낮거나, 또는 결정을 형성하여 약물의 방출속도를 저하시키는 약물 흡수 촉진제들을 두가지 이상 혼합하여 사용함으로써 우수한 피부 흡수율을 가질 뿐만 아니라, 결정생성을 억제하여 시간이 지나도 약물 방출속도가 유지되는 경피투여 제형을 개발하여 본 발명의 완성에 이르게 되었다.The present inventors have continued to improve the drug release rate, which is a disadvantage of the simple matrix transdermal formulation, and to develop a formulation in which the skin absorption rate is continuously maintained. As a result, the skin absorption rate is low or crystals are formed when used alone. By using two or more drug absorption promoters to reduce the release rate of the drug by using a mixture of not only has excellent skin absorption rate, but also inhibits crystal formation to develop a transdermal dosage form that maintains the drug release rate over time to complete the present invention Came to.
본 발명에서 흡수 촉진제로 사용된 디에틸렌글리콜 모노에틸에테르와 소르비탄 모노라우레이트는 각각 개별적으로 사용된 선행기술은 있으나, 본 발명과 같이 이들을 결합하여 사용된 바가 없다.In the present invention, diethylene glycol monoethyl ether and sorbitan monolaurate used as absorption accelerators have prior art used individually, but they are not used in combination with the present invention.
본 발명의 목적은 피부에서 경피흡수율을 증진시키고, 결정생성을 억제하여 지속적으로 균일한 약물흡수속도를 보장하는 스테로이드계 약물의 경피흡수투여용 조성물 및 이를 포함하는 경피흡수투여용 제형을 제공하는 것이다.It is an object of the present invention to provide a composition for transdermal absorption of a steroidal drug and a transdermal absorption formulation comprising the same, which enhances percutaneous absorption in the skin and inhibits crystal formation to ensure a uniform drug absorption rate. .
도 1은 본 발명의 단순 기질형 경피흡수투여용 제형의 구조를 도식화한 단면도이다.1 is a cross-sectional view illustrating the structure of a simple matrix-type transdermal absorption formulation of the present invention.
도 2는 흡수 촉진제의 조성에 따른 에스트라디올의 피부 흡수량 누적치를 나타낸 그래프이다.Figure 2 is a graph showing the skin absorption amount of estradiol according to the composition of the absorption accelerator.
도 3은 흡수 촉진제의 조성에 따른 초산 노르에치스테론의 피부 흡수량 누적치를 나타낸 그래프이다.Figure 3 is a graph showing the skin absorption amount cumulative value of norechsterone acetate in accordance with the composition of the absorption accelerator.
도 4는 흡수 촉진제의 조성에 따른 사람사체 피부에서의 초산 노르에치스테론의 피부 흡수량 누적치를 나타낸 그래프이다.Figure 4 is a graph showing the cumulative value of the skin absorption amount of the norecoster acetate acetate in human carcasses according to the composition of the absorption accelerator.
도 5는 소르비탄 모노라우레이트와 디에틸렌글리콜 모노에틸에테르의 함량변화에 따른 사람 사체 피부에서의 초산 노르에치스테론의 피부 흡수량 누적치를 나타낸 그래프이다.Figure 5 is a graph showing the cumulative value of the skin uptake of acetic acid noretchosterone in human cadaver skin according to the change of the content of sorbitan monolaurate and diethylene glycol monoethyl ether.
상기 목적에 따라, 본 발명에서는 경피흡수될 스테로이드계 약물, 디에틸렌글리콜 에테르 및 소르비탄 에스테르를 1:2 내지 2:1의 비율로 포함하는 경피흡수촉진제 및 점착성 기질을 포함하는 경피흡수투여용 조성물을 제공하고, 또한 경피흡수될 스테로이드계 약물에 불투과성인 보호층, 보호층의 상면에 상기 경피흡수투여용 조성물을 포함하는 점착성 기질층 및 점착성 기질층의 상면에 박리층을 포함하는 경피흡수투여용 제형을 제공한다.In accordance with the above object, in the present invention, the composition for transdermal absorption comprising a transdermal absorption accelerator and an adhesive substrate comprising a steroidal drug, diethylene glycol ether, and sorbitan ester to be transdermal in a ratio of 1: 2 to 2: 1. To provide a transdermal absorption, and also a protective layer impermeable to the steroid-based drug to be transdermally absorbed, the transdermal absorption comprising a pressure-sensitive adhesive substrate layer and a release layer on the upper surface of the transdermal absorption composition on the upper surface of the protective layer. It provides a formulation.
이하 본 발명을 좀더 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명의 경피흡수투여용 제형은 도 1에서 보듯이, 기본적으로 보호층, 경피투여 점착성 기질층 및 경피투여 시스템을 외부환경으로부터 보호하고, 사용시에는 쉽게 제거가 가능한 박리층으로 이루어져 있다. 또한, 피부 접착성을 좋게 하기 위해 보조 점착층이 부가될 수 있다.As shown in Figure 1, the transdermal absorption formulation of the present invention basically comprises a protective layer, a transdermal adhesive substrate layer, and a transdermal administration system from an external environment, and a peeling layer that can be easily removed when used. In addition, an auxiliary adhesive layer may be added to improve skin adhesion.
본 발명에 따른 제형의 주된 구성부위인 점착성 기질층은 점착성 고분자인 폴리아크릴레이트계 접착제에 약물의 흡수 촉진제로서 디에틸렌글리콜 모노에틸에테르 또는 디에틸렌글리콜 모노메틸에테르인 디에틸렌글리콜 에테르 성분과 소르비탄 모노라우레이트 또는 소르비탄 모노올레이트인 소르비탄 에스테르를 일정비율로 약물과 함께 미분산시킴으로써 구성된다. 폴리아크릴레이트계 접착제로는 에틸-, 부틸-, 2-에틸헥실 아크릴레이트 등이 포함된다. 상기 흡수 촉진제로 사용되는 디에틸렌글리콜 에테르 성분과 소르비탄 에스테르를 혼합하여 사용할 경우, 바람직하게는 1:4 내지 4:1, 더욱 바람직하게는 1:2 내지 2:1로 혼합하여 사용할 경우, 흡수 촉진효과가 더욱 향상될 수 있다. 또한 점착층은 디에틸렌글리콜 에테르 성분과 소르비탄 에스테르는 각각 2.5 내지 15 중량% 포함하는 것이 바람직하다.The adhesive substrate layer, which is a main component of the formulation according to the present invention, is a diethylene glycol ether component and sorbitan, which are diethylene glycol monoethyl ether or diethylene glycol monomethyl ether, as an absorption accelerator of a drug to a polyacrylate-based adhesive which is an adhesive polymer. Sorbitan esters, which are monolaurate or sorbitan monooleate, are undispersed with the drug in a proportion. Polyacrylate adhesives include ethyl-, butyl-, 2-ethylhexyl acrylate and the like. When the diethylene glycol ether component and the sorbitan ester used as the absorption promoter are mixed and used, the absorption is preferably 1: 4 to 4: 1, more preferably 1: 2 to 2: 1. The promoting effect can be further improved. In addition, the pressure-sensitive adhesive layer preferably contains 2.5 to 15% by weight of diethylene glycol ether component and sorbitan ester, respectively.
본 발명의 경피흡수투여용 조성물에 사용될 수 있는 대표적인 약물은 에스트로겐, 프로게스토겐, 안드로겐 또는 이들의 혼합물이다. 에스트로겐으로는 에스트라디올, 에티닐 에스트라디올 또는 에스트라디올 에스테르를 들 수 있고, 프로게스토겐으로는 노르에치스테론, 초산 노르에치스테론, 메드록시프로게스테론 아세테이트, 데소게스트렐, 게스타텐 또는 레보노르게스트렐을 들 수 있으며, 에스트로겐과 프로게스토겐의 혼합사용시, 점착성 기질층을 100 중량%로 하여 에스트로겐은 0.05 내지 5.0 중량%, 프로게스토겐은 1.0 내지 10 중량%, 흡수 촉진제는 5 내지 30 중량%, 그리고 잔량은 점착성 기질인 접착제로 구성되는 것이 바람직하다.Representative drugs that can be used in the transdermal absorption composition of the present invention are estrogens, progestogens, androgens or mixtures thereof. Examples of estrogens include estradiol, ethynyl estradiol or estradiol esters, and progestogens include norechsterone, norechsterone acetate, methoxyprogesterone acetate, desogestrel, and gestatene. Or levonorgestrel, and when the mixture of estrogen and progestogen is used, the adhesive substrate layer is 100% by weight, estrogen is 0.05 to 5.0% by weight, progestogen is 1.0 to 10% by weight, absorption accelerator. Is 5 to 30% by weight, and the balance is preferably composed of an adhesive which is an adhesive substrate.
안드로겐으로는 테스토스테론, 테스토스테론 프로피오네이트, 테스토스테론 에난테이트, 테스토스테론 시피오네이트, 메틸테스토스테론 또는 디히드로에피안드로스테론을 들 수 있고, 이 때 점착성 기질층을 100 중량%로 하여 안드로겐은 0.5 내지 30 중량%, 흡수 촉진제는 5 내지 30 중량%, 그리고 잔량은 점착성 기질인 접착제로 구성되는 것이 바람직하다.Examples of androgens include testosterone, testosterone propionate, testosterone enanthate, testosterone cypionate, methyltestosterone or dihydroepiandrosterone, wherein the adhesive substrate layer is 100% by weight androgen is 0.5-30% by weight. The absorption accelerator is preferably 5 to 30% by weight, and the balance is composed of an adhesive which is an adhesive substrate.
본 발명의 조성물에는 방향제, 보존제, 항산화제, 안정화제, 색소 등의 부형제가 포함될 수 있다.The composition of the present invention may include excipients such as perfumes, preservatives, antioxidants, stabilizers, pigments.
이상의 본 발명에 따른 경피흡수투여용 제형의 특징을 요약해 보면 다음과 같다. 첫째, 본 발명의 경피흡수투여용 제형은 단순 기질형으로써 제조가 간편할 뿐만 아니라 피부 흡수율이 지속적이고, 적어도 1일 동안 지속성을 갖는 0차의 피부 흡수율을 나타내며, 둘째, 2종 이상 흡수 촉진제의 병용 사용으로 흡수 촉진효과와 함께 결정 생성을 억제하는 효과가 있고, 세째, 약물 함량과 흡수 촉진제의 함량을 조절함으로써 피부 흡수율을 쉽게 조정할 수 있어 사람에 따라 적합한 투여용량을 선택할 수 있다.The characteristics of the percutaneous absorption formulation according to the present invention are as follows. First, the transdermal absorption dosage form of the present invention is not only easy to prepare as a simple matrix type, but also exhibits a skin absorption rate of zero order having a sustained skin absorption rate and a sustainability for at least one day. Combined use has the effect of promoting absorption and suppressing crystal formation. Third, the skin absorption rate can be easily adjusted by adjusting the drug content and the content of the absorption accelerator, so that a suitable dosage can be selected according to a person.
이하, 본 발명을 하기 실시예에 의거하여 좀더 상세하게 설명하고자 한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐, 본 발명의 범위가 이들 만으로 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail based on the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.
비 교 실 시 예 1Example 1
에스트라디올(ED) 0.6 중량%, 초산 노르에치스테론(NETA) 3.0 중량%와 하기 표 1과 같은 조성을 갖는 흡수 촉진제를 점착성 고분자 물질인 폴리아크릴레이트계 접착제 듀로탁 87-2074에 첨가하고 약물이 점착성 고분자 용액 중에 용해되거나 골고루 혼합될 때까지 충분히 교반하였다. 불투과성 보호층인 스카치팩 1109 위에 상기 혼합용액을 부어 기질층을 코팅한 후 60℃에서 시작하여 120℃까지 단계적으로 온도를 올리면서 연속적으로 건조시켰다. 이 때 습식 코팅두께는 1000㎛로 하였다. 코팅된 점착성 기질층은 1 시간 동안 공기건조시킨 후 그 위에 탁착층을 적층시켜 상온에서 보관하였다.An absorption accelerator having 0.6 wt% estradiol (ED), 3.0 wt% norachetone acetate (NETA) and a composition as shown in Table 1 was added to the polyacrylate adhesive Durotax 87-2074, which is a tacky polymer, The mixture was sufficiently stirred until dissolved or evenly mixed in the tacky polymer solution. The mixed solution was poured onto the Scotch Pack 1109, which is an impermeable protective layer, and then coated on a substrate layer, and subsequently dried at 60 ° C. to 120 ° C. in stepwise temperature. At this time, the wet coating thickness was 1000 µm. The coated adhesive substrate layer was air-dried for 1 hour, and then deposited on it and stored at room temperature.
이와 같이 제조된 제형의 피부흡수 실험을 위해 발리아-치엔(Valia-Chien) 확산셀에 6 주령의 무모마우스(hairless mouse) 암컷으로부터 적출한 피부를 각질층이 셀 바깥을 향하도록 부착하고, 이 피부 위에 상기에서 건조한 패취를 부착한 후 셀 고정기의 나사로 고정시켰다. 셀에 폴리에틸렌글리콜 400을 40% 함유하는 생리식염수 용액을 일정량 채우고 교반시켰다. 정해진 시간에 일정량(100㎕)의 샘플을 채취하여 고속 액체 크로마토그래프로 정량한 후 피부 흡수 촉진제 간의 피부 흡수 촉진효과를 비교하는 실험을 각 제형 별로 3번씩 실시하여 그 결과를 하기 표 1과 도 2 및 도 3에 나타내었다.For skin absorption experiment of the formulation thus prepared, the skin extracted from 6 week old hairless mouse females was attached to the Valia-Chien diffusion cell so that the stratum corneum was directed out of the cell. After attaching the dry patch above it was fixed with screws of the cell holder. The cell was filled with a predetermined amount of saline solution containing 40% of polyethylene glycol 400 and stirred. After taking a certain amount (100 μl) of the sample at a predetermined time and quantitating it with a high performance liquid chromatograph, the experiment for comparing the skin absorption promoting effect between the skin absorption promoters was performed three times for each formulation, and the results are shown in Tables 1 and 2 below. And shown in FIG. 3.
SPR: 피부 흡수율(평균 ± 표준편차(㎍/㎠/hr))SPR: skin absorption rate (mean ± standard deviation (μg / cm 2 / hr))
도 2는 흡수 촉진제의 조성에 따른 에스트라디올이 피부 흡수량 누적치를 나타낸 그래프이고, 도 3은 흡수 촉진제의 조성에 따른 초산 노르에치스테론의 피부 흡수량 누적치를 나타낸 그래프이다.2 is a graph showing the cumulative value of the estradiol skin absorption amount according to the composition of the absorption accelerator, Figure 3 is a graph showing the cumulative value of the skin absorption amount of norechsterone acetate according to the composition of the absorption accelerator.
이상에서 보듯이, 본 발명의 제형은 스쿠알렌과 소르비탄 모노라우레이트를 흡수 촉진제로 사용할 때 효과가 가장 큼을 알 수 있다. 그러나 흡수 촉진제를 단독으로 사용한 모든 제형에서는 결정이 생성되었다.As described above, it can be seen that the formulation of the present invention has the greatest effect when using squalene and sorbitan monolaurate as absorption accelerators. However, crystals formed in all formulations using absorption accelerators alone.
비 교 실 시 예 2Comparative Example 2
초산 노르에치스테론(NETA) 4 중량%와 하기 표 2와 같은 조성을 갖는 흡수 촉진제 및 점착성 고분자 물질인 폴리아크릴레이트계 접착제 듀로탁 87-2074를 총 100 중량%가 되도록 혼합한 후 비교 실시예 1과 동일한 방법으로 사람 사체 피부에 부착하고 흡수 촉진제 간의 피부흡수 촉진효과를 비교하는 실험을 각 제형별로 3번씩 실시하여 그 결과를 하기 표 2 및 도 4에 나타내었다.Comparative Example after mixing 4% by weight of no-ethacetic acid acetate (NETA) and the absorption accelerator having a composition as shown in Table 2 and a polyacrylate-based adhesive Durotax 87-2074 as a tacky polymer material to a total of 100% by weight Attached to the human carcass skin in the same manner as in 1 and the experiment to compare the skin absorption promoting effect between the absorption accelerator was carried out three times for each formulation, the results are shown in Table 2 and FIG.
도 4는 흡수 촉진제의 조성에 따른 사람 사체 피부에서 초산 노르에치스테론의 피부 흡수량 누적치를 나타낸 그래프이다.Figure 4 is a graph showing the cumulative value of the skin uptake amount of norechsterone acetate in human cadaver skin according to the composition of the absorption accelerator.
이상에서 보듯이, 사람 사체 피부에서는 흡수 촉진제로서 소르비탄 모노라우레이트, 디에틸렌글리콜 모노에틸에테르, 스쿠알렌을 사용한 제형은 피부 흡수 촉진효과를 나타내며, 비교 실시예 1의 무모마우스 피부에 비해 낮은 피부 흡수율을 나타냄을 알 수 있다. 또한 비교 실시예 1에서와 마찬가지로 소르비탄 모노라우레이트 또는 스쿠알렌 만을 흡수 촉진제로 사용하였을 경우 제조한 제형에서 결정이 형성되는 문제점이 발생하였고, 디에틸렌글리콜 모노에틸에테르를 사용한 경우는 결정이 생성되지 않았다.As described above, in human carcass skin, the formulation using sorbitan monolaurate, diethylene glycol monoethyl ether, and squalene as an absorption accelerator shows a skin absorption promoting effect, and a lower skin absorption rate than the skinless mouse skin of Comparative Example 1 It can be seen that. In addition, as in Comparative Example 1, when only sorbitan monolaurate or squalene was used as an absorption accelerator, there was a problem in that crystals were formed in the prepared formulation, and when diethylene glycol monoethyl ether was used, no crystals were formed. .
실 시 예 1Example 1
에스트라디올(ED) 0.4 중량%, 초산 노르에치스테론(NETA) 2.7 중량%, 하기 표 3과 같은 조성을 갖는 흡수 촉진제와 점착성 고분자 물질인 폴리아크릴레이트계 접착제 듀로탁 87-2074를 총 100 중량%가 되도록 혼합한 후 비교 실시예 2와 동일한 방법으로 실험하여 소르비탄 모노라우레이트(SML)와 디에틸렌글리콜 모노에틸에테르(TC)의 함량변화에 따른 사람 사체 피부에서 에스트라디올과 초산 노르에치스테론에 대한 피부 흡수 촉진효과를 비교하는 실험을 각 제형별로 3번씩 실시하였으며, 양성 대조군으로는 시판 중인 저장형 경피 흡수 제형인 시바가이기사의 에스트라제스트,(EG)를 사용하여 그 결과를 표 3에 나타내었다.0.4 weight% of estradiol (ED), 2.7 weight% of norethosterone acetate (NETA), 100% by weight of the absorption accelerator having a composition as shown in Table 3 and the polyacrylate-based adhesive Durotax 87-2074, which is a tacky polymer material After mixing up to%, experiments were carried out in the same manner as in Comparative Example 2, and the estradiol and nore acetate in human cadaver skin according to the change of the content of sorbitan monolaurate (SML) and diethylene glycol monoethyl ether (TC) Three experiments were conducted to compare the effect of promoting skin absorption on sterons for each formulation, and the results were obtained using a commercially available storage transdermal absorption formulation, Estrazest from Shivagaigi, (EG). 3 is shown.
도 5는 소르비탄 모노라우레이트와 디에틸렌글리콜 모노에틸에테르의 함량변화에 따른 사람 사체 피부에서의 초산 노르에치스테론의 피부 흡수량 누적치를 나타낸 그래프이다.Figure 5 is a graph showing the cumulative value of the skin uptake of acetic acid noretchosterone in human cadaver skin according to the change of the content of sorbitan monolaurate and diethylene glycol monoethyl ether.
이상에서 보듯이, 사람 사체 피부에서는 흡수 촉진제로서 소르비탄 모노라우레이트를 단독으로 사용한 경우 보다 디에틸렌글리콜 모노에틸에테르와 1:1 또는 2:1로 혼합하여 사용하였을 때 초산 노르에치스테론의 피부 흡수율이 우수하였으며, 양성 대조군인 에스트라제스트, 보다 우수한 피부 흡수율을 나타내었으며, 피부 흡수 양상은 0차의 흡수 속도에 보다 가까움을 알 수 있다. 또한, 소르비탄 모노라우레이트와 디에틸렌글리콜을 모노에틸에테르를 함께 사용한 3-5, 3-6 및 3-7의 제형에서는 결정 형성이 억제됨을 알 수 있었다.As can be seen, in human carcass skin, when used in combination with diethylene glycol monoethyl ether 1: 1 or 2: 1 than sorbitan monolaurate as an absorption accelerator, The skin absorption rate was excellent, and the positive control, estrazest, showed a better skin absorption rate, and the skin absorption pattern was closer to the zeroth order absorption rate. In addition, it was found that crystal formation was inhibited in the formulations of 3-5, 3-6, and 3-7 using sorbitan monolaurate and diethylene glycol together with monoethyl ether.
실 시 예 2Example 2
테스토스테론 3.5 중량%에 하기 표 4와 같은 조성을 갖는 흡수 촉진제를 점착성 고분자 물질인 폴리아크릴레이트계 접착제 듀로탁 87-2074에 첨가하여 혼합한 후 비교 실시예 2와 동일한 방법으로 각각의 흡수 촉진제의 조성에 따른 피부 흡수 촉진 효과를 비교하는 실험을 각 제형별로 3번씩 실시하여 그 결과를 표 4에 나타내었다.The absorption accelerator having a composition as shown in Table 4 to 3.5% by weight of testosterone was added to the polyacrylate adhesive Duro-Tak 87-2074, which is a tacky polymer material, and mixed, and then the composition of each absorption accelerator was prepared in the same manner as in Comparative Example 2. Three experiments were performed for each formulation to compare the skin absorption promoting effect, and the results are shown in Table 4.
PGML: 프로필렌글리콜 모노라우레이트PGML: Propylene Glycol Monolaurate
이상에서 보듯이, 본 발명의 제형은 소르비탄 모노라우레이트와 디에틸렌글리콜 모노에틸에테르를 병용 사용할 때 단독으로 사용한 경우 보다 피부 흡수 촉진효과가 크다는 것을 알 수 있다.As can be seen from the above, it can be seen that the formulation of the present invention has a greater skin absorption promoting effect than when sorbitan monolaurate and diethylene glycol monoethyl ether are used in combination.
경피흡수될 스테로이드계 약물, 디에틸렌글리콜 에테르 및 소르비탄 에스테르를 포함하는 경피흡수촉진제, 및 점착성 기질을 포함하는 경피흡수투여용 조성물, 및 이를 포함하는 경피흡수투여용 제형은 단순 기질형으로써 제조가 간편할 뿐만 아니라 피부 흡수율이 지속적이고, 적어도 1일 동안 지속성을 갖는 0차의 피부 흡수율을 나타내며, 2종 이상의 흡수 촉진제를 병용 사용함으로써 흡수 촉진효과 및 결정 생성을 억제하는 효과가 있고, 약물 함량과 흡수 촉진제의 함량을 조절함으로써 피부 흡수율을 쉽게 조정할 수 있어 사람에 따라 적합한 투여용량을 선택할 수 있다.Transdermal absorption accelerators comprising a steroidal drug to be transdermally absorbed, a diethylene glycol ether and a sorbitan ester, and a transdermal absorption composition comprising an adhesive substrate, and a transdermal absorption formulation including the same, are prepared in a simple matrix form. Not only is it simple, it has a sustained skin absorption rate, exhibits a skin absorption rate of zero order having persistence for at least one day, and has the effect of inhibiting absorption promotion and crystal formation by using two or more absorption accelerators in combination. By adjusting the content of the absorption enhancer, the skin absorption rate can be easily adjusted so that a suitable dosage can be selected according to the person.
Claims (16)
Priority Applications (13)
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KR1019970002233A KR100215027B1 (en) | 1997-01-27 | 1997-01-27 | Composition for transdermal administration of steroid drugs and formulation containing same |
EP98902269A EP1001812A1 (en) | 1997-01-27 | 1998-01-23 | Composition for the transdermal administration of steroid drugs |
JP10531848A JP2000508349A (en) | 1997-01-27 | 1998-01-23 | Composition for transdermal administration of steroid drug |
AU58820/98A AU727811B2 (en) | 1997-01-27 | 1998-01-23 | Composition for the transdermal administration of steroid drugs |
RU99118582/14A RU2176499C2 (en) | 1997-01-27 | 1998-01-23 | Composition for percutaneous administration of steroid medicinal agents and preparation containing thereof |
CA002277970A CA2277970A1 (en) | 1997-01-27 | 1998-01-23 | Composition for the transdermal administration of steroid drugs |
CN98802010A CN1244806A (en) | 1997-01-27 | 1998-01-23 | Compositions for transdermal administration of streoid drugs |
PCT/KR1998/000013 WO1998032465A1 (en) | 1997-01-27 | 1998-01-23 | Composition for the transdermal administration of steroid drugs |
BR9807009-6A BR9807009A (en) | 1997-01-27 | 1998-01-23 | Composition for administration of steroid drug transfer |
TW087101089A TW537899B (en) | 1997-01-27 | 1998-01-26 | Composition for the transdermal administration of steroid drugs |
ARP980100352A AR011577A1 (en) | 1997-01-27 | 1998-01-27 | COMPOSITION FOR THE TRANSDERMIC ADMINISTRATION OF A STEROID DRUG AND TRANSDERMIC FORMULATION INCLUDING IT |
IDP980113A ID19755A (en) | 1997-01-27 | 1998-01-27 | COMPOSITION FOR TRANSDERMAL PROVISION OF STEROID MEDICINES |
US09/746,448 US20010023261A1 (en) | 1997-01-27 | 2000-12-12 | Novel composition for the transdermal administration of drugs |
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KR1019970002233A KR100215027B1 (en) | 1997-01-27 | 1997-01-27 | Composition for transdermal administration of steroid drugs and formulation containing same |
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JP (1) | JP2000508349A (en) |
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CN (1) | CN1244806A (en) |
AR (1) | AR011577A1 (en) |
AU (1) | AU727811B2 (en) |
BR (1) | BR9807009A (en) |
CA (1) | CA2277970A1 (en) |
ID (1) | ID19755A (en) |
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KR100403051B1 (en) * | 2000-07-25 | 2003-10-23 | 일양약품주식회사 | Composition of matrix type patch for transdermal testosterone delivery and process for preparing the same |
WO2020060128A1 (en) * | 2018-09-21 | 2020-03-26 | 아이큐어 주식회사 | Cosmetic composition comprising botulinum-derived peptide having excellent cell penetrating ability |
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FR2848112B1 (en) * | 2002-12-10 | 2007-02-16 | Besins Int Belgique | PHARMACEUTICAL COMPOSITION FOR TRANSDERMAL OR TRANSMUCTIVE DELIVERY COMPRISING AT LEAST ONE PROGESTATIVE AND / OR AT LEAST ONE OESTROGEN, PREPARATION METHOD AND USES THEREOF |
WO2004054544A1 (en) * | 2002-12-10 | 2004-07-01 | Besins International Belgique | Pharmaceutical composition for transdermal or transmucous administration comprising a progestin or an estrogen, method for preparing same and uses thereof |
FR2851470B1 (en) | 2003-02-20 | 2007-11-16 | Besins Int Belgique | PHARMACEUTICAL COMPOSITION FOR TRANSDERMAL OR TRANSMUCTIVE DELIVERY |
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- 1997-01-27 KR KR1019970002233A patent/KR100215027B1/en not_active IP Right Cessation
-
1998
- 1998-01-23 WO PCT/KR1998/000013 patent/WO1998032465A1/en not_active Application Discontinuation
- 1998-01-23 JP JP10531848A patent/JP2000508349A/en active Pending
- 1998-01-23 CN CN98802010A patent/CN1244806A/en active Pending
- 1998-01-23 EP EP98902269A patent/EP1001812A1/en not_active Withdrawn
- 1998-01-23 RU RU99118582/14A patent/RU2176499C2/en not_active IP Right Cessation
- 1998-01-23 BR BR9807009-6A patent/BR9807009A/en not_active Application Discontinuation
- 1998-01-23 CA CA002277970A patent/CA2277970A1/en not_active Abandoned
- 1998-01-23 AU AU58820/98A patent/AU727811B2/en not_active Ceased
- 1998-01-26 TW TW087101089A patent/TW537899B/en active
- 1998-01-27 AR ARP980100352A patent/AR011577A1/en not_active Application Discontinuation
- 1998-01-27 ID IDP980113A patent/ID19755A/en unknown
Cited By (2)
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KR100403051B1 (en) * | 2000-07-25 | 2003-10-23 | 일양약품주식회사 | Composition of matrix type patch for transdermal testosterone delivery and process for preparing the same |
WO2020060128A1 (en) * | 2018-09-21 | 2020-03-26 | 아이큐어 주식회사 | Cosmetic composition comprising botulinum-derived peptide having excellent cell penetrating ability |
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CA2277970A1 (en) | 1998-07-30 |
ID19755A (en) | 1998-07-30 |
RU2176499C2 (en) | 2001-12-10 |
TW537899B (en) | 2003-06-21 |
JP2000508349A (en) | 2000-07-04 |
KR100215027B1 (en) | 1999-08-16 |
EP1001812A1 (en) | 2000-05-24 |
BR9807009A (en) | 2000-03-14 |
AR011577A1 (en) | 2000-08-30 |
AU727811B2 (en) | 2000-12-21 |
CN1244806A (en) | 2000-02-16 |
WO1998032465A1 (en) | 1998-07-30 |
AU5882098A (en) | 1998-08-18 |
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