KR102083023B1 - Method for preparing surface functionalized drug transportable eluted microspheres - Google Patents
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Abstract
본 발명은 표면 기능화된 약물 운반 가능한 용출 마이크로스피어의 제조 방법을 개시하며, 생물 의약 재료 분야에 관한 것으로, 상기 제조 방법은 이하 단계를 포함한다: (1) 카르복시 메틸 키토산을 원료로, 폴리에틸렌 글리콜 디글리시딜 에테르를 가교 결합제로 사용해, 역상 마이크로 부유 가교 결합 방법을 통해 입경이 주로 300~400μm에 분포되어 있는 가교 결합된 카르복시 메틸 키토산 마이크로스피어를 제조해내는 단계; (2) 제조해낸 건조 가교 결합된 카르복시 메틸 키토산 마이크로스피어를 2-아크릴아미드-2-메틸 프로필 술폰산 수용액에 담근 후, 질산세륨 암모늄을 기폭제로 사용해 2-아크릴아미드-2-메틸 프로필 술폰산을 마이크로스피어의 표면에 접목 중합 시켜, 마이크로스피어가 변성되는 단계. 상기 마이크로스피어의 표면은 접목 중합에 의해 변성되므로 대량의 술폰산 그룹을 지니게 되어, 염산 아드리아마이신과 같이 양전하를 지니고 있는 약물을 효과적으로 부하할 수 있어, 용출 마이크로스피어를 제조하는 데 사용될 가능성이 있다.The present invention discloses a process for the preparation of surface functionalized drug transportable eluting microspheres, which relates to the field of biopharmaceutical materials, comprising the following steps: (1) Polyethylene glycol di, based on carboxy methyl chitosan; Using a glycidyl ether as a crosslinking agent to prepare a crosslinked carboxymethyl chitosan microsphere having a particle size distributed mainly at 300 to 400 μm through a reversed phase microfloating crosslinking method; (2) The resulting dried cross-linked carboxy methyl chitosan microspheres were immersed in a 2-acrylamide-2-methyl propyl sulfonic acid aqueous solution, and then 2-acrylamide-2-methyl propyl sulfonic acid was microspheres using cerium ammonium nitrate as an initiator. Graft polymerization on the surface of the microspheres. Since the surface of the microspheres is modified by grafting polymerization, it has a large amount of sulfonic acid groups, so that it can effectively load a positively charged drug such as adriamycin hydrochloride, which may be used to prepare an eluted microsphere.
Description
본 발명은 생물학적으로 분해 가능한 약물 운반체의 제조 방법에 관한 것이며, 생물 의약 분야에 관한 것으로, 보다 상세하게는 표면 기능화된 운반 가능한 약물 용출 마이크로스피어의 제조 방법에 관한 것이다.FIELD OF THE INVENTION The present invention relates to methods of making biologically degradable drug carriers, and to the field of biopharmaceuticals, and more particularly to methods of making surface functionalized transportable drug-eluting microspheres.
원발성 간암은 흔한 악성 종양으로서 발병률과 사망률이 모두 높으며, 전 세계적으로 간암의 발병률은 해마다 상승하는 추세를 보이고 있다. 중국은 전 세계에서 간암 발병률이 가장 높고 질병 사망자가 가장 많은 국가로, 간암의 발병률은 사망률이 위암, 폐암에 버금가는 3대 악성 종양이 되었다. 이 병은 사람들의 건강을 심각하게 위협한다. 일반적인 종양 치료 방법은 절제 수술이지만, 중기나 말기의 종양 환자에게는 개입 요법(ranscatheter arterial chemoembolization, TACE)이 이상적인 치료 방법이다. 개입 치료란 도관을 통한 동맥 화학 요법 색전 수술로서, 도관을 통해 약물이 함유된 마이크로스피어를 표적 조직으로 수송하고, 종양의 혈액 공급 동맥을 차단한 후 천천히 약물을 방출해, 화학 요법 약물의 국부 농도를 높이고 전신 독 부작용을 감소시키는 치료를 말한다. 일련의 임상 분석 결과에 따르면, TACE는 종양의 성장을 효과적으로 제어하고 환자의 생존 기간을 연장할 수 있는 것으로 나타났다. 절제 수술을 받을 수 없는 중기나 말기의 간암 환자에게 TACE는 우선적으로 선택되는 비수술 치료 방법이다.Primary liver cancer is a common malignant tumor with a high incidence and mortality rate, and the incidence of liver cancer is increasing year by year. China has the highest incidence of liver cancer and the highest number of disease deaths in the world. The incidence of liver cancer has become one of the three malignant tumors with mortality comparable to stomach and lung cancer. This disease seriously threatens people's health. A common method of tumor treatment is resection, but interventional therapy (TACE) is an ideal treatment option for patients with medium or late tumors. Interventional therapy is an arterial chemotherapy embolization via a catheter, which transports drug-containing microspheres to the target tissue through the catheter, blocks the tumor's blood supply artery, and then slowly releases the drug to produce a local concentration of the chemotherapy drug. Refers to treatments that increase and reduce systemic poison side effects. A series of clinical analyzes show that TACE can effectively control tumor growth and prolong patient survival. TACE is the preferred non-surgical treatment option for patients with mid- or late-stage liver cancer that cannot undergo resection.
카르복시 메틸 키토산(CCN)은 키토산 유도체로서, 출처가 광범위하고 수용성이 우수하며 항균성이 강한 장점을 지닌 수용성 고분자이다. 생물 수용성이 양호하고 세포 독성이 없기 때문에 화장품, 식품, 의약 등의 업계에서 광범위하게 사용되며, 특히 생물 의약 재료 방면에서 약물 운반체로 주목받고 있다. 카르복시 메틸 키토산을 원료로 하여 약물 운반 색전 마이크로스피어를 제조하는 방법은 이미 일부 보도된 적이 있으나, 현재 카르복시 메틸 키토산을 이용해 약물 운반 마이크로스피어를 제조하는 방법은 여전히 결점이 있다. 첫 번째로, 사용되는 가교 결합제가 글루타르알데히드와 같이 세포에 해독을 끼치거나, 제니핀과 같이 출처가 협소하고 가격이 비싸다. 두 번째로, 적절한 약물 운반 그룹이 부족하다. 카르복시 메틸 키토산 내의 카르복실기는 약한 이온 그룹으로, 양전하 약물과의 작용력이 강하지 않아 약물 부하율이 매우 낮고 반응 속도가 느리다.Carboxymethyl chitosan (CCN) is a chitosan derivative, a water-soluble polymer with a wide range of sources, excellent water solubility and strong antibacterial properties. It is widely used in the industry of cosmetics, food, medicine, etc. because of its good bioavailability and lack of cytotoxicity, and in particular, it is attracting attention as a drug carrier in the area of biopharmaceutical materials. Although some methods of preparing drug-carrying embolism microspheres using carboxymethyl chitosan as a raw material have already been reported, methods of preparing drug-carrying microspheres using carboxy methyl chitosan are still disadvantageous. Firstly, the crosslinkers used are detoxifying cells such as glutaraldehyde, or are of narrow origin and expensive, such as jennypin. Second, there is a lack of adequate drug delivery groups. The carboxyl groups in the carboxymethyl chitosan are weak ionic groups, which do not have strong action with positively charged drugs, resulting in very low drug loading rates and slow reaction rates.
표면 기능화된 약물 운반 가능한 용출 마이크로스피어는 개입 요법을 통해 종양 조직 주변의 동맥 혈관 안으로 유도되는데, 종양 조직에 대한 영양 공급을 차단할 뿐만 아니라 항종양 약물을 방출해, 종양 조직에서 항암 약물의 농도가 높아짐에 따라 종양의 성장을 억제하는 작용을 한다. 카르복시 메틸 키토산 마이크로스피어는 체내에서 분해 될 수 있으며, 인체 대사를 따라 체외로 배출된다.Surface-functionalized drug-deliverable elution microspheres are guided into arterial vessels around tumor tissue through interventional therapy, which not only blocks the nutritional supply of tumor tissue, but also releases anti-tumor drugs, resulting in higher levels of anticancer drugs in tumor tissue. As a function of inhibiting the growth of tumors. Carboxymethyl chitosan microspheres can be broken down in the body and are released into the body following human metabolism.
의료용 재료로서의 인체에 대한 안전성은 매우 중요하다. 따라서, 본 작업은 카르복시 메틸 키토산 색전 마이크로스피어를 합성할 때 신형 "친환경" 계면 활성제인 알킬 글리코시드(약칭: APG0810)를 사용했다. 알킬 글리코시드는 천연 지방알코올과 포도당으로 합성되어 높은 표면 활성, 우수한 생태 안전성 및 호환성을 지니며, 국제적으로 인정받은 "친환경" 기능성 계면 활성제이다.Safety for the human body as a medical material is very important. Thus, this work used a new "green" surfactant, alkyl glycoside (abbreviated: APG0810) when synthesizing carboxy methyl chitosan embolic microspheres. Alkyl glycosides are synthesized from natural fatty alcohols and glucose with high surface activity, good ecological safety and compatibility, and are internationally recognized "green" functional surfactants.
현재의 용출 마이크로스피어의 제조 및 그 성능의 결점에 대해, 본 특허는 표면 기능화된 약물 운반 가능한 용출 마이크로스피어를 합성했다. 우선, 카르복시 메틸 키토산 마이크로스피어를 제조한 후, 건조된 마이크로스피어를 2-아크릴아미드-2-메틸 프로필 술폰산(AMPS) 수용액에 넣고, 세륨 이온을 기폭제로 사용해 카르복시 메틸 키토산을 산화시키고 유리 라디칼을 생성한다. 나아가, 2-아크릴아미드-2-메틸 프로필 술폰산(AMPS)의 중합을 유발함으로써 마이크로스피어의 표면을 접목, 변성시켜 표면 기능화된 약물 운반이 가능한 용출 마이크로스피어를 제조한다. 2-아크릴아미드-2-메틸 프로필 술폰산 분자 내의 술폰산 기는 강한 이온 그룹으로서 친수성이 매우 강하므로, 상기 그룹을 카르복시 메틸 키토산 분자에 인입하면 약물 아드리아마이신에 대한 카르복시 메틸 키토산 마이크로스피어의 부하율을 크게 높일 수 있다. 또한, 술폰산 기를 함유하는 카르복시 메틸 키토산 마이크로스피어는 세포 독성이 없고, 생체 호환성이 좋으며, 원료 출처가 광범위하다는 장점이 있다.In view of the drawbacks of current production of eluted microspheres and their performance, the patent has synthesized surface functionalized drug transportable eluted microspheres. First, the carboxy methyl chitosan microspheres are prepared, and the dried microspheres are then added to an aqueous 2-acrylamide-2-methyl propyl sulfonic acid (AMPS) solution, and cerium ions are used as initiators to oxidize carboxy methyl chitosan and generate free radicals. do. Further, by inducing polymerization of 2-acrylamide-2-methyl propyl sulfonic acid (AMPS), the surface of the microsphere is grafted and modified to prepare an eluted microsphere capable of surface functionalized drug delivery. Since sulfonic acid groups in 2-acrylamide-2-methyl propyl sulfonic acid molecules are strong ionic groups and have very high hydrophilicity, the introduction of these groups into carboxymethyl chitosan molecules can greatly increase the loading rate of carboxymethyl chitosan microspheres against the drug adriamycin. have. In addition, carboxy methyl chitosan microspheres containing sulfonic acid groups have the advantages of no cytotoxicity, good biocompatibility, and a wide range of raw materials.
본 발명에 따른 표면 기능화된 약물 운반 가능한 용출 마이크로스피어를 제조하기 위한 기술방안은 이하 단계를 순차적으로 포함한다.Technical solutions for preparing surface functionalized drug transportable eluting microspheres according to the present invention include the following steps sequentially.
단계 1) 카르복시 메틸 키토산 마이크로스피어를 제조, 가교 결합하는 단계로서, 카르복시 메틸 키토산 수용액과 폴리에틸렌 글리콜 디글리시딜 에테르를 4wt%의 카르복시 메틸 키토산 수용액 10ml와 폴리에틸렌 글리콜 디글리시딜 에테르 1.0g의 비율로 균일하게 혼합한다. 제조 시 고분자 가교 결합제, 폴리에틸렌 글리콜 디글리시딜 에테르(PEGDE)를 사용해 카르복시 메틸 키토산 용액과 균일하게 혼합한 후, 오일 탱크 안에 떨어뜨리고 역상 마이크로 부유 방법을 통해 카르복시 메틸 키토산 마이크로스피어를 제조한다.Step 1) preparing and crosslinking the carboxy methyl chitosan microspheres, in which the ratio of the aqueous solution of carboxymethyl chitosan and aqueous polyethylene glycol diglycidyl ether of 4wt% of 10 ml of carboxymethyl chitosan aqueous solution and 1.0 g of polyethylene glycol diglycidyl ether Mix evenly. In preparation, the polymer crosslinker, polyethylene glycol diglycidyl ether (PEGDE) is used to uniformly mix with the carboxy methyl chitosan solution, which is then dropped into an oil tank to prepare a carboxy methyl chitosan microsphere via a reversed phase microsuspension method.
단계 2) 가교 결합된 카르복시 메틸 키토산 마이크로스피어를 표면 기능화하는 단계로서, 질산세륨 암모늄을 기폭제로 사용해 상기 건조된 마이크로스피어를 2-아크릴아미드-2-메틸 프로판 술폰산 수용액에 담궈, 2-아크릴아미드-2-메틸 프로필 술폰산을 마이크로스피어의 표면에 접목 중합시킨다. 반응이 끝나면, 마이크로스피어를 여러 차례 증류수로 반복 세척한 후 냉동 건조해 표면 기능화된 약물 운반 가능한 용출 마이크로스피어를 얻는다.Step 2) surface functionalizing the cross-linked carboxy methyl chitosan microspheres, wherein the dried microspheres are immersed in an aqueous 2-acrylamide-2-methyl propane sulfonic acid solution using cerium ammonium nitrate as initiator; 2-methyl propyl sulfonic acid is grafted to the surface of the microspheres. At the end of the reaction, the microspheres are washed repeatedly with distilled water several times and freeze-dried to obtain surface functionalized drug transportable eluting microspheres.
상기 단계 1)에서, 카르복시 메틸 키토산 용액의 바람직한 질량 분율은 3%~4%이고, 폴리에틸렌 글리콜 디글리시딜 에테르의 중합도는 2~8로서, 그 용량은 카르복시 메틸 키토산 중량의 1~5배이며, 혼합 용액을 자력 교반 하는 시간은 15~30분이다.In step 1), the preferred mass fraction of the carboxy methyl chitosan solution is 3% -4%, the degree of polymerization of polyethylene glycol diglycidyl ether is 2-8, the capacity is 1-5 times the weight of carboxy methyl chitosan. The time to magnetically stir the mixed solution is 15 to 30 minutes.
구체적으로, 상기 단계 1)에서 유상은 n-헵테인, n-옥탄, 파라핀유 또는 대두유이고, 유상과 수상의 체적비는 3:1~6:1이다.Specifically, in step 1), the oil phase is n-heptane, n-octane, paraffin oil or soybean oil, and the volume ratio of the oil phase and the water phase is 3: 1 to 6: 1.
구체적으로, 상기 단계 1)에서 유화제는 알킬 글리코시드(약칭: APG0810)로서, 그 용량은 유상의 0.5%~2%이다.Specifically, the emulsifier in step 1) is an alkyl glycoside (abbreviation: APG0810), the capacity is 0.5% ~ 2% of the oil phase.
구체적으로, 상기 단계 1)에서 유화제를 유상에 첨가하고 20분간 교반한 후, 카르복시 메틸 키토산과 폴리에틸렌 글리콜 디글리시딜 에테르의 혼합물을 유상에 서서히 떨어뜨리면서, 교반 속도는 200~500바퀴/분으로 조절한다.Specifically, after adding the emulsifier to the oil phase in step 1) and stirring for 20 minutes, while slowly dropping the mixture of carboxymethyl chitosan and polyethylene glycol diglycidyl ether into the oil phase, the stirring speed is 200 to 500 laps / minute Adjust
구체적으로, 상기 단계 2)에서 2-아크릴아미드-2-메틸 프로판 술폰산의 용량 농도는 0.1~1.5mol/L이다.Specifically, the dose concentration of 2-acrylamide-2-methyl propane sulfonic acid in step 2) is 0.1-1.5 mol / L.
구체적으로, 상기 단계 2)에서 기폭제는 질산세륨 암모늄으로서, 첨가량은 2-아크릴아미드-2-메틸 프로판 술폰산 중량의 0.1%~2%이며, N2의 보호를 통해 50℃의 조건 하에서 8시간 동안 반응시킨다.Specifically, the initiator in step 2) is cerium ammonium nitrate, the addition amount is 0.1% to 2% of the weight of 2-acrylamide-2-methyl propane sulfonic acid, and for 8 hours under the condition of 50 ℃ through N 2 protection React.
카르복시 메틸 키토산 분자는 -NH2그룹을 함유하고 있으며 물에서 약염기성을 띠기 때문에, 폴리에틸렌 글리콜 디글리시딜 에테르 내의 에폭시 그룹은 염기 촉매 하에서 카르복시 메틸 키토산 분자의 아미노기와 고리열림중합을 하고, 역상 마이크로 부유 중합 조건 하에서 카르복시 메틸 키토산은 가교 결합해 마이크로스피어를 형성한다. 제조된 건조 후의 마이크로스피어를 2-아크릴아미드-2-메틸 프로필 술폰산 수용액에 10시간 담근 후 질산세륨 암모늄을 넣으면, 카르복시 메틸 키토산 분자가 부분적으로 산화되어 유리 라디칼을 생성하고, 2-아크릴아미드-2-메틸 프로필 술폰산 중합을 유발해 카르복시 메틸 키토산 분자에 접목된다. 상기 원리에 따르면, 술폰산 그룹은 마이크로스피어의 표면에 효과적으로 접목될 수 있다.Since the carboxy methyl chitosan molecule contains -NH 2 group and is weakly basic in water, the epoxy group in the polyethylene glycol diglycidyl ether undergoes ring opening polymerization with the amino group of the carboxy methyl chitosan molecule under the base catalyst, Under suspended polymerization conditions, carboxy methyl chitosan crosslinks to form microspheres. After dipping the prepared microspheres in 2-acrylamide-2-methyl propyl sulfonic acid aqueous solution for 10 hours and adding cerium ammonium, the carboxymethyl chitosan molecules are partially oxidized to generate free radicals, and 2-acrylamide-2 Methyl propyl sulfonic acid polymerisation leads to carboxymethyl chitosan molecules. According to this principle, sulfonic acid groups can be effectively grafted to the surface of the microspheres.
본 발명은 또한 화학 요법 약물 운반체에서의 표면 기능화된 약물 운반 가능한 용출 마이크로스피어의 응용을 더 제공한다. 마이크로스피어 표면의 술폰산 기의 음전하와 염산 아드리아마이신 분자의 아미노기 양전하 사이의 상호 작용을 통해, 약물 부하율 및 제어 방출 성능을 향상시킨다.The present invention further provides for the application of surface functionalized drug transportable eluting microspheres in chemotherapy drug carriers. Through the interaction between the negative charge of the sulfonic acid group on the surface of the microsphere and the positive charge of the amino group of the adriamycin hydrochloride molecule, the drug loading rate and the controlled release performance are improved.
상기 방안을 통해 봤을 때, 본 발명은 적어도 이하 장점을 가지고 있다.In view of the above, the present invention has at least the following advantages.
1. 독이 없고, 가격이 저렴하며, 쉽게 얻을 수 있는 새로운 고분자 가교 결합제를 사용했다. 또한, 폴리에틸렌 글리콜 디글리시딜 에테르는 올리고머이기 때문에, 형성된 겔의 "메쉬" 공간은 글루타르 알데히드의 작은 분자에 비해 훨씬 크며, 아드리아마이신 분자가를 마이크로스피어 내부로 훨씬 쉽게 확산시킬 수 있어 마이크로스피어의 약물 운반률을 향상시킨다.1. It uses a new polymer crosslinker that is free of poison, inexpensive, and easily obtainable. In addition, because polyethylene glycol diglycidyl ether is an oligomer, the "mesh" space of the formed gel is much larger than the small molecules of glutaraldehyde, which makes it easier to diffuse the adriamycin molecule into the microspheres and thus the microspheres. Improves drug delivery rate.
2. 상기 마이크로스피어는 카르복실기와 술폰산 그룹을 함유하고 있어, 항종양 약물인 아드리아마이신과의 상호 작용을 증진시킬 수 있으므로, 약물에 대한 운반체의 부하율을 향상시킬 수 있다.2. The microspheres contain a carboxyl group and a sulfonic acid group, so that the microspheres can enhance the interaction with the antitumor drug, adriamycin, thereby improving the loading rate of the carrier on the drug.
3. 마이크로스피어를 합성할 때 신형 "친환경" 유화제인 알킬 글리코시드 APG0810을 사용했다. 알킬 글리코시드 APG0810은 표면 활성도가 높고 생태 안전성 및 상용성이 우수하며, 국제적으로 인정받은 "친환경" 기능성 계면 활성제이다. 마이크로스피어를 합성하는 유화제로 사용함으로써 제품의 안전성을 보장했다.3. A new "green" emulsifier, alkyl glycoside APG0810, was used to synthesize microspheres. Alkyl glycoside APG0810 is an internationally recognized "green" functional surfactant with high surface activity, excellent ecological safety and compatibility. The use of microspheres as an emulsifier for the synthesis ensures the safety of the product.
4. 역상 마이크로 부유 중합 방법을 통해 용출 마이크로스피어를 합성했다. 상기 방법은 방법이 간단하고 조건이 온화하며, 생성되는 부산물이 없고 반응이 안전하며, 생성물이 순수하다.4. The eluted microspheres were synthesized through a reversed phase microsuspension polymerization method. The method is simple in method, mild in condition, free of by-products, safe in reaction and pure in product.
상술한 설명은 단지 본 발명의 기술방안에 대한 약술일 뿐이다. 본 발명의 기술수단을 보다 명확하게 이해함으로써 명세서의 내용에 따라 실시할 수 있도록, 첨부 도면을 조합해 본 발명의 바람직한 실시예에 대해 아래와 같이 상세하게 설명한다.The above description is merely an outline of the technical solutions of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS Preferred embodiments of the present invention will be described in detail below in combination with the accompanying drawings so that the technical means of the present invention can be more clearly understood in accordance with the contents of the specification.
도 1은 표면 기능화된 약물 운반 가능한 용출 마이크로스피어의 합성 경로이다.
도 2는 변성 전후의 카르복시 메틸 키토산의 적외선 스펙트로그램이며, 여기에서 a는 변성 전의 카르복시 메틸 키토산 마이크로스피어이고, b는 변성 후의 카르복시 메틸 키토산 마이크로스피어이다.
도 3은 본 발명에 따른 표면 기능화된 약물 운반 가능한 용출 마이크로스피어의 초피사계 심도 현미경 사진이다.
도 4는 본 발명에 따른 마이크로스피어의 PBS(pH 7.4) 매개체에서의 누계 방출 곡선이다. a는 변성 후의 표면 기능화된 약물 운반 가능한 용출 마이크로스피어이고, b는 변성되지 않은 카르복시 메틸 키토산의 약물 운반 마이크로스피어이다.1 is a synthetic route of surface functionalized drug transportable eluting microspheres.
2 is an infrared spectrogram of carboxy methyl chitosan before and after denaturation, where a is a carboxy methyl chitosan microsphere before denaturation and b is a carboxy methyl chitosan microsphere after denaturation.
3 is a super depth-of-field micrograph of a surface functionalized drug transportable eluting microsphere according to the present invention.
4 is a cumulative emission curve in the microspheres PBS (pH 7.4) mediator according to the present invention. a is the surface functionalized drug transportable eluting microsphere after denaturation and b is the drug transport microsphere of unmodified carboxy methyl chitosan.
이하 첨부 도면 및 실시예를 조합해, 본 발명의 구체적인 실시방식에 대해 보다 상세하게 설명한다. 이하 실시예는 본 발명을 설명하는 데 이용되나, 본 발명의 범위를 한정하지는 않는다.Hereinafter, specific embodiments of the present invention will be described in detail with reference to the accompanying drawings and examples. The following examples are used to illustrate the invention, but do not limit the scope of the invention.
실시예 1Example 1
1) 카르복시 메틸 키토산 마이크로스피어의 제조:1) Preparation of Carboxy Methyl Chitosan Microspheres:
1.0g의 폴리에틸렌 글리콜 디글리시딜 에테르를 4% 농도의 카르복시 메틸 키토산 용액 10ml에 첨가하고, 일반 온도에서 20분간 자력 교반해 양자를 균일하게 혼합한다. 40ml의 n-헵테인을 250ml의 3구 플라스크에 넣고, 0.27g(유상 질량의 1%)의 유화제 APG0810을 첨가한 후 300rad/min의 회전 속도로 기계 교반한다. 유화제가 균일하게 분산되면 상기 혼합물을 n-헵테인에 서서히 떨어뜨리고, 30℃의 조건에서 유화시키는 동시에 가교 결합시켜, 24시간 동안 가교 결합 반응시키고, 반응이 끝나면, 대량의 에탄올로 에멀젼화를 파괴하고 마이크로스피어를 세척하며, 여러 차례 반복해서 세정한다. 마지막으로, 마이크로스피어를 35℃의 진공 건조기에 넣고 24시간 동안 건조시킨다. 얻어낸 마이크로스피어의 입경은 350㎛에 집중되어 있다.1.0 g of polyethylene glycol diglycidyl ether is added to 10 ml of 4% carboxy methyl chitosan solution, and magnetically stirred at normal temperature for 20 minutes to uniformly mix both. 40 ml of n-heptane are placed in a 250 ml three neck flask, 0.27 g (1% of oil phase mass) of emulsifier APG0810 is added and mechanically stirred at a rotational speed of 300 rad / min. When the emulsifier is uniformly dispersed, the mixture is slowly dropped into n-heptane, emulsified at 30 ° C. and simultaneously crosslinked, crosslinked for 24 hours, and when the reaction is finished, the emulsification is destroyed with a large amount of ethanol. The microspheres are washed and washed several times. Finally, the microspheres are placed in a vacuum dryer at 35 ° C. and dried for 24 hours. The particle diameter of the obtained microsphere is concentrated in 350 micrometers.
2) 표면 기능화된 약물 운반 가능한 용출 마이크로스피어의 제조:2) Preparation of surface functionalized drug transportable eluting microspheres:
상기 건조된 카르복시 메틸 키토산 마이크로스피어 50mg을 0.9mol/L 농도의 2-아크릴아미드-2-메틸 프로판 술폰산 수용액 10ml에 넣고, 자력으로 교반해 일반 온도에서 10시간 동안 담근 후, 0.0186g의 질산세륨 암모늄을 첨가하고 N2 보호를 통해 50℃의 조건에서 8시간 동안 반응시킨다. 반응이 끝나면, 변성된 마이크로스피어를 증류수에 여러 차례 담궈 세정한 다음, 진공 건조시켜 약물 운반 가능한 용출 마이크로스피어를 얻는다.50 mg of the dried carboxymethyl chitosan microspheres were added to 10 ml of an aqueous solution of 2-acrylamide-2-methyl propane sulfonic acid at a concentration of 0.9 mol / L, stirred by magnetic force for 10 hours, and then 0.0186 g of ammonium nitrate Was added and reacted for 8 hours at 50 ° C. through N2 protection. After the reaction, the denatured microspheres are immersed in distilled water several times, washed and then dried in vacuo to obtain an elutable microcarrier for drug transport.
실시예 2Example 2
실시예 1의 4%의 카르복시 메틸 키토산 용액을 1%의 카르복시 메틸 키토산 용액으로 변경한다. 기타 용량 및 합성 과정은 실시예 1과 동일하다.The 4% carboxy methyl chitosan solution of Example 1 is changed to 1% carboxy methyl chitosan solution. Other doses and synthesis procedures are the same as in Example 1.
실시예 3Example 3
실시예 1의 4%의 카르복시 메틸 키토산 용액을 2%의 카르복시 메틸 키토산 용액으로 변경한다. 기타 용량 및 합성 과정은 실시예 1과 동일하다.The 4% carboxy methyl chitosan solution of Example 1 is changed to 2% carboxy methyl chitosan solution. Other doses and synthesis procedures are the same as in Example 1.
실시예 4Example 4
실시예 1의 4%의 카르복시 메틸 키토산 용액을 3%의 카르복시 메틸 키토산 용액으로 변경한다. 기타 용량 및 합성 과정은 실시예 1과 동일하다.The 4% carboxy methyl chitosan solution of Example 1 is changed to 3% carboxy methyl chitosan solution. Other doses and synthesis procedures are the same as in Example 1.
실시예 5Example 5
실시예 1의 4%의 카르복시 메틸 키토산 용액을 5%의 카르복시 메틸 키토산 용액으로 변경한다. 기타 용량 및 합성 과정은 실시예 4와 동일하다.The 4% carboxy methyl chitosan solution of Example 1 is changed to 5% carboxy methyl chitosan solution. Other doses and synthesis procedures are the same as in Example 4.
실시예 6Example 6
상기 실시예1의 변성 후의 건조된 카르복시 메틸 키토산 25mg을 농도가 2mg/ml인 염산 아드리아마이신 용액 10ml에 넣는다. 실온에서 천천히 흔들면서, 자외선 분광 광도계를 사용해 서로 다른 시간대에서 483nm의 파장에 있는 아드리아마이신 용액의 농도를 측정하고, 마이크로스피어의 약물 운반률을 계산했다. 아래 공식에 따라 마이크로스피어의 약물 운반률(LR)을 계산했다.25 mg of the dried carboxymethyl chitosan after the denaturation of Example 1 was added to 10 ml of adriamycin hydrochloride solution having a concentration of 2 mg / ml. While shaking slowly at room temperature, an ultraviolet spectrophotometer was used to measure the concentration of the adriamycin solution at a wavelength of 483 nm at different times and the drug delivery rate of the microspheres was calculated. The drug delivery rate (LR) of the microspheres was calculated according to the formula below.
LR(%) = WD/WS × 100LR (%) = W D / W S × 100
여기에서, WD는 마이크로스피어 내 약물의 양(mg)이고, Where W D is the amount of drug in microspheres (mg),
WS는 투입되는 마이크로스피어의 양(mg)이다.W S is the amount of microspheres injected (mg).
계산 결과, 변성된 카르복시 메틸 키토산 마이크로스피어 약물 운반률은 37.1%로, 변성되지 않은 마이크로스피어에 비해 54.8% 증가했다.Calculations showed that the modified carboxy methyl chitosan microsphere drug delivery rate was 37.1%, an increase of 54.8% compared to unmodified microspheres.
실시예 7Example 7
건조된 변성되지 않은 카르복시 메틸 키토산 마이크로스피어와 변성된 카르복시 메틸 키토산 마이크로스피어를 각각 소량으로 취한 후, 전반사 푸리에 적외 분광계를 사용해 4000~500cm-1의 파수 범위 내에서 적외 흡수 스캐닝을 진행해 적외선 스펙트로그램을 얻었다. 도 2는 변성 전후의 카르복시 메틸 키토산 마이크로스피어의 적외선 스펙트로그램이며, 여기에서 a는 변성되지 않은 카르복시 메틸 키토산 마이크로스피어이고, b는 변성된 카르복시 메틸 키토산 마이크로스피어이다.Take small amounts of dried, unmodified carboxymethyl chitosan microspheres and denatured carboxymethyl chitosan microspheres, respectively, and perform infrared absorption scanning using a total reflection Fourier infrared spectrometer within the wave range of 4000-500 cm -1 to obtain infrared spectrogram. Got it. 2 is an infrared spectrogram of carboxy methyl chitosan microspheres before and after denaturation, where a is an unmodified carboxy methyl chitosan microsphere and b is a denatured carboxy methyl chitosan microsphere.
실시예 8Example 8
입경이 350μm인 변성된 카르복시 메틸 키토산 마이크로스피어를 선택하고, 각각 초피사계 심도 현미경으로 마이크로스피어의 형태를 관찰했다. 도 3은 본 발명에 따른 표면 기능화된 약물 운반 가능한 용출 마이크로스피어의 초피사계 심도 현미경 사진이다.Denatured carboxy methyl chitosan microspheres with a particle size of 350 μm were selected, and the shape of the microspheres was observed under a super-depth field microscope, respectively. 3 is a super depth-of-field micrograph of a surface functionalized drug transportable eluting microsphere according to the present invention.
실시예 9Example 9
입경이 350μm인 변성된 약물 운반 마이크로스피어와 변성되지 않은 약물 운반 마이크로스피어를 선택하고, 각각 25mg을 PBS(pH7.4) 완충 용액에 넣는다. 그리고 나서, 항온 수욕 발진기에 넣고 온도를 37±0.5℃로 조절한 후, 지정된 양의 상청액 5mL를 취하고, 동일한 체적의 신선한 매개체를 즉시 보충한다. 그런 다음 자외선 분광 광도계로 완충 용액 내 약물 함량을 측정하고, 3회 반복적으로 조작해 평균값을 구해, 서로 다른 시간대에서 PBS(pH7.4) 매개체 내의 누계 방출률을 계산했다.Denatured drug delivery microspheres and unmodified drug delivery microspheres with a particle size of 350 μm are selected and 25 mg each is placed in PBS (pH 7.4) buffer solution. Then, place in a constant temperature water bath oscillator, adjust the temperature to 37 ± 0.5 ℃, take 5 mL of the specified amount of supernatant, and immediately replenish the same volume of fresh medium. The drug content in the buffer solution was then measured with an ultraviolet spectrophotometer, repeated three times, and averaged to calculate the cumulative release rate in the PBS (pH7.4) media at different time points.
이상 서술은 단지 본 발명의 바람직한 실시방식일 뿐, 본 발명을 한정하기 위한 것은 아니다. 당업자는 본 발명의 기술적 사상을 벗어나지 않는 범위 내에서 약간의 개량 및 변형을 할 수 있으며, 이러한 개량 및 변형 역시 본 발명의 보호범위에 속하는 것으로 이해되어야 한다.The foregoing descriptions are merely preferred embodiments of the present invention, but are not intended to limit the present invention. Those skilled in the art may make some improvements and modifications without departing from the spirit of the present invention, and such improvements and modifications should also be understood as falling within the protection scope of the present invention.
Claims (10)
가교 결합된 카르복시 메틸 키토산 마이크로스피어를 표면 기능화하는 단계로서, 상기 건조된 마이크로스피어를 2-아크릴아미드-2-메틸 프로판 술폰산 수용액에 10시간 담궈, 질산세륨 암모늄을 기폭제로 첨가하고, N2의 보호를 통해 50℃ 승온시키고, 2-아크릴아미드-2-메틸 프로필 술폰산을 마이크로스피어의 표면에 접목 중합 시키고, 8시간 반응시켜, 반응이 끝나면, 마이크로스피어를 여러 차례 증류수로 반복 세척한 후 다시 냉동 건조해 최종적으로 표면 기능화된 약물 운반 가능한 용출 마이크로스피어를 얻는 단계 2)
상기 두 단계를 진행하는 것을 특징으로 하는 표면 기능화된 약물 운반 가능한 용출 마이크로스피어의 제조 방법.Preparation and crosslinking of the carboxymethyl chitosan microspheres, the carboxymethyl chitosan aqueous solution and polyethylene glycol diglycidyl ether are uniformly added at a ratio of 10 ml of 4wt% carboxymethyl chitosan aqueous solution and 1.0 g of polyethylene glycol diglycidyl ether. After mixing, the mixed solution is dropped into a tank containing an emulsifier and an oil, a reversed phase microfloating crosslinking method is employed, and the reaction is stirred by stirring under 30 ° C. conditions to prepare a carboxymethyl chitosan microsphere, and the obtained microsphere is obtained. Repeated washing with ethanol, distilled water several times, vacuum drying step 1);
Surface functionalization of the cross-linked carboxy methyl chitosan microspheres, wherein the dried microspheres are immersed in an aqueous 2-acrylamide-2-methyl propane sulfonic acid solution for 10 hours to add cerium ammonium nitrate as a initiator and to protect N 2 . Heated to 50 ° C., and 2-acrylamide-2-methyl propyl sulfonic acid was grafted to the surface of the microsphere and reacted for 8 hours. After the reaction was completed, the microsphere was repeatedly washed with distilled water several times and then freeze-dried again. Solution to finally obtain a surface functionalized drug transportable elution microsphere 2).
A method for producing a surface functionalized drug transportable eluted microsphere, characterized in that the two steps are carried out.
상기 단계 1)에서, 폴리에틸렌 글리콜 디글리시딜 에테르의 중합도는 2~8로서, 그 용량은 카르복시 메틸 키토산 중량의 1~5배이며, 폴리에틸렌 그리콜 디글리시딜 에테르를 카르복시 메틸 키토산 용액에 느리게 떨어뜨리고, 자력 교반하는 시간은 15~30분인 것을 특징으로 하는 표면 기능화된 약물 운반 가능한 용출 마이크로스피어의 제조 방법.The method of claim 1,
In step 1), the degree of polymerization of polyethylene glycol diglycidyl ether is 2 to 8, the capacity is 1 to 5 times the weight of carboxy methyl chitosan, and the polyethylene glycol diglycidyl ether is slowly added to the carboxy methyl chitosan solution. A method for producing a surface-functionalized drug transportable eluted microsphere, wherein the time for dropping and magnetic stirring is 15 to 30 minutes.
상기 단계 1)에서 유상을 형성하는 오일은 n-헵테인, n-옥탄, 파라핀유 또는 대두유이고, 유상과 수상의 체적비는 3:1~6:1인 것을 특징으로 하는 표면 기능화된 약물 운반 가능한 용출 마이크로스피어의 제조 방법.The method of claim 1,
The oil forming the oil phase in step 1) is n-heptane, n-octane, paraffin oil or soybean oil, and the volume ratio of the oil phase and the water phase is 3: 1 to 6: 1. Method for producing eluted microspheres.
상기 단계 1)에서 유화제는 알킬 글리코시드로서, 그 용량은 유상의 0.5%~2%인 것을 특징으로 하는 표면 기능화된 약물 운반 가능한 용출 마이크로스피어의 제조 방법.The method of claim 1,
The emulsifier in step 1) is an alkyl glycoside, the capacity of which is 0.5% to 2% of the oil phase, the method of producing a surface-functionalized drug transportable elution microsphere.
상기 단계 1)에서 유화제를 유상을 형성하는 오일에 첨가하고 20분간 교반한 후, 카르복시 메틸 키토산과 폴리에틸렌 글리콜 디글리시딜 에테르의 혼합물을 유상에 서서히 떨어뜨리면서, 교반 속도는 200~500바퀴/분으로 조절하는 것을 특징으로 하는 표면 기능화된 약물 운반 가능한 용출 마이크로스피어의 제조 방법.The method of claim 1,
Was added to five days to form the oil phase to emulsifier in the above step 1) and tteurimyeonseo gradually dropped a mixture of The mixture was stirred for 20 minutes, carboxymethyl chitosan, and polyethylene glycol diglycidyl ether to the oil phase, the stirring speed is 200-500 wheel / A method for producing a surface functionalized drug transportable eluted microsphere, characterized in that it is controlled in minutes.
상기 단계 2)에서 2-아크릴아미드-2-메틸 프로판 술폰산의 농도는 0.1~1.5mol/L인 것을 특징으로 하는 표면 기능화된 약물 운반 가능한 용출 마이크로스피어의 제조 방법.The method of claim 1,
The concentration of 2-acrylamide-2-methyl propane sulfonic acid in step 2) is 0.1 ~ 1.5mol / L method of producing a surface-functionalized drug transportable eluting microspheres.
상기 단계 2)에서 기폭제는 질산세륨 암모늄으로서, 첨가량은 2-아크릴아미드-2-메틸 프로판 술폰산 중량의 0.1%~2%인 것을 특징으로 하는 표면 기능화된 약물 운반 가능한 용출 마이크로스피어의 제조 방법.The method of claim 1,
The initiator in step 2) is cerium ammonium nitrate, the addition amount is 0.1% ~ 2% of the weight of 2-acrylamide-2-methyl propane sulfonic acid, characterized in that the method of producing a drug-deliverable microsphere surface-elutable.
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| CN102462664A (en) * | 2010-11-18 | 2012-05-23 | 华侨大学 | Sulfonyl sulfhydryl chitosan interventional chemoembolization slow-release microsphere and preparation method thereof |
| CN103304417B (en) * | 2012-03-15 | 2014-12-24 | 江南大学 | Preparation method and application of amphiphatic copolymer modified chitosan compound |
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| CN105273209B (en) * | 2014-06-09 | 2018-05-22 | 南京顺昌医药科技有限公司 | A kind of preparation of modification of chitosan and poly- (2- acrylamide-2-methyl propane sulfonics) complex microsphere |
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| CN104258474B (en) * | 2014-10-15 | 2015-09-23 | 江南大学 | A kind of embolism microball containing ion exchanging function group and preparation method thereof |
| CN104338185B (en) * | 2014-11-06 | 2019-04-05 | 石家庄亿生堂医用品有限公司 | A kind of carboxymethyl chitosan microsphere suppository and preparation method thereof |
| CN104474575B (en) * | 2014-12-03 | 2017-06-30 | 广州肽莱医药科技有限公司 | Shitosan hemostatic material that covalent cross-linking is formed and preparation method thereof |
| CN104548123B (en) * | 2014-12-11 | 2017-10-10 | 江南大学 | A kind of preparation of acylation modification Gelatin embolism microsphere |
| CN107321326A (en) * | 2017-07-03 | 2017-11-07 | 重庆大学 | Anionic polymer grafting chitosan magnetic composite microsphere and preparation method and application |
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| CN102784112A (en) | 2011-05-19 | 2012-11-21 | 东华理工大学 | Preparation method for porous slow-release microsphere of chitosan graft copolymer |
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