KR100449904B1 - The Preparation Method of Self-Assembled Sericin Nanoparticle - Google Patents
The Preparation Method of Self-Assembled Sericin Nanoparticle Download PDFInfo
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Abstract
본 발명은 하기 화학식의 세리신-PEG 결합체의 제조방법에 관한 것으로, 누에고치로부터 추출된 세리신에 2-(O-메톡시폴리에틸렌 글리콜)-4,6-디클로로-S-트리아진(actPEG1) 또는 2,4-비스(O-메톡시폴리에틸렌 글리콜)-6-클로로-S-트리아진 (actPEG2)를 염기성 완충 수용액에서 반응시킨 뒤 투석에 의해 나노입자를 제조하는 것을 특징으로 한다. 여기에서 actPEGn의 분자량은 1,000 내지 40,000이다.The present invention relates to a method for preparing a sericin-PEG conjugate represented by the formula: 2- (O-methoxypolyethylene glycol) -4,6-dichloro-S-triazine (actPEG1) or 2 to sericin extracted from silkworm cocoon The nanoparticles are prepared by dialysis after reacting, 4-bis (O-methoxypolyethylene glycol) -6-chloro-S-triazine (actPEG2) in a basic buffered aqueous solution. Here, the molecular weight of actPEGn is 1,000 to 40,000.
Description
본 발명은 누에고치로부터 얻어지는 천연단백질인 세리신에 수용성 고분자인 폴리에틸렌글리콜(PEG)을 화학결합시킨 뒤 투석방법에 의해 얻어지는 세리신 나노입자의 제조에 관한 것이다. 이러한 방법에 의해 제조된 나노입자는 높은 수율로 얻어지며 회합이 잘 일어나지 않고 1㎛ 이하의 크기 및 구형모양을 지니며 또한 생체분해가 잘 일어난다는 장점을 지니고 있다.(M. Yokoyama et. al Journal of Controlled Release 32, 269(1994))The present invention relates to the production of sericin nanoparticles obtained by a dialysis method after chemically bonding polyethylene glycol (PEG), a water-soluble polymer, to sericin, a natural protein obtained from silkworm cocoons. The nanoparticles prepared by this method are obtained in high yield, do not easily associate, have a size of less than 1 μm and have a spherical shape, and also have the advantage of biodegradation (M. Yokoyama et. Al Journal). of Controlled Release 32, 269 (1994))
1㎛ 이하 크기를 지닌 입자를 나노입자라고 하는데, 이는 분리기술, 조직학적인 연구, 임상진단 방법, 약물전달, 기능성 화장품 같은 생명과학의 다양한 분야에 활발히 응용된다. 이는 나노입자가 정제, 살균의 용이성과 약물의 목표에 효과적인 작용, 지속적인 약물 방출거동 등의 응용에 대한 이점을 가지고 있기 때문이다(C.Cho et.al, Macromolecularie Chemie, Rapid Communication, 18 361-369(1997))Particles with a size of less than 1 μm are called nanoparticles, which are actively applied in various fields of life sciences such as separation technology, histological studies, clinical diagnostic methods, drug delivery, and functional cosmetics. This is because nanoparticles have advantages for applications such as purification, ease of sterilization, effective action on drug targets, and sustained drug release behavior (C.Cho et.al, Macromolecularie Chemie, Rapid Communication, 18 361-369). (1997)
본 발명에서 사용되는 천연고분자인 실크 세리신은 많은 수산화기를 가지고 있지만 세리신 자체의 물리적인 특성으로 인해 용매에 잘녹지 않는 특성을 가지고 있다. 또한, 세리신은 그 자체로 뛰어난 보습성을 가지고 있지만 물리적 방법에 의해 제조된 세리신은 안정성이 결여(젤형성)되어 있어 약물캐리어나 화장품용 보습제등 여러가지 응용면에서 문제점으로 지적되어져 왔다.(특허출원번호 99-6533, 한국특허공개공보 95-5839, 98-042150)Silk sericin, which is a natural polymer used in the present invention, has many hydroxyl groups, but has a property of being insoluble in a solvent due to physical properties of sericin itself. In addition, sericin has excellent moisturizing properties per se, but sericin produced by physical methods is lacking in stability (gel formation) and has been pointed out as a problem in various applications such as drug carriers and cosmetic moisturizers. No. 99-6533, Korean Patent Publication No. 95-5839, 98-042150)
따라서, 본 발명의 목적은 양친매성 성질을 가지고 있는 합성고분자인 폴리에틸렌글리콜(PEG)을 세리신에 반응시켜 세리신-PEG 결합체를 합성한 후 유기용매에 녹여 투석방법에 의해 기능성화장품 및 의약전달용으로 응용이 가능한 자기조합형 나노입자(self-assembled nanoparticle)를 제조 하는것이다.Accordingly, an object of the present invention is to synthesize a sericin-PEG conjugate by reacting polyethylene glycol (PEG), a synthetic polymer having amphiphilic properties with sericin, and then dissolved in an organic solvent and applied for functional cosmetics and pharmaceutical delivery by dialysis method. To make this possible self-assembled nanoparticles.
본 발명의 또 다른 목적은 독성이 없고 수용해도가 우수한 폴리에틸렌글리콜 (PEG)을 세리신의 수산기나 아미노기에 결합시켜 세리신의 수용해도 및 안정성을 높여 주름개선제 및보습제로서 이용하기에 적당한 세리신- PEG 결합체를 합성하여 제공하는데 있다.Another object of the present invention is to combine sericin-PEG conjugate suitable for use as a wrinkle improver and moisturizer by increasing the water solubility and stability of sericin by combining polyethylene glycol (PEG), which is not toxic and has excellent water solubility, with hydroxyl or amino groups of sericin. To provide a composite.
도 1은 본 발명의 방법에 의해 합성된 자기조합형 세리신 나노입자의 전자현미경 사진.1 is an electron micrograph of the self-assembled sericin nanoparticles synthesized by the method of the present invention.
상기, 본 발명의 목적은 선별된 누에고치로부터 추출된 세리신 또는 효소처리하여 조절된 분자량을 가지는 세리신 수용액에 활성화된 폴리에틸렌글리콜(actPEGn)을 일정량 첨가한 후 반응시켜 투석막을 사용하여 미반응물질을 제거 시킨 다음 동결건조를 통해 세리신-PEG 결합체를 제조하는 것을 특징으로 하는 제조법에 의해 달성된다.The object of the present invention is to remove unreacted substances using a dialysis membrane by adding a predetermined amount of activated polyethylene glycol (actPEGn) to a sericin solution having a molecular weight controlled by enzymatic treatment or sericin extracted from the selected cocoon. And lyophilization to achieve a sericin-PEG conjugate.
actPEGn은 그 한가지 일반식으로서actPEGn is one general formula
로 표시되며, 여기서 R1과R2은 각각 CH3O(CH2-CH2-O)n-과 CH3O(CH2-CH2-O)n-(actPEG1) 또는 CH3O(CH2-CH2-O)n-과 Cl(actPEG2)이며 분자량 범위는 1,000-40,000 이 사용될수 있다.Wherein R 1 and R 2 are each CH 3 O (CH 2 -CH 2 -O) n- and CH 3 O (CH 2 -CH 2 -O) n- (actPEG1) or CH 3 O (CH 2 -CH 2 -O) n- and Cl (actPEG2) and a molecular weight range of 1,000-40,000 can be used.
또 다른 actPEGn 으로서 다음과 같은 일반식을 가지는 활성화된 PEG가 사용될수 있고,As another actPEGn, activated PEG having the general formula
R3-O-CH2CH2NH2 R 3 -O-CH 2 CH 2 NH 2
R4-OSO2-CH2CF3 R 4 -OSO 2 -CH 2 CF 3
여기서, R1은 eO-PEG-OCH2CH2-(actPEG3), MeO-PEG-OCH2CH2CH2-(actPEG4), MeO-PEG-O2CNH(CH2)5-(actPEG5), MeO-PEG-S-CH2CH2-(actPEG6), MeO-PEG-NHCOCH2CH2-(actPEG7), MeO-O2(CH2)3-(actPEG8), MeO-PEG-O2CCH2CH2-(actPEG9), MeO-PEG-O-(actPEG10), MeO-PEG-OCH2-(actPEG11)이고 분자량 범위는 1,000-40,000 이 사용될수 있다. R2, R3, R4는 MeO-PEG- (각각 actPEG12, actPEG13, actPEG14)이며 분자량범위는 1,000-40,000이 사용될수 있다.Wherein R 1 is eO-PEG-OCH 2 CH 2- (actPEG3), MeO-PEG-OCH 2 CH 2 CH 2- (actPEG4), MeO-PEG-O 2 CNH (CH 2 ) 5- (actPEG5), MeO-PEG-S-CH 2 CH 2- (actPEG6), MeO-PEG-NHCOCH 2 CH 2- (actPEG7), MeO-O 2 (CH 2 ) 3- (actPEG8), MeO-PEG-O 2 CCH 2 CH 2- (actPEG9), MeO-PEG-O- (actPEG10), MeO-PEG-OCH 2- (actPEG11) and a molecular weight range of 1,000-40,000 can be used. R 2 , R 3 and R 4 are MeO-PEG- (actPEG12, actPEG13, actPEG14, respectively) and the molecular weight range is 1,000-40,000.
활성화된 폴리에틸렌글리콜의 양은 세리신의 양에 대해 무게백분율로 10-20배 사용할수 있다.The amount of activated polyethylene glycol can be used 10-20 times in weight percentage relative to the amount of sericin.
사용되는 세리신은, 예를 들어 40-120℃ 범위의, 열수에서 추출된 세리신또는 효소처리되어 분자량이 조절된 세리신(분자량범위 1,000-20,000)이 사용될수 있다.The sericin used may be, for example, a sericin extracted from hot water or an enzyme-treated sericin (molecular weight range 1,000-20,000) in the range of 40-120 ° C.
수용액으로서는 pH 8-10사이의 완충 수용액을 사용할수 있고 완충 수용액으로서 붕산염 완충액, 트리스 완충액, AMPSO(3-[(1,1-디메틸-2-히드록시에틸)아미노]-2-히드록시프로판술폰산) 완충액, CHES(2-[N-시클로헥실아미노]에탄술폰산) 완충액, CAPSO(3-[시클로헥실아미노]-2-히드록시-1-프로판술폰산) 완충액, AMP(2-아미노-2-메틸-1-프로판올) 완충액, CAPS(3-[시클로헥실아미노]-1-프로판술폰산) 완충액을 사용할수 있다.As an aqueous solution, a buffered aqueous solution of pH 8-10 can be used, and as a buffered aqueous solution, borate buffer, Tris buffer, AMPSO (3-[(1,1-dimethyl-2-hydroxyethyl) amino] -2-hydroxypropanesulfonic acid ) Buffer, CHES (2- [N-cyclohexylamino] ethanesulfonic acid) buffer, CAPSO (3- [cyclohexylamino] -2-hydroxy-1-propanesulfonic acid) buffer, AMP (2-amino-2-methyl -1-propanol) buffer, CAPS (3- [cyclohexylamino] -1-propanesulfonic acid) buffer can be used.
반응온도는 4-40℃, 그리고 반응시간은 3-36시간이 바람직하다.The reaction temperature is 4-40 ° C., and the reaction time is preferably 3-36 hours.
본 발명을 하기 실시예에 의해 자세히 설명한다. 하기 실시예는 단지 본 발명을 설명하기 위한 것이며 본 특허의 내용이 실시예에 국한되는 것은 아니다.The invention is illustrated in detail by the following examples. The following examples are merely to illustrate the present invention and the contents of the patent are not limited to the examples.
실시예 1Example 1
pH 9.4 의 붕산염 완충액 12ml에 12mg의 세리신(분자량 7,000)을 용해 시킨 후 actPEG1(MW 1,000)을 27mg 첨가 하였다. 4℃에서 24시간 반응시킨 다음 동결건조 후 에탄올에 녹여 증류수에서 투석막을 사용하여 24시간 투석 시켰다. 투석액을 동결건조하여 25mg의 세리신-PEG 결합체(Sericin-PEG1)를 얻었다. 수율 64%.12 mg of sericin (molecular weight 7,000) was dissolved in 12 ml of borate buffer at pH 9.4, and 27 mg of actPEG1 (MW 1,000) was added. After reacting for 24 hours at 4 ℃ and lyophilized, dissolved in ethanol and dialyzed for 24 hours using a dialysis membrane in distilled water. The dialysate was lyophilized to obtain 25 mg of sericin-PEG conjugate (Sericin-PEG1). Yield 64%.
실시예 2-4Example 2-4
actPEG1의 분자량이 각각 5,000, 10,000, 20,000인 actPEG1를 사용하고 실시예 1과 동일한 방법으로 합성하여 그 결과를 표 1에 기재하였다.ActPEG1 having a molecular weight of 5,000, 10,000, and 20,000 of actPEG1 was synthesized in the same manner as in Example 1, and the results are shown in Table 1.
표 1Table 1
실시예 actPEG1의 분자량 actPEG1의 양(mg) 수율(%)Example Molecular weight of actPEG1 Amount (mg) Yield (%) of actPEG1
2 5,000 135 602 5,000 135 60
3 10,000 270 683 10,000 270 68
4 20,000 540 704 20,000 540 70
실시예 5Example 5
pH 9.4의 붕산염 완충액 12ml에 24mg의 세리신을 용해 시킨 후 actPEG2, (MW 2,000)을 54mg 첨가 하였다. 4℃에서 24시간 반응시킨 다음 동결건조 후 에탄올에 녹여 증류수에서 투석막을 사용하여 24시간 투석 시켰다. 투석액을 동결건조하여 51mg 의 세리신-PEG 결합체를 얻었다. 수율 65%.After dissolving 24 mg of sericin in 12 ml of borate buffer at pH 9.4, 54 mg of actPEG2, (MW 2,000) was added. After reacting for 24 hours at 4 ℃ and lyophilized, dissolved in ethanol and dialyzed for 24 hours using a dialysis membrane in distilled water. The dialysate was lyophilized to obtain 51 mg of sericin-PEG conjugate. Yield 65%.
실시예 6-8Example 6-8
actPEG2의 분자량이 각각 10,000, 20,000, 40,000인 actPEG2를 사용하고 실시예 5와 동일한 방법으로 합성하여 그 결과를 표 2에 기재하였다.ActPEG2 having a molecular weight of 10,000, 20,000, and 40,000 of actPEG2 was synthesized in the same manner as in Example 5, and the results are shown in Table 2.
표 2TABLE 2
실시예 actPEG1의 분자량 actPEG1의 양(mg) 수율(%)Example Molecular weight of actPEG1 Amount (mg) Yield (%) of actPEG1
6 10,000 270 636 10,000 270 63
7 20,000 540 687 20,000 540 68
8 40,000 1080 848 40,000 1080 84
실시예 9-17Example 9-17
분자량이 5,000인 actPEG3 , actPEG4 , actPEG5 , actPEG6 ,actPEG7 , actPEG8 , actPEG9 , actPEG10 , actPEG11 사용하고 그 양은 모두 135mg을 사용하였으며 실시예 5와 동일한 방법으로 합성하여 그 결과를 표 3에 기재한다.ActPEG3, actPEG4, actPEG5, actPEG6, actPEG7, actPEG8, actPEG9, actPEG10, and actPEG11 having a molecular weight of 5,000 were used and the amounts were all 135 mg. The results were synthesized in the same manner as in Example 5, and the results are shown in Table 3.
표 3TABLE 3
실시예 actPEGn의 종류 수율(%)Example Type yield of actPEGn (%)
9 n=3 639 n = 3 63
10 n=4 6810 n = 4 68
11 n=5 5811 n = 5 58
12 n=6 7312 n = 6 73
13 n=7 6513 n = 7 65
14 n=8 6514 n = 8 65
15 n=9 5515 n = 9 55
16 n=10 6016 n = 10 60
17 n=11 8117 n = 11 81
실험예 1Experimental Example 1
상기 세리신-PEG 결합체들에 대하여 레이저 광산란법에 의해 입자의 크기를 측정하였으며 그 결과를 하기 표 3에 나타내었고 실시예 2에서 합성된 나노입자의 전자현미경 사진을 도 1 에 나타내었다.The particle size of the sericin-PEG conjugates was measured by laser light scattering, and the results are shown in Table 3 below, and electron micrographs of the nanoparticles synthesized in Example 2 are shown in FIG. 1.
표 3TABLE 3
실시예 particle size(nm)Example particle size (nm)
1 1821 182
2 2042 204
3 2233 223
4 1984 198
5 3525 352
6 2066 206
7 2947 294
8 2878 287
9 1229 122
10 24510 245
11 23311 233
12 43512 435
13 11013 110
14 26714 267
15 29015 290
16 35516 355
17 37817 378
상기에서 알 수 있는 바와 같이, 본 발명에 의해 양친매성 성질을 가지고 있는 합성고분자인 폴리에틸렌글리콜(PEG)을 세리신에 반응시켜 세리신-PEG 결합체를 합성한 후 유기용매에 녹여 투석방법에 의해 기능성화장품 및 의약전달용으로 응용이 가능한 자기조합형 나노입자(self-assembled nanoparticle)의 제조가 가능하게 되었다.As can be seen from the above, by synthesizing the sericin-PEG conjugate by reacting polyethylene glycol (PEG), a synthetic polymer having amphiphilic properties with sericin according to the present invention, it is dissolved in an organic solvent and functional cosmetics by dialysis method It is now possible to manufacture self-assembled nanoparticles that can be used for drug delivery.
또한, 본 발명에서는 독성이 없고 수용해도가 우수한 폴리에틸렌글리콜(PEG)을 세리신의 수산기나 아미노기에 결합시킴으로써 세리신의 수용해도 및 안정성을높여 주름개선제 및 보습제로 이용하기에 적당한 세리신- PEG 결합체를 제공할 수 있게 되었다.In addition, the present invention provides a sericin-PEG conjugate which is suitable for use as an anti-wrinkle and moisturizing agent by increasing the solubility and stability of sericin by binding polyethylene glycol (PEG) having no toxicity and excellent water solubility to hydroxyl or amino groups of sericin. It became possible.
Claims (8)
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| KR100509717B1 (en) * | 2002-07-31 | 2005-08-23 | 재단법인서울대학교산학협력재단 | Anti-wrinkle cosmetic compositions |
| EP2442786A1 (en) * | 2009-06-15 | 2012-04-25 | Chemyunion Química Ltda | Sericin cationic nanoparticles for application in products for hair and dyed hair |
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| JPS6157228A (en) * | 1984-08-28 | 1986-03-24 | Kanebo Ltd | Preparation of proteinaceous emulsifier |
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| JPS6157228A (en) * | 1984-08-28 | 1986-03-24 | Kanebo Ltd | Preparation of proteinaceous emulsifier |
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| Title |
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| Int. J. Indust. Entomol, Hae Yong Kweon et al., 2001, 3(1), p.1-6 * |
| J Appl Polym Sci, HY KWEON et al., 2001, 80, 1848-1853 * |
| J.Biomed Mater Res., Peracchia MT et al., 1997, 34(3), p.317-326 * |
| macromer[Int J Pharm., Kim IS et al., 2000, 205(1-2),p.109-116 * |
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