KR101430293B1 - Composition for treating or preventing osteoporosis comprising platinum nanoparticle - Google Patents
Composition for treating or preventing osteoporosis comprising platinum nanoparticle Download PDFInfo
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- KR101430293B1 KR101430293B1 KR1020110108928A KR20110108928A KR101430293B1 KR 101430293 B1 KR101430293 B1 KR 101430293B1 KR 1020110108928 A KR1020110108928 A KR 1020110108928A KR 20110108928 A KR20110108928 A KR 20110108928A KR 101430293 B1 KR101430293 B1 KR 101430293B1
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- Prior art keywords
- platinum nanoparticles
- osteoporosis
- platinum
- bone
- treating
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Abstract
본 발명은 백금 나노입자를 유효성분으로 포함하는 골다공증 치료 또는 예방용 조성물에 관한 것으로, 보다 상세하게는 상기 백금 나노입자는 파골세포형성을 억제하여 골다공증 특히, 폐경 후 골다공증의 치료 또는 예방에 매우 유용하게 사용될 수 있다. The present invention relates to a composition for treating or preventing osteoporosis comprising platinum nanoparticles as an effective ingredient. More particularly, the platinum nanoparticles inhibit osteoclast formation and are useful for the treatment or prevention of osteoporosis, particularly postmenopausal osteoporosis Lt; / RTI >
Description
본 발명은 백금 나노입자를 유효성분으로 포함하는 골다공증 특히, 폐경 후 골다공증 치료 또는 예방용 조성물에 관한 것이다. The present invention relates to a composition for treating or preventing osteoporosis, particularly postmenopausal osteoporosis, comprising platinum nanoparticles as an active ingredient.
뼈는 동적 조직의 하나로서 노화된 뼈는 제거되며, 뼈 재형성(bone remodeling)을 통해 새로운 조직으로 된다. 생리학적 뼈 재형성은 뼈 형성 및 뼈 재흡수의 균형적인 작용에 의해 일어난다. 에스트로겐 결핍은 뼈 재형성을 촉진시켜 재형성 공간이 확대하고 망상 표면 상의 피상골 유공성과 재흡수 면적을 증가시키며, 에스트로겐의 주요 작용은 파골세포형성을 감소시킨다. Bone is one of the dynamic tissues, the aged bone is removed, and bone tissue is remodeled to form a new tissue. Physiological bone remodeling is caused by a balanced action of bone formation and bone resorption. Estrogen deficiency promotes bone reshaping, enlarging the remodeling space, increasing the osseointegration and reabsorption area on the reticular surface, and estrogen's main function is to reduce osteoclast formation.
뼈 재흡수를 위해 필수적인 파골세포(OC)는 단핵구/대식세포 계통의 조혈세포로부터 유래하며, 대식세포와 유사한 형상적 및 기능적 특성을 공유한다. 파골세포형성을 위한 2가지 필수 분자로서 종양괴사인자(TNF) 패밀리 중 하나인 대식세포증식자극인자(M-CSF) 및 핵인자 kB 리간드의 수용체 활성화제(RANKL)가 필요한데, 이러한 분자들은 골수 중간엽줄기세포로부터 생성된다. RANKL은 수용체 결합을 통해 RANK가 활성산소종(ROS)의 생성을 포함한 분화 및 활성화된 T 세포2의 핵인자(NFAT2)의 유도에 필요한 신호경로를 자극하고 활성화하여 OC 분화에 대한 신호를 개시하게 된다. 활성화된 전사인자는 주석산염 저항성 알칼리성 포스파타제(tartarate resistant alkaline phosphatase, TRAP) 및 칼시토닌 수용체를 포함한 표적 유전자의 발현을 초래한다.Osteoclasts (OCs) essential for bone resorption are derived from monocyte / macrophage lineage hematopoietic cells and share similar morphological and functional characteristics as macrophages. One of the two essential molecules for osteoclast formation is the macrophage proliferative factor (M-CSF), a member of the tumor necrosis factor (TNF) family, and the receptor activator of the nuclear factor kB ligand (RANKL) Lt; / RTI > stem cells. RANKL initiates signaling for OC differentiation by stimulating and activating the signaling pathways necessary for the induction of nuclear factor (NFAT2) in differentiated and activated T cells 2, including the production of reactive oxygen species (ROS), through receptor binding do. Activated transcription factors result in the expression of target genes, including tartrate-resistant alkaline phosphatase (TRAP) and calcitonin receptors.
ROS는 RANKL/RANK 상호작용의 신호경로에 관여한다고 알려져 있다. RANKL 자극은 OC 세포에서 ROS를 형성시키며, 이는 NADPH 산화효소를 발현시킨다. OC 분화 및 뼈 재흡수에서의 ROS의 역할로 인하여 골 소실을 방어하기 위하여 항산화제가 치료적으로 응용되어 왔다. 인간에 대한 연구를 통해 골다공증 환자에서 낮은 수준의 항산화제가 나타남을 확인하였으며, N-아세틸시스테인(NAC)과 같은 항산화제는 폐경기후 여성에서 골 소실을 감소시킨다고 보고되어 있다. 동물 모델에서, 난소절제술(OVX)은 산화적 스트레스를 유발하여 골 소실을 초래하며, NAC 및 비타민C는 마우스에서 OVX-유도 골 소실을 유도한다고 보고되어 있다.ROS is known to be involved in the signal path of the RANKL / RANK interaction. RANKL stimulation forms ROS in OC cells, which express NADPH oxidase. Because of the role of ROS in OC differentiation and bone resorption, antioxidants have been applied therapeutically to prevent bone loss. Studies in humans have shown low levels of antioxidants in osteoporosis patients and antioxidants such as N-acetylcysteine (NAC) have been reported to reduce bone loss in postmenopausal women. In animal models, ovariectomy (OVX) induces oxidative stress leading to bone loss, and NAC and vitamin C are reported to induce OVX-induced bone loss in mice.
한편, 지금까지 여러 물질이 골다공증 치료제로 개발되었으며, 그 중 골다공증 치료제로 가장 많이 사용되는 에스트로겐은 그 실제적인 효능이 아직 검증되지 않은 상태이며 생애 동안 계속 복용해야 하는 단점이 있으며, 장기간 투여하는 경우 유방암이나 자궁암이 증가하는 부작용이 있다. 알렌드로네이트(alrendronate)도 그 효능이 명확하지 않고 소화관에서의 흡수가 더디며 위장과 식도점막에 염증을 유발하는 문제가 있다. 칼슘제제는 부작용이 적으면서도 효과가 우수한 것으로 알려져 있지만 치료제라기보다는 예방제에 해당한다. 그 외에 칼시토닌과 같은 비타민 D 제제가 알려져 있으나 아직 효능 및 부작용에 대한 연구가 충분히 되어있지 않은 상태이다. 그러므로, 부작용이 적고 효과가 우수한 새로운 골다공증 치료제가 요구되는 실정이다.Meanwhile, various substances have been developed to treat osteoporosis. Among them, estrogen, which is most used as a treatment for osteoporosis, has not yet been proven its practical efficacy and has a disadvantage that it should be continuously taken during life, And uterine cancer. Alrendronate is also less effective, has less absorption in the digestive tract, and causes inflammation in the stomach and esophageal mucosa. Calcium preparations are known to have good efficacy with fewer side effects, but they are more preventive than treatments. In addition, vitamin D preparations such as calcitonin are known, but studies on efficacy and side effects have not yet been conducted. Therefore, there is a need for a new osteoporosis treatment agent with less side effects and excellent effects.
이에, 본 발명자들은 항산화 활성을 나타내는 물질에 대한 골다공증 치료 또는 예방 효과를 검토하던 중, 특정 제조방법으로 얻어진 백금 나노입자가 파골세포형성 억제를 통해 OVX-유도 골 소실에서 치료 또는 예방적인 효과를 가짐을 밝혀냄으로써 본 발명을 완성하였다. Accordingly, the inventors of the present invention have investigated the therapeutic or preventive effect of osteoporosis on a substance exhibiting antioxidative activity, and the platinum nanoparticles obtained by a specific manufacturing method have a therapeutic or prophylactic effect on OVX-induced bone loss through inhibition of osteoclast formation Thereby completing the present invention.
본 발명의 목적은 백금 나노입자를 유효성분으로 포함하는 골다공증 치료 또는 예방용 약학조성물을 제공하는 데에 있다.It is an object of the present invention to provide a pharmaceutical composition for treating or preventing osteoporosis comprising platinum nanoparticles as an active ingredient.
또한, 본 발명의 다른 목적은 백금 나노입자를 유효성분으로 포함하는 골다공증 개선용 건강식품을 제공하는 데에 있다.Another object of the present invention is to provide a health food for osteoporosis improvement comprising platinum nanoparticles as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 백금 나노입자를 유효성분으로 포함하는 골다공증 치료 또는 예방용 약학조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for treating or preventing osteoporosis comprising platinum nanoparticles as an active ingredient.
상기 백금 나노입자는 백금의 전기폭발을 통해 제조될 수 있다.The platinum nanoparticles can be prepared through an electrical explosion of platinum.
상기 골다공증은 폐경 후 골다공증일 수 있다.The osteoporosis may be postmenopausal osteoporosis.
상기 백금 나노입자는 파골세포형성을 억제함으로써 골다공증을 치료하거나 예방할 수 있다.The platinum nanoparticles can prevent or prevent osteoporosis by inhibiting osteoclast formation.
또한, 본 발명은 백금 나노입자를 유효성분으로 포함하는 골다공증 개선용 건강식품을 제공한다.The present invention also provides a health food for osteoporosis improvement comprising platinum nanoparticles as an active ingredient.
본 발명에 따른 백금 나노입자는 파골세포형성을 억제함으로써 골 소실을 막아 골다공증 특히, 폐경 후 골다공증의 치료 또는 예방에 매우 유용하게 사용될 수 있다.The platinum nanoparticles according to the present invention can be effectively used for the treatment or prevention of osteoporosis, especially postmenopausal osteoporosis, by inhibiting bone formation by inhibiting osteoclastogenesis.
도 1은 OVX-유도 골 소실에서의 백금 나노입자의 효과를 나타낸 것으로서, 도 1a는 X-선 방사선 촬영을 통해, 도 1b는 이미지 J 프로그램(Image J program)을 통해 분석한 것이다.
도 2는 RANKL-유도 OC 형성에 대한 백금 나노입자의 효과를 나타낸 것으로서, 도 2a는 OC의 TRAP 염색 결과를 나타낸 것이고, 도 2b는 세포당 TRAP-양성 MNC의 수를 나타낸 것이다.FIG. 1 shows the effect of platinum nanoparticles on OVX-induced bone loss. FIG. 1A is an X-ray radiograph and FIG. 1B is an image J program.
FIG. 2 shows the effect of platinum nanoparticles on RANKL-induced OC formation. FIG. 2A shows the result of TRAP staining of OC, and FIG. 2B shows the number of TRAP-positive MNCs per cell.
본 발명의 일실시예에 따르면, 백금 나노입자를 위내로 투여하면 in vivo 뼈 재흡수의 수준이 감소되며 난소절제술(OVX)-유도 골 소실을 감소시킴을 확인하였으며, 백금 나노입자는 감소된 활성산호종에 의한 RANKL 신호계의 손상된 수용체 활성화제를 통해 파골세포 형성을 억제함으로써 OVX-유도 골 소실을 완화시킴을 확인하였다.According to one embodiment of the present invention, it has been shown that platinum nanoparticles administered in the stomach reduce the levels of in vivo bone resorption and reduce ovariectomy (OVX) -induced bone loss, while platinum nanoparticles have reduced activity It was confirmed that OVX-induced bone loss is alleviated by inhibiting osteoclast formation through a damaged receptor activator of the RANKL signal system by the coral species.
첨부된 도면을 참조하여 본 발명을 보다 상세하게 설명하면 다음과 같다.The present invention will be described in detail with reference to the accompanying drawings.
도 1a 및 도 1b에 도시된 바와 같이 백금 나노입자가 투여된 마우스의 대퇴부 골밀도는 비히클-투여 마우스보다 8주 후 유의성 있게 증가하였으며, 특히 대퇴부의 원위부 골간단에서 증가하였다. 한편, sham 수술 후에는 둘 간의 어떠한 유의적인 차이가 나지 않았다. OVX는 sham 수술과 비교하여 체중을 증가시켜, sham은 6.60 ± 0.50 g이고, OVX는 12.02 ± 0.53 g이었다. As shown in FIGS. 1A and 1B, the femoral bone density of the mice treated with platinum nanoparticles was significantly increased after 8 weeks of vehicle-injected mice, particularly in the distal femoral condyle. On the other hand, there was no significant difference between the two after sham operation. OVX increased body weight compared to sham surgery, with sham 6.60 ± 0.50 g and OVX 12.02 ± 0.53 g.
따라서, 백금 나노입자는 OVX-유도성 골소실을 보호하며, 백금 나노입자의 처리는 OVX 마우스에서 체중의 상승을 감소(7.82 ± 0.45 g)시키므로 백금 나노입자에 의한 골질량의 평가는 체질량의 증가로 인한 것은 아님을 확인할 수 있었다.Thus, platinum nanoparticles protect OVX-induced bone loss and treatment of platinum nanoparticles reduces the body weight gain in OVX mice (7.82 ± 0.45 g), so the assessment of bone mass by platinum nanoparticles is an increase in body mass I can confirm that it is not caused.
도 2a 및 도 2b와 같이 백금 나노입자는 농도의존적으로 골수 대식세포(bone marrow macrophage, BMM)로부터 OC 형성을 억제한 반면, 총 세포수에는 영향을 주지 않았으므로, 백금 나노입자의 OC 형성 억제효과는 세포독성은 아님을 알 수 있었다.As shown in FIGS. 2A and 2B, the platinum nanoparticles inhibited the formation of OC from bone marrow macrophages (BMM) in a concentration-dependent manner, but did not affect the total cell number, Was not cytotoxic.
따라서, 본 발명에 따른 백금 나노입자는 파골세포 형성을 억제함으로써 OVX-유도 골 소실을 억제시켜 골다공증, 특히 폐경 후 골다공증 치료 또는 예방에 유용하게 사용될 수 있음을 확인하였다.Therefore, it has been confirmed that the platinum nanoparticles according to the present invention can inhibit OVX-induced bone loss by inhibiting osteoclast formation, and thus can be effectively used for the treatment or prevention of osteoporosis, especially postmenopausal osteoporosis.
그러므로, 본 발명은 백금 나노입자를 유효성분으로 포함하는 골다공증 치료 또는 예방용 약학조성물을 제공할 수 있다.Therefore, the present invention can provide a pharmaceutical composition for treating or preventing osteoporosis comprising platinum nanoparticles as an active ingredient.
본 명세서에서 골다공증이라 함은 뼈를 생성하는 조골세포(osteoblast) 및 뼈를 파괴하는 파골세포(osteoclast) 사이의 균형이 깨지면서 발생하는 뼈 관련 질환으로서, 원발성 골다공증, 특발성 골다공증, 폐경 후 골다공증과 노인성 골다공증 등을 모두 포함하지만, 바람직하게는 폐경 후 골다공증을 의미할 수 있다.In the present specification, osteoporosis refers to a bone-related disease caused by a balance between an osteoblast producing osteoblasts and osteoclasts destroying bones, wherein the bone-related diseases include primary osteoporosis, idiopathic osteoporosis, postmenopausal osteoporosis and senile osteoporosis Etc., but may preferably mean postmenopausal osteoporosis.
본 발명에 따른 백금 나노입자는 백금의 전기폭발을 통해 제조될 수 있으며, 보다 상세하게는 증류수에서 백금의 전기 폭발 즉, 0.1 mm 와이어에 대하여 3 kV의 하전 전압을 가해 전기 폭발시켜 분산성이 매우 우수한 백금 현탁액을 제조할 수 있다.The platinum nanoparticles according to the present invention can be produced through an electric explosion of platinum. More specifically, the electrolytic explosion of platinum in an electrolytic explosion by applying a charging voltage of 3 kV to a 0.1 mm wire in distilled water, An excellent platinum suspension can be produced.
본 발명에 따른 약학조성물은 약학적으로 허용되는 담체를 추가로 포함할 수 있다. 상기에서 "약학적으로 허용되는"이란 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증 등과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 조성물을 말한다. 약학적으로 허용되는 담체로는 예를 들면, 락토스, 전분, 셀룰로스 유도체, 마그네슘 스테아레이트, 스테아르산 등과 같은 경구 투여용 담체 및 물, 적합한 오일, 식염수, 수성 글루코스 및 글리콜 등과 같은 비경구 투여용 담체 등이 있으며 안정화제 및 보존제를 추가로 포함할 수 있다. 적합한 안정화제로는 아황산수소나트륨, 아황산나트륨 또는 아스코르 브산과 같은 항산화제가 있다. 적합한 보존제로는 벤즈알코늄 클로라이드, 메틸- 또는 프로필-파라벤 및 클로로부탄올이 있다. 그밖의 약학적으로 허용되는 담체로는 다음의 문헌에 기재되어 있는 것을 참고로 할 수 있다(Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995). The pharmaceutical composition according to the present invention may further comprise a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable" as used herein refers to a composition that is physiologically acceptable and does not normally cause an allergic reaction such as gastrointestinal disorder, dizziness, or the like when administered to humans. Pharmaceutically acceptable carriers include, for example, carriers for oral administration such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like, water for parenteral administration such as water, suitable oils, saline, aqueous glucose and glycols And may further contain stabilizers and preservatives. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Other pharmaceutically acceptable carriers can be found in Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, Pa., 1995).
본 발명에 따른 약학조성물은 상술한 바와 같은 약학적으로 허용되는 담체와 함께 당업계에 공지된 방법에 따라 적합한 형태로 제형화 될 수 있다. 즉, 본 발명의 약학조성물은 공지의 방법에 따라 다양한 비경구 또는 경구 투여용 형태로 제조될 수 있으며, 비경구 투여용 제형의 대표적인 것으로는 주사용 제형으로 등장성 수용액 또는 현탁액이 바람직하다. 주사용 제형은 적합한 분산제 또는 습윤제 및 현탁화제를 사용하여 당업계에 공지된 기술에 따라 제조할 수 있다. 예를 들면, 각 성분을 식염수 또는 완충액에 용해시켜 주사용으로 제형화될 수 있다. 또한, 경구 투여용 제형으로는, 이에 한정되지는 않으나, 분말, 과립, 정제, 환약 및 캡슐 등이 있다.The pharmaceutical composition according to the present invention, together with a pharmaceutically acceptable carrier as described above, may be formulated into a suitable form according to a method known in the art. That is, the pharmaceutical composition of the present invention can be prepared in various parenteral or oral dosage forms according to known methods, and isotonic aqueous solutions or suspensions are preferred for injection formulations typical of parenteral administration formulations. The injectable formulations may be prepared according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. For example, each component may be formulated for injection by dissolving in saline or buffer. In addition, formulations for oral administration include, but are not limited to, powders, granules, tablets, pills, and capsules.
상기와 같은 방법으로 제형화된 약학조성물은 유효량으로 경구, 경피, 위내, 피하, 피하, 정맥 또는 근육을 포함한 여러 경로를 통해 투여될 수 있으며, 상기 유효량이란 환자에게 투여하였을 때, 예방 또는 치료 효과를 나타내는 양을 의미한다. The pharmaceutical composition formulated in the above manner may be administered through various routes including oral, transdermal, intragastric, subcutaneous, subcutaneous, intravenous, or muscular, in an effective amount. The effective amount is an amount effective to prevent or treat . ≪ / RTI >
본 발명에 따른 약학조성물의 투여량은 투여 경로, 투여 대상, 연령, 성별 체중, 개인차 및 질병 상태에 따라 적절히 선택할 수 있다. 바람직하게는, 본 발명의 약학조성물은 질환의 정도에 따라 유효 성분의 함량을 달리할 수 있으나, 0.001 내지 100mg/kg으로, 바람직하게는 0.01 내지 10mg/kg을 일일 1회 내지 수회 투여할 수 있다. The dosage of the pharmaceutical composition according to the present invention can be appropriately selected depending on the route of administration, subject to be administered, age, gender, individual difference, and disease state. Preferably, the pharmaceutical composition of the present invention may be administered at a dose of 0.001 to 100 mg / kg, preferably 0.01 to 10 mg / kg, once to several times per day, although the content of the active ingredient may vary depending on the degree of the disease .
본 발명에 따른 화합물은 50% 치사량(LC50)이 5 g/kg 이상으로 안정성이 확보된 것으로서, 본 발명의 약학조성물에 사용할 수 있다. The compound according to the present invention has a stability of 5 g / kg or more at 50% lethal dose (LC 50 ) and can be used in the pharmaceutical composition of the present invention.
또한, 본 발명은 백금 나노입자를 유효성분으로 포함하는 골다공증 개선용 건강식품을 제공할 수 있다.In addition, the present invention can provide a health food for osteoporosis improvement comprising platinum nanoparticles as an active ingredient.
상기 건강식품은 분말, 과립, 정제, 캡슐, 시럽 또는 음료의 형태로 제공될 수 있으며, 상기 건강식품은 유효성분인 본 발명에 따른 화합물 이외에 다른 식품 또는 식품 첨가물과 함께 사용되고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 그의 사용 목적 예를들어 예방, 건강 또는 치료적 처치에 따라 적합하게 결정될 수 있다. The health food may be provided in the form of powder, granules, tablets, capsules, syrups or beverages. The health food may be used in combination with food or food additives other than the compound according to the present invention, which is an active ingredient, Can be suitably used. The amount of the active ingredient to be mixed can be suitably determined according to its use purpose, for example, prevention, health or therapeutic treatment.
상기 건강식품에 함유된 화합물의 유효용량은 상기 약학조성물의 유효용량에 준해서 사용할 수 있으나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있으며, 유효성분은 안전성 면에서 아무런 문제가 없기 때문에 상기 범위 이상의 양으로도 사용될 수 있음은 확실하다.The effective dose of the compound contained in the health food may be used in accordance with the effective dose of the pharmaceutical composition, but may be less than the above range for the purpose of health and hygiene or long-term intake for the purpose of health control, Since the active ingredient has no problem in terms of safety, it can be used in an amount exceeding the above range.
상기 건강식품의 종류에는 특별한 제한이 없고, 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등을 들 수 있다.
There is no particular limitation on the type of the health food, and examples thereof include meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, Drinks, alcoholic beverages and vitamin complexes.
이하, 본 발명을 하기 실시예에 의해 보다 상세하게 설명하도록 한다. 다만, 이러한 실시예에 의해 본 발명이 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the present invention is not limited by these examples.
<실시예 1> 백금 나노입자 제조≪ Example 1 > Preparation of platinum nanoparticles
백금 나노입자는 알려진 한 단계 공정(J. Kor. Powder Metal Inst., 16, 217-222, 2009)에 의해 제조하였다. 즉, 증류수에서 백금의 전기 폭발 즉, 0.1 mm 와이어에 대하여 3 kV의 하전 전압을 가하여 매우 분산성이 우수한 백금 현탁액을 제조하였다. 상기 백금 나노입자는 UV 하에서 1일 동안 멸균되었으며, 처리 전 1 내지 5%(v/v) α-MEM으로 조정하였다.Platinum nanoparticles were prepared by a known one-step process ( J. Kor. Powder Metal Inst ., 16, 217-222, 2009). That is, a platinum suspension having excellent dispersibility was prepared by applying an electric explosion of platinum in distilled water, that is, a charging voltage of 3 kV to 0.1 mm wire. The platinum nanoparticles were sterilized for one day under UV and adjusted to 1 to 5% (v / v) a-MEM before treatment.
<실험예 1> OVX-유도성 골소실 보호 효과 검토Experimental Example 1 OVX-Induced Bone Loss Protective Effect
1. 동물 및 실험 설계1. Animal and experimental design
6주령 C57BL/6J 마우스(Jackson Laboratory로부터 구매)를 울산대학교 면역조절연구센터(IRC)에서 사육하였으며, OVX(n=13)군과 대조군(n=11)으로 분류하였다. 백금 나노입자는 인산 완충 생리식염수(PBS) 용액으로 매일 준비하여 사용하였다. 수술 후, 비히클(n=12) 또는 백금 나노입자(n=12)를 각각 0.5 mL의 용량으로 식도 캐뉼라를 통해 8주 동안 매일 위내로 주입하였으며, 골밀도를 분석하였다. 모든 마우스는 IRC의 무특이병원균(SPF) 동물 설비에서 사육되었으며, IRC의 실험동물관리위원회(Institutional Animal Care and Use Committee)의 가이드라인(2010-021)에 따라 취급하였다. Six-week old C57BL / 6J mice (purchased from Jackson Laboratory) were housed at the Ulsan University Immunomodulation Research Center (IRC) and classified into OVX (n = 13) and control (n = 11). Platinum nanoparticles were prepared and used daily in phosphate buffered saline (PBS) solution. After surgery, vehicle (n = 12) or platinum nanoparticles (n = 12) were injected into the stomach daily for 8 weeks via a esophageal cannula in a volume of 0.5 mL, and bone mineral density was analyzed. All mice were housed in an IRC non-specific pathogenic bacterium (SPF) animal facility and treated according to IRC's guidelines (2010-021) of the Institutional Animal Care and Use Committee.
2. 대퇴골 골밀도 분석2. Femur bone density analysis
대퇴골의 방사선 촬영 분석은 연질 X-선 시스템(model CMB-2)을 이용하여 수행하였으며, 대퇴골의 원위부 골간단의 상대적 골밀도는 실시간 이미지 가공 및 측정 시스템을 구비한 X-선 방사선 촬영 분석(ZET-1)을 통해 측정하였다. 각각 측정의 정확도 및 정밀도는 종래 알려진 방법(J. Nutr. 139, 502-506, 2009) 에 따라 평가하였다. 이때, 각 동물로부터 대퇴골을 회수하고 10% 중성 완충 포르말린에 보관하였다. 뼈 재형성과정(Bone remodeling) 마커는 혈청 콜라겐-제I형 프레그먼트(CTX-1, by RatLaps EIA; Immunodiagnostic Systems Inc.)를 이용하여 제조자의 지시에 따라 측정하였다.Radiographic analysis of the femur was performed using a soft X-ray system (model CMB-2), and the relative bone density of the distal osteotomy of the femur was measured by X-ray radiography (ZET- 1). The accuracy and precision of each measurement was evaluated according to a known method ( J. Nutr. 139, 502-506, 2009). At this time, the femur was collected from each animal and stored in 10% neutral buffered formalin. Bone remodeling markers were measured according to the manufacturer's instructions using serum collagen-type I fragment (CTX-1, by RatLaps EIA; Immunodiagnostic Systems Inc.).
도 1a 및 도 1b와 같이 백금 나노입자를 투여한 마우스의 대퇴부 골밀도는 비히클-투여 마우스보다 8주 후 유의성 있게 증가하였으며, 특히 대퇴부의 원위부 골간단에서 증가하였다. 한편, sham 수술 후에는 둘 간의 어떠한 유의적인 차이가 나지 않았다. OVX는 sham 수술과 비교하여 체중을 증가시켰다. 즉, sham은 6.60 ± 0.50 g이고. OVX는 12.02 ± 0.53 g이었다. As shown in FIGS. 1A and 1B, the platelet bone density of the platinum nanoparticle-treated mice was significantly increased after 8 weeks of vehicle-injected mice, particularly in the distal femoral bone. On the other hand, there was no significant difference between the two after sham operation. OVX increased weight compared to sham surgery. That is, sham is 6.60 ± 0.50 g. The OVX was 12.02 ± 0.53 g.
따라서, 백금 나노입자는 OVX-유도성 골소실을 보호하며, 백금 나노입자의 처리는 OVX 마우스에서 체중의 상승을 감소(7.82 ± 0.45 g)시키므로 백금 나노입자에 의한 골질량의 평가는 체질량의 증가로 인한 것은 아님을 확인할 수 있었다.Thus, platinum nanoparticles protect OVX-induced bone loss and treatment of platinum nanoparticles reduces the body weight gain in OVX mice (7.82 ± 0.45 g), so the assessment of bone mass by platinum nanoparticles is an increase in body mass I can confirm that it is not caused.
<실험예 2> OC 형성 억제 효과 검토≪ Experimental Example 2 >
골 대사 시 백금 나노입자의 거동 형태를 규명하기 위하여, OC 전구체인 골수 대식세포(bone marrow macrophage, BMM) 상에서의 효과를 검토하였다. To investigate the morphological behavior of platinum nanoparticles during bone metabolism, we examined the effect of BM precursor on bone marrow macrophages (BMM).
즉, 종래 알려진 방법(Experimental Hematol., 35, 1100-1108, 2007)에 따라 골수세포를 4-5주령 C57BL/6J 마우스로부터 분리하였다. 대퇴골과 경골을 각각 무균적으로 회수하고, 부착성 연질 조직으로부터 절개하였다. 골단을 잘라 내고, 골수강이 멸균 21-게이지 주사를 이용하여 α-MEM(α-modified minimum essential medium)로 뼈의 일측 골단 밖으로 씻어내었다. 골수 현탁액을 파스퇴르 피펫으로 조심스럽게 휘저어 단일 세포를 얻었다. 이러한 단일 세포를 M-CSF(20 ng/ml)(R & D Systems, Inc., Minneapolis, MN, USA)와 함께 플레이트 상에 분주하여 16시간 동안 배양하였다. 그후 부착되지 않은 세포를 회수한 후, 이틀 동안 M-CSF로 추가적으로 배양하여 배양 플레이트의 바닥에 부착성 단핵구/대식세포 유사 세포의 형성을 도모하였다. 소량의 비부착성 세포는 PBS로 세정하여 제거하였으며, 남아있는 부착성 BMM을 회수하고 플레이트 상에 분주하였다. M-CSF 및 RANKL(40 ng/ml)를 함유한 배지를 첨가하고 3일째에 배지를 교체하였다. 정해진 시간 동안 배양한 후, 세포를 10% 포르말린에서 10분 동안 고정하였으며, 알려진 방법(Experimental Hematol., 35, 1100-1108, 2007)에 따라 TRAP를 위해 염색하였다. TRAP-양성 다핵 세포(MNC) 즉, 3개 이상 핵을 가진 세포의 수를 계산하였다.That is, bone marrow cells were isolated from 4-5 week-old C57BL / 6J mice according to a conventionally known method ( Experimental Hematol ., 35, 1100-1108, 2007). The femur and tibia were each aseptically recovered and incised from adherent soft tissue. The alveoli were cut and the bone marrow was washed out of one side of the bone with α-MEM (α-modified minimum essential medium) using a sterile 21-gauge injection. The bone marrow suspension was carefully shaken with a Pasteur pipette to obtain single cells. These single cells were plated on plates with M-CSF (20 ng / ml) (R & D Systems, Inc., Minneapolis, MN, USA) and cultured for 16 hours. The unattached cells were then harvested and further incubated with M-CSF for two days to form adherent monocytes / macrophage-like cells at the bottom of the culture plate. A small amount of non-adherent cells were removed by washing with PBS, and the remaining adherent BMM was recovered and dispensed onto the plate. The medium containing M-CSF and RANKL (40 ng / ml) was added and the medium was changed on the third day. After incubation for a fixed period of time, cells were fixed in 10% formalin for 10 min and stained for TRAP according to the known method ( Experimental Hematol ., 35, 1100-1108, 2007). The number of TRAP-positive multinuclear cells (MNC), ie, cells with more than 3 nuclei, was calculated.
도 2a 및 도 2b와 같이 백금 나노입자는 농도의존적으로 BMM으로부터 OC 형성을 억제한 반면, 총 세포수에는 영향을 주지 않았으므로, 백금 나노입자의 OC 형성 억제효과는 세포독성은 아님을 알 수 있었다.As shown in FIGS. 2A and 2B, the platinum nanoparticles inhibited the formation of OC from BMM in a concentration-dependent manner, but did not affect the total number of cells, so that the effect of inhibiting OC formation of platinum nanoparticles was not cytotoxic .
<실험예 3> 독성실험<Experimental Example 3> Toxicity test
백금 나노입자를 인산 완충 생리식염수(PBS)에 현탁하여 1g/kg 및 5g/kg의 용량으로 암컷 C57BL/6 마우스에 매일, 8주간 경구투여하여 마우스의 생존율 및 체중을 조사하였다.Platinum nanoparticles were suspended in phosphate buffered saline (PBS) and orally administered to female C57BL / 6 mice at a dose of 1 g / kg and 5 g / kg daily for 8 weeks, and the survival rate and body weight of the mice were examined.
이러한 투여 후 동물의 폐사여부, 임상증상, 체중변화를 관찰하고 혈액학적 검사와 혈액생화학적 검사를 실시하였으며, 부검하여 육안으로 복강장기와 흉강장기의 이상여부를 관찰하였다.After this administration, we observed the mortality of the animal, clinical symptoms, weight change, hematologic test and blood biochemical test, and autopsied the visceral organs and thoracic organs were observed.
그 결과, 모든 동물에서 특기할 만한 임상증상이나 폐사된 동물은 없었으며, 체중변화, 혈액검사, 혈액생화학 검사, 부검소견 등에서도 독성변화는 관찰되지 않았다. As a result, no clinical symptoms or dead animals were found in all animals, and no toxic changes were observed in weight changes, blood tests, blood biochemical tests, and autopsy findings.
이상의 결과, 본 발명의 백금 나노입자는 마우스에서 5g/㎏까지 독성변화를 나타내지 않으며, 따라서, 경구 투여 중간치사량(LD50)은 5g/kg 이상인 안전한 물질로 판단되었다.
As a result, the platinum nanoparticles of the present invention did not show any toxic change up to 5 g / kg in mouse, and thus it was judged that the oral LD50 was 5 g / kg or more.
하기에 본 발명에 따른 백금 나노입자를 포함하는 조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.The preparation examples of the composition containing the platinum nanoparticles according to the present invention will now be described, but the present invention is not intended to be limited thereto but is specifically described.
<처방예 1> 약학조성물의 처방예≪ Prescription Example 1 > Prescription Example of Pharmaceutical Composition
<처방예 1-1> 산제의 제조≪ Prescription Example 1-1 > Preparation of powder
백금 나노입자 20 mg, 유당 100 mg 및 탈크 10 mg을 혼합하고 기밀포에 충진하여 산제를 제조하였다.20 mg of platinum nanoparticles, 100 mg of lactose and 10 mg of talc were mixed and packed in airtight bags to prepare powders.
<처방예 1-2> 정제의 제조≪ Prescription Example 1-2 > Preparation of tablets
백금 나노입자 20 mg, 옥수수전분 100 mg, 유당 100 mg 및 스테아린산 마그네슘 2 mg을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.20 mg of platinum nanoparticles, 100 mg of corn starch, 100 mg of lactose, and 2 mg of magnesium stearate were mixed and tableted according to a conventional preparation method.
<처방예 1-3> 캅셀제의 제조≪ Prescription Example 1-3 > Preparation of capsules
백금 나노입자 10 mg, 옥수수전분 100 mg, 유당 100 mg 및 스테아린산 마그네슘 2mg을 혼합한 후 통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.After mixing 10 mg of platinum nanoparticles, 100 mg of corn starch, 100 mg of lactose and 2 mg of magnesium stearate, the above components were mixed according to a conventional capsule preparation method and filled in gelatin capsules to prepare capsules.
<처방예 1-4> 주사제의 제조≪ Prescription Example 1-4 > Preparation of injection
백금 나노입자 5 mg, 주사용 멸균 증류수 적량 및 pH 조절제 적량을 혼합한 후 통상의 주사제의 제조방법에 따라 1 앰플당(2㎖) 상기의 성분 함량으로 제조하였다.5 mg of platinum nanoparticles, sterilized distilled water suitable for injection, and pH adjuster were mixed, and the contents were adjusted to the above contents in accordance with the usual injection preparation method (2 ml) per ampoule.
<처방예 1-5> 연고제의 제조≪ Prescription Example 1-5 > Preparation of ointment preparation
백금 나노입자 10mg, PEG-4000 250mg, PEG-400 650mg, 백색바셀린 10mg, 파라옥시안식향산메칠 1.44mg, 파라옥시안식향산프로필 0.18mg 및 잔량의 정제수를 혼합한 후 통상의 연고제의 제조방법에 따라서 연고제를 제조하였다.After mixing 10 mg of platinum nanoparticles, 250 mg of PEG-4000, 650 mg of PEG-400, 10 mg of white petrolatum, 1.44 mg of methyl p-hydroxybenzoate, 0.18 mg of p-hydroxybenzoyl propyl and remaining amount of purified water, .
<처방예 2> 건강보조식품≪ Prescription Example 2 >
<처방예 2-1> 건강식품의 제조≪ Prescription Example 2-1 > Preparation of health food
백금 나노입자 1 ㎎, 비타민 혼합물 적량(비타민 A 아세테이트 70 ㎍, 비타민 E 1.0 ㎎, 비타민 B 1 0.13 ㎎, 비타민 B 2 0.15 ㎎, 비타민 B 6 0.5 ㎎, 비타민 B 12 0.2 ㎍, 비타민 C 10 ㎎, 비오틴 10 ㎍, 니코틴산아미드 1.7 ㎎, 엽산 50 ㎍, 판토텐산 칼슘 0.5 ㎎) 및 무기질 혼합물 적량(황산제1철 1.75 ㎎, 산화아연 0.82 ㎎, 탄산마그네슘 25.3 ㎎, 제1인산칼륨 15 ㎎, 제2인산칼슘 55 ㎎, 구연산칼륨 90 ㎎, 탄산칼슘 100 ㎎, 염화마그네슘 24.8 ㎎)을 혼합한 다음 과립을 제조하고 통상의 방법에 따라 건강식품을 제조하였다.1 mg of platinum nanoparticles, a vitamin mixture amount (70 비 of vitamin A acetate, 1.0 mg of vitamin E, 0.13 mg of vitamin B 1, 0.15 mg of vitamin B 2, 0.5 mg of vitamin B 6, 0.2 비 of
<처방예 2-2> 건강음료의 제조≪ Prescription Example 2-2 > Preparation of health drink
백금 나노입자 1 ㎎, 구연산 1000 ㎎, 올리고당 100 g, 매실농축액 2 g, 타우린 1 g 및 정제수를 가하여 전체 900 ㎖가 되도록 하며, 통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간 동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2 L 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관하였다.
1 mg of platinum nanoparticles, 1000 mg of citric acid, 100 g of oligosaccharide, 2 g of a plum concentrate, 1 g of taurine and purified water were added to make a total of 900 mL, and the above components were mixed according to a conventional health drink manufacturing method, After stirring for 1 hour at 85 ° C, the solution was filtered and sterilized in a sterilized 2 L container, and then refrigerated.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.
While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.
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