KR101038616B1 - Pharmaceutical compositions for the treatment, prevention, or alleviation of bone and cartilage diseases - Google Patents
Pharmaceutical compositions for the treatment, prevention, or alleviation of bone and cartilage diseases Download PDFInfo
- Publication number
- KR101038616B1 KR101038616B1 KR1020110023372A KR20110023372A KR101038616B1 KR 101038616 B1 KR101038616 B1 KR 101038616B1 KR 1020110023372 A KR1020110023372 A KR 1020110023372A KR 20110023372 A KR20110023372 A KR 20110023372A KR 101038616 B1 KR101038616 B1 KR 101038616B1
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- South Korea
- Prior art keywords
- bone
- vas
- treatment
- hyaluronic acid
- cartilage
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Abstract
뼈 또는 연골 상태의 치료, 예방 또는 완화를 위한 약제학적 조성물 및 그의 제조 및 사용 방법이 제공된다. 본 발명은 지방줄기세포, 혈소판 풍부 혈장, 염화칼슘, 및 히알루론산으로 이루어지는 뼈 질환의 치료, 예방, 및 완화용 약제학적 조성물 및 상기 조성물에 덱사메타손을 추가로 포함하는 연골 질환의 치료, 예방, 및 완화용 약제학적 조성물을 개시한다.Pharmaceutical compositions for the treatment, prevention or alleviation of bone or cartilage conditions and methods of making and using the same are provided. The present invention provides a pharmaceutical composition for the treatment, prevention, and alleviation of bone diseases consisting of adipose stem cells, platelet rich plasma, calcium chloride, and hyaluronic acid, and the treatment, prevention, and alleviation of cartilage disease further comprising dexamethasone in the composition. Disclosed is a pharmaceutical composition.
Description
본 발명은 뼈 및 관절의 치료, 예방 또는 완화를 하기 위한 약제학적 조성물에 관한 것으로, 특히 지방줄기세포, 혈소판 풍부 혈장, 히알루론산, 염화칼슘을 포함하는 뼈 질환용 조성물 및 상기 조성물에 덱사메타손을 추가로 포함하는 관절용 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for the treatment, prevention or alleviation of bones and joints, in particular, a composition for bone diseases comprising adipose stem cells, platelet-rich plasma, hyaluronic acid, calcium chloride, and dexamethasone in the composition It relates to a composition for a joint comprising.
퇴행성 관절염은 나이가 들면서 무릎 관절이 닳고 닳아 통증을 일으키는 질환으로 무릎의 안쪽과 앞쪽 관절 모두를 과도하게 사용할 때 발생하는데, 종래의 인식과 달리 최근에는 젊은 층에서도 많이 발생하고 있는 추세다. 종래에는 이러한 반월상 연골판(meniscus)의 손상에 의한 질환이나 퇴행성 관절 질환을 치료하기 위해 손상된 조직을 제거하거나 손상된 관절 전체를 제거하는 시술법이 활용되었다. 그러나 이러한 시술법들은 외과 수술에 의한 심한 절개나 상처가 생길 수 있고 회복이 늦은 한계가 있었다.Degenerative arthritis is a disease in which the knee joint wears down and wears with age, causing pain when the inner and front joints of the knee are excessively used. Conventionally, in order to treat a disease caused by meniscus damage or degenerative joint disease, a procedure of removing the damaged tissue or removing the entire damaged joint has been used. However, these procedures could have severe incisions or injuries due to surgical procedures and had a late recovery.
한편, 지방줄기세포(Adipose tissue-Derived Stem Cells:ADSCs)는 최근 반영구적 부피 확장용으로 성형외과 시술에서 널리 사용되고 있다. 2009년 이후 한국식품의약품안정청(KFDA)은 동일한 병원에서 최소한으로 처리되고 얻어지는 조건하에 ADSCs를 자가세포이식에 사용하도록 허용하였다.Adipose tissue-Derived Stem Cells (ADSCs), on the other hand, have recently been widely used in plastic surgery for semi-permanent volume expansion. Since 2009, the Korea Food and Drug Administration (KFDA) has allowed ADSCs to be used for autologous cell transplantation under minimally processed and obtained conditions in the same hospital.
중간엽 줄기세포(mesenchymal stem cells:MSCs)는 골수, 관절활액 및 지방조직을 포함한 인간의 여러 조직에서 분포하며, 뼈, 연골, 근육 및 지방조직으로 분화되기 때문에 재생의학 분야에서 유망한 새로운 치료법으로 각광받고 있다(Arnoczky S. P.: Building a meniscus. Biologic considerations. Clin Orthop Relat Res (367 Suppl): S244-53 (1999)). 이들의 잠재적인 능력 때문에 MSCs는 동물 실험에서 관절 연골(cartilage) 및 뼈의 재생에 성공적으로 사용되어 왔다(Barry F.P.: Mesenchymal stem cell therapy in joint disease. Novartis Found. Symp, 249: p. 86-96; discussion 96-102, 170-4, 239-41 (2003). and Zhang HN, Li L, Leng P, Wang YZ, Lv CY. Uninduced adipose-derived stem cells repair the defect of full-thickness hyaline cartilage. Chin J Traumatol 2009; 12:92-97). Mesenchymal stem cells (MSCs) are distributed in many human tissues, including bone marrow, joint synovial fluid and adipose tissue, and differentiate into bone, cartilage, muscle and adipose tissue, making them a promising new treatment in regenerative medicine. Arnoczky SP: Building a meniscus.Biologic considerations. Clin Orthop Relat Res (367 Suppl): S244-53 (1999). Because of their potential, MSCs have been successfully used for cartilage and bone regeneration in animal experiments (Barry FP: Mesenchymal stem cell therapy in joint disease. Novartis Found. Symp, 249: p. 86-96 ; discussion 96-102, 170-4, 239-41 (2003). and Zhang HN, Li L, Leng P, Wang YZ, Lv CY.Uninduced adipose-derived stem cells repair the defect of full-thickness hyaline cartilage. J Traumatol 2009; 12: 92-97).
조직 재생(tissue regeneration)에 관련된 문헌으로서는 WO2010/089379(2010. 8. 12일자 공개)을 들 수 있다. 그러나 이 문헌은 혈소판 풍부 혈장(Platelet-rich-plasma: PRP)과 응고 인자(coagulation factor)를 약제로 사용하기 위한 조성물(청구항 1), 이를 이용하여 줄기세포 풀(pool)을 풍부하게 하기 위한 사용방법(청구항 3), 및 혈소판 풍부 혈장과 응고 인자를 포함하는 조성물을 심장질환(청구항 4), 심근증, (선천성) 심장질환, 관상동맥 질환, 국소성 빈혈, 심장 장애, 아테롬성 동맥 경화증, 심근염, 심내막염, 및/또는 경색(청구항 5), 신경계 질환(청구항 6), 파킨슨 질환, 알츠하이머 질환, 헌팅턴 질환, Tay-Sachs 질환, 척추 코드 질환, 뇌졸증, 뇌혈관 질환 및 근위축 측상경화(청구항 7), 자가 면역 질환(청구항 8) 빈혈, 다발성 경화증, 류머티스성 관절염, Sjorgen 신드롬, 당뇨병 1, Grave's 질환 및/또는 전신성 홍반성 루푸스(청구항 9), 뼈 퇴행성 질환(청구항 10), 골 위축, 골 다공증, 뼈 재생 및 뼈 강화(청구항 11)에 사용하는 방법 등 혈소판 풍부 혈장과 응고 인자의 조성비율도 기재하지 않고 효과도 제시하지 아니한 상태에서 매우 광범위하고도 다양한 질환을 치료할 수 있음을 개시하고 있다. Documents related to tissue regeneration include WO2010 / 089379 (published Aug. 12, 2010). However, this document does not describe compositions for the use of platelet-rich-plasma (PRP) and coagulation factors as medicaments (claim 1), using them to enrich stem cell pools. Method (Claim 3), and a composition comprising platelet-rich plasma and coagulation factor may be used for treating heart disease (Claim 4), cardiomyopathy, (congenital) heart disease, coronary artery disease, focal anemia, heart disorder, atherosclerosis, myocarditis, endocarditis And / or infarction (claim 5), nervous system disease (claim 6), Parkinson's disease, Alzheimer's disease, Huntington's disease, Tay-Sachs disease, spinal cord disease, stroke, cerebrovascular disease and muscular dystrophy (claim 7) , Autoimmune disease (claim 8) anemia, multiple sclerosis, rheumatoid arthritis, Sjorgen syndrome, diabetes 1, Grave's disease and / or systemic lupus erythematosus (claim 9), bone degenerative disease (claim 10), bone atrophy, bone porosity It is disclosed that it is possible to treat a wide variety of diseases without mentioning the composition ratio of platelet-rich plasma and coagulation factor and not showing the effects such as the method used for the increase, bone regeneration and bone strengthening (Claim 11). .
여기에서 상기 응고 인자는 트롬빈플라스틴(hTf 즉 human tissue factor), 팩턴 Xa, 팩터 Vila, 팩터 X, 팩터 VII이 사용될 수 있음을 보여주고 있다(청구항 15). 따라서 이 문헌의 식별항목 [29]의 c)단계에서 혈소판 풍부 혈장과 CaCl2와 의 조성을 제시하고는 있으나, PRP와 CaCl2의 조성은 이 문헌에서 중요하게 다루어지지 아니하다. 이러한 사실은 청구항 17에서 더욱 잘 나타나고 있는데, 여기에서는 상기 PRP와 활성 화합물(문헌의 전체적인 의미에서 응고 인자를 뜻하는 것으로 보인다)의 예로서는 트롬보플라스틴, 재조합 트롬보플라스틴, hTf, 재조합 인간 조직 팩턴(rhTf), 재조합 수용성 조직 팩터, 포스포리피드, 포스파티딜콜린, 포스파티딜세린, 포스파티딜에탄올아민, 팩터 VII, 팩터 X, 팩터 Vila, 팩터 Xa, 팩터 VIII, 팩터 IX, 또는 활성화되거나/되지 않은 이들 팩터의 조합으로 이루어진 킷을 청구하고 있기 때문이다.The coagulation factor here shows that thrombinplastin (hTf, human tissue factor), Factor Xa, Factor Vila, Factor X, Factor VII can be used (Claim 15). Therefore, although the composition of platelet-rich plasma and CaCl 2 is presented in step c) of Identification [29] of this document, the composition of PRP and CaCl 2 is not important in this document. This fact is better illustrated in claim 17, where examples of such PRPs and active compounds (which appear to mean coagulation factors in the overall sense of the literature) include thromboplastin, recombinant thromboplastin, hTf, recombinant human tissue. Factor (rhTf), recombinant water soluble tissue factor, phospholipid, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, factor VII, factor X, factor Vila, factor Xa, factor VIII, factor IX, or of these factors not activated or This is because you are claiming a combination kit.
또한 이 문헌에서 사용되고 있는 PRP는 기저 정맥에 비하여 적어도 100%, 바람직하게는 200% 내지 1000%의 농축된 PRP이기 때문에 (식별항목 [43]. 및 페이지 7, 3째 줄 참조), 본원의 PRP와는 상이하다. In addition, since the PRP used in this document is a concentrated PRP of at least 100%, preferably 200% to 1000% relative to the basal vein (see Identification [43] and page 7, line 3), the PRP herein Is different.
또한 이 문헌은 상기의 농축된 PRP 응고인자를 이용하여 인간 비 배아 줄기세포를 실험관내에서 배양하는 방법(청구항 28-34)을 개시하고 있다. 이렇게 배양하는 구체적인 방법은 청구항 35 및 식별항목 [29]에 상세히 기재하고 있다. This document also discloses a method for culturing human non-embryonic stem cells in vitro using the concentrated PRP coagulation factor (claims 28-34). The specific method of culturing is described in detail in Claim 35 and Identification [29].
따라서 이 문헌은 농축된 혈소판 풍부 혈장과 트롬보플라스틴과 같은 응고 인자로 이루어진 조성물로서 매우 광범위하고 다양한 질환을 치료할 수 있음을 개시하고 또한 농축된 혈소판 풍부 혈장과 응고 인자를 이용하여 줄기세포를 배양하는 방법을 개시하고 있어서 본원의 발명과는 상이하다. 이 문헌은 농축된 PRP와 응고인자의 조성비율도 기재하지 않고 효과도 제시하지 아니하고 있기 때문에 당업자는 이렇게 간단한 조성물로서 상기한 바와 같은 수십여가지 넘는 다양한 질환에 효과가 있을까 하는 의문을 가질 것이 당연하다 할 수 있겠다.Thus, this document discloses that a composition consisting of concentrated platelet-rich plasma and coagulation factor such as thromboplastin can be used to treat a wide variety of diseases and to cultivate stem cells using the concentrated platelet-rich plasma and coagulation factor. It is different from the invention of this application in the method to disclose. Since this document does not describe the composition ratio of concentrated PRP and coagulation factor and does not suggest any effect, it is natural for those skilled in the art to question whether such a simple composition is effective for dozens of various diseases as described above. I can do it.
조직 재생(tissue regeneration)에 관련된 또다른 문헌으로서는 WO2010/065854(2010. 6. 10일자 공개)을 들 수 있다. 이 문헌은 식별번호 [2]에서 [8]까지에 나타나 있는 바와 같이 전체적으로 척추 디스크에 관한 발명이다. 또한, 식별번호 [6]과 [7]에서는 디스크, 히프, 무릎, 어깨와 같은 질환의 치료에 줄기세포를 직접 임플랜트하여 치료하는 것은 어렵다고 하고 있어서, 본원 발명과 같이 다른 조성성분과 함께 줄기세포를 직접 주입하여 도면에 나타난 바와 같은 효과를 나타낸 발명에 진보성을 인정할 수 있음을 나타내고 있다. Another document relating to tissue regeneration is WO2010 / 065854 (published June 10, 2010). This document is an invention relating to a vertebral disc as a whole, as indicated by identification numbers [2] to [8]. In addition, identification numbers [6] and [7] are difficult to treat by directly implanting stem cells in the treatment of diseases such as discs, hips, knees, and shoulders. It is shown that the inventive concept can be recognized by the invention having the effects as shown in the drawings by direct injection.
이 문헌에서 청구하고 있는 조성물은 줄기세포, 혈소판, 하나 이상의 성장인자(growth factor)를 포함하고 있어서 본원의 조성물과는 상이하다(청구항 17).The composition claimed in this document differs from the composition of the present disclosure because it contains stem cells, platelets and one or more growth factors (claim 17).
이 문헌에서 사용하고 있는 줄기세포는 시험관내(in vitro)에서 배양하여 사용하고 있다(식별번호 [9]). 이 조성물의 성장인자는 경막외 보충제인 사이토카인, 인테그린, 캐드헤린을 의미함을 알 수 있다(식별번호 [11]). 또한 다른 구현예에서는 줄기세포를 시험관내(in vitro)에서 1-10% 및 바람직하게는 3-7%의 산소하에서 1 내지 28일간 배양하여 사용하기 때문에 환자에게서 지방줄기세포를 직접 채취하여 주입하는 본 발명과는 상이하다. Stem cells used in this document are cultured in vitro (identification number [9]). It can be seen that the growth factor of the composition means epidural supplements cytokines, integrins, and Cadherin (identification number [11]). In another embodiment, since stem cells are incubated for 1 to 28 days under oxygen of 1-10% and preferably 3-7% in vitro, the stem cells are directly collected and injected from the patient. It is different from this invention.
더우기 이 문헌에서는 실시예에서 환자 1, 2, 3 모두에서 디스크 질환을 앓고 있는 환자를 대상으로 하여 그 효과를 기재하고 있다. 도 1은 수평 허리를 나타내고 있는데, 보다 구체적으로 후면 디스크 환을 보여주고 있다(도 1 및 식별번호 [19]).Moreover, this document describes the effects of the patients in patients with disc disease in all of the patients 1, 2, 3 in the examples. Figure 1 shows a horizontal waist, more specifically the rear disc ring (Figure 1 and identification number [19]).
따라서 이 문헌은 본원과 사용되는 조성성분이 다르고 치료하고자 하는 부위가 다르기 때문에 본원과 그 목적 및 효과가 다른 문헌이다.Therefore, this document is different from the present application and its purpose and effects because the composition and components to be used and the site to be treated are different.
기타 본원과 관련된 특허로서는 대한민국 공개특허공보 제2003-15160호, 제2005-64068호, 특허 제803576호, 공개특허 제10-2005-0029118호, 및 미합중국 특허 제7,807,461호, 특허 6,391,297호 등에서 반월상 연골판이 손상된 부위에 연골 재생을 위한 조성물 또는 뼈 재생을 위한 조성물 및/또는 방법들은 외과적 시술을 어느 정도 줄일 수는 있었지만 연골 재생 또는 뼈 재생의 효과가 만족할 정도는 아니어서 더 개선될 필요가 있었다. Other patents related to the present application include half moon images in Korean Patent Application Publication Nos. 2003-15160, 2005-64068, Patent No. 803576, Publication No. 10-2005-0029118, and United States Patent Nos. 7,807,461 and 6,391,297. Compositions for cartilage regeneration or compositions and / or methods for bone regeneration at the site where cartilage was damaged could reduce surgical procedures to some extent, but the effects of cartilage regeneration or bone regeneration were not satisfactory and needed further improvement. .
따라서 본 발명의 다른 목적은 뼈의 재생을 위한 약제학적 조성물을 제공하는데 있다.Accordingly, another object of the present invention is to provide a pharmaceutical composition for bone regeneration.
본 발명의 또 다른 목적은 연골의 재생을 위한 약제학적 조성물을 제공하는데 있다It is another object of the present invention to provide a pharmaceutical composition for regeneration of cartilage.
본원에서 사용되는 용어 "뼈"는 골아세포 및 용골세포와 같이 히드록시아파타이트, 콜라겐(주로 I형 콜라겐) 및 골 세포 형태의 침적된 칼슘 및 인산염 네트워크를 주로 포함하는 석회화 결합조직을 의미한다.As used herein, the term "bone" refers to calcified connective tissue that primarily comprises deposited calcium and phosphate networks in the form of hydroxyapatite, collagen (mainly type I collagen), and bone cell types, such as osteoblasts and keel cells.
본원에서 사용되는 용어 "연골"은 콜라겐 원섬유(대부분의 II형 콜라겐과 기타 소량의 IX형 및 XI형 콜라겐), 각종 프로테오글리칸(예, 콘드로이틴 설페이트 프로테오글리칸, 케라탄 설페이트 프로테오글리칸 및 더마탄설페이트 프로테오글리칸), 기타 단백질 및 물을 포함한 세포간 물질(" 연골 매트릭스" 로 언급되기도 함)에 매립되어 있는 연골 세포를 포함하는 결합 조직 유형을 의미한다. 본원에서 사용된 바와 같은 연골은 관절 연골과 반월 연골을 포함한다. 관절 연골은 관절의 뼈 부위 표면을 덮고 있어서 뼈-뼈가 직접 접촉되지 않은 상태로 관절로 이동하도록 함으로써, 뼈 표면의 마모 및 손상을 방지한다. 또한 대부분 정상의 건강한 관절 연골은 " 유리질" 로 일컬어지는데, 이는 무광택 유리 표면을 갖는 것을 특징으로 한다(문헌: Gray's Anatomy.뉴욕: Bounty Books, 1977).As used herein, the term “cartilage” refers to collagen fibrils (most of type II collagen and other small amounts of type IX and XI collagen), various proteoglycans (eg, chondroitin sulfate proteoglycans, keratan sulfate proteoglycans, and dermatansulfate proteoglycans), A connective tissue type comprising chondrocytes embedded in an intercellular material (also referred to as a "cartilage matrix"), including other proteins and water. Cartilage as used herein includes articular cartilage and meniscus. Articular cartilage covers the bone site surface of the joint and allows bone-bone to move into the joint without direct contact, thereby preventing wear and damage to the bone surface. Most normal healthy articular cartilage is also referred to as "glassy", which is characterized by having a matte glass surface (Gray's Anatomy. New York: Bounty Books, 1977).
본원에서 사용되는 용어 "혈소판 풍부 혈장"은 전혈(whole blood)에서 분리한 혈소판을 소량의 플라즈마에 재현탁한 것으로, 약 95%의 적혈구, 약 5%의 혈소판과 1%의 백혈구를 포함하고 있는 전혈에 비하여, 본원에서 사용되는 혈소판 풍부 혈장은 약 45%의 적혈구와 약 50%의 혈소판 및 약 5%의 백혈구를 포함하고 있는 것을 의미한다.As used herein, the term “platelet-rich plasma” refers to the resuspension of platelets isolated from whole blood in a small amount of plasma, including whole blood containing about 95% red blood cells, about 5% platelets and 1% white blood cells. In comparison, platelet rich plasma as used herein means containing about 45% red blood cells and about 50% platelets and about 5% white blood cells.
본 발명은 지방줄기세포(Adipose-Derived Stem Cells, 이하 "ADSCs"라 칭한다), 혈소판 풍부 혈장(Platelet Rih Plasma, 이하 "PRP"라 칭한다), 히알루론 산 및 1-5% 염화칼슘으로 이루어진 뼈의 치료, 예방 또는 완화를 위한 약제학적 조성물을 제공한다.The present invention relates to bones composed of Adipose-Derived Stem Cells (hereinafter referred to as "ADSCs"), Platelet Rih Plasma (hereinafter referred to as "PRP"), hyaluronic acid and 1-5% calcium chloride. Provided are pharmaceutical compositions for treatment, prevention or alleviation.
본 발명은 4-15중량부의 ADSCs, 1-10중량부의 PRP, 0.1-0.4중량부의 1-5%염화칼슘, 0.5-2중량부의 히알루론산으로 이루어진 뼈의 치료, 예방, 또는 완화를 위한 약제학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for treating, preventing or alleviating bones consisting of 4-15 parts by weight of ADSCs, 1-10 parts by weight of PRP, 0.1-0.4 parts by weight of 1-5% calcium chloride, and 0.5-2 parts by weight of hyaluronic acid. To provide.
본 발명은 특히, 무혈성 괴사로 인한 엉덩이 뼈의 재생을 위한 약제학적 조성물을 제공한다.The present invention particularly provides a pharmaceutical composition for regeneration of hip bone due to avascular necrosis.
본 발명은 또한, 상기 뼈 재생용 약제학적 조성물에 0.05-0.2중량부의 덱사메타손(dexamethason)을 추가적으로 포함하는 연골의 치료, 예방 또는 완화를 위한 약제학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for treating, preventing or alleviating cartilage further comprising 0.05-0.2 parts by weight of dexamethasone (dexamethason) in the pharmaceutical composition for bone regeneration.
본 발명은 특히, 반월상 연골판 손상 등에 따른 무릎 연골의 재생을 위한 약제학적 조성물을 제공한다.In particular, the present invention provides a pharmaceutical composition for regeneration of knee cartilage due to meniscus damage.
상기 약제학적 조성물은 포유류에 투여하여 뼈 및/또는 연골의 치료, 예방 또는 완화하는 것을 포함한다. The pharmaceutical composition comprises administering to a mammal to treat, prevent or alleviate bone and / or cartilage.
본 발명자의 연구에 의하면, 상기 조성비의 조성물이 뼈 및 연골의 치료, 예방, 또는 완화에 특히 효과가 있음을 알 수 있었다. 염화칼슘의 농도는 상기 범위를 벗어나면 효과가 없음을 알 수 있었다.According to the study of the present inventors, it was found that the composition of the composition ratio is particularly effective in the treatment, prevention, or alleviation of bone and cartilage. The concentration of calcium chloride was found to be ineffective when out of the above range.
본 발명의 약학 조성물은 부작용 없이 엉덩이 뼈와 무릎 연골 재생이 가능하여 엉덩이 뼈의 치료, 예방, 또는 완화를 가져올 수 있다.The pharmaceutical composition of the present invention is capable of regenerating hip bone and knee cartilage without side effects, thereby bringing about treatment, prevention, or alleviation of hip bone.
본 발명의 약학 조성물을 엉덩이 뼈 환자 또는 무릎 연골 환자 등에 주사하면 절개 등의 외과적 시술을 시행하지 않아도 효과가 있을 수 있다.When the pharmaceutical composition of the present invention is injected into a hip bone patient or a knee cartilage patient, etc., it may be effective even without performing a surgical procedure such as an incision.
본 발명의 약학 조성물은 지방 줄기세포(ADSCs), 혈소판 풍부 혈장 (PRP), 1-5% CaCl2 및 히알루론산을 최적 함량으로 조합 사용함으로써 엉덩이 뼈의 재생에 있어 뛰어난 상승효과를 나타낸다.The pharmaceutical composition of the present invention exhibits an excellent synergistic effect in the regeneration of hip bones by using a combination of fat stem cells (ADSCs), platelet rich plasma (PRP), 1-5% CaCl 2 and hyaluronic acid in an optimal amount.
도 1은 치료 전과 3개월 치료 후의 오른쪽 엉덩이 뼈의 MRI 사진(T1 관상).
도 2는 치료 전과 3개월 치료 후의 오른쪽 엉덩이 뼈의 MRI 사진(T2 관상).
도 3은 치료 전과 3개월 치료 후의 오른쪽 무릎의 MRI 사진(T2 시상).
도 4는 치료 전과 3개월 치료 후의 오른쪽 무릎의 MRI 사진(T2 관상).1 is an MRI image (T1 coronary) of the right hip bone before and after 3 months of treatment.
FIG. 2 shows MRI images (T2 coronary) of right hip bone before treatment and after 3 months of treatment.
3 is an MRI photograph (T2 thalamus) of the right knee before and after 3 months of treatment.
4 is an MRI picture (T2 coronary) of the right knee before and after 3 months of treatment.
본 발명은 지방 줄기세포(Adipose-Derived Stem Cells), 혈소판 풍부 혈장 (Platelet Rich Plasma), CaCl2 및 히알루론산을 특정의 함량으로 포함하는 약제학적 조성물로서 부작용 없이 뼈의 재생이 가능하여 절개 등의 외과적 시술을 최소화할 수 있어 흉터가 없고 회복이 빠른 장점이 있는 뼈 질환용 약학 조성물에 관한 것이다.The present invention is a pharmaceutical composition comprising adipose-Derived Stem Cells, Platelet Rich Plasma, CaCl 2 and hyaluronic acid in a specific content to enable bone regeneration without side effects, such as incision, etc. It relates to a pharmaceutical composition for bone diseases that can minimize the surgical procedure is scar-free and fast recovery.
본 발명은 특히 무혈성 괴사로 인한 사람의 엉덩이 뼈를 재생시키는 약학 조성물을 제공한다.The present invention particularly provides a pharmaceutical composition for regenerating the hip bone of a person due to avascular necrosis.
본 발명은 또한 상기 조성물에 소량의 덱사메타손을 포함하는 연골 질환용 약학 조성물에 관한 것이다.The present invention also relates to a pharmaceutical composition for cartilage disease comprising a small amount of dexamethasone in the composition.
본 발명은 특히 무릎 연골을 재생시키는 약학 조성물에 관한 것이다.The present invention relates in particular to pharmaceutical compositions for regenerating knee cartilage.
중간엽 줄기세포는 관절연골 재생을 위해 동물연구에서 및 인간에서의 뼈 재생에 사용되어 왔으며, 덱사메타손은 중간엽 줄기세포의 분화를 촉진하는 잠재적인 분화유도 물질로 작용하는 것으로 알려져 왔다. 또한, 히알루론산은 윤활제 및 충격 흡수제 모두로서 작용하는 활액의 점탄성 특질을 담당한다. 히알루론산은 관절 연골의 표면을 코팅하고, 콜라겐 피브릴 및 술페이트화 프로테오글리칸 중에서 연골 내의 더 깊은 공간을 공유한다. 이것은 연골을 보호하고 연골 매트릭스로부터 윤활 공간 내로의 프로테오글리칸의 손실을 차단하여, 정상 연골 매트릭스를 유지시킨다. 골관절염의 무릎 관절에 있는 활액에서는 히알루론산, 글리코사미노글리칸, 및 케라탄 술페이트의 농도가 정상 무릎 관절에 있는 활액보다 낮다. 부가적으로, 토끼 윤활 세포를 사용한 실험에서 전염증성 사이토카인 IL-1베타 및 TNF-알파가 히알루론산 신테타아제의 발현을 촉진하여, 이것이 염증성 조건 하에서 히알루론산의 분절화에 기여할 수 있다는 것이 제시되었다. 외인성 히알루론산은 새롭게 합성되는 히알루론산의 생성을 용이하게 할 수 있다. 히알루론산 및 유도체는 교합 표면의 윤활을 증가시켜 관절 통증을 감소시키는 일환으로서 골관절염의 치료에서 치료 보조제로서 사용되어 왔다. 더우기, 여러 시험관 내 배양 연구는 히알루론산이 피브로넥틴 조각에 의해 매개되는 연골세포 연골분해를 억제함으로써 유리한 효과를 갖는다는 것을 입증하였다. 히알루론산은 또한 항-염증성 효과 뿐 아니라, 프로스타글란딘 합성, 및 프로테오글리칸 방출 및 분해에 대한 억제 효과를 갖는다는 것이 제시되었다.Mesenchymal stem cells have been used in animal studies and in bone regeneration in humans for articular cartilage regeneration, and dexamethasone has been known to act as a potential differentiation-inducing substance that promotes the differentiation of mesenchymal stem cells. Hyaluronic acid is also responsible for the viscoelastic nature of the synovial fluid, which acts as both a lubricant and an impact absorber. Hyaluronic acid coats the surface of articular cartilage and shares deeper spaces in the cartilage among collagen fibrils and sulfated proteoglycans. This protects the cartilage and blocks the loss of proteoglycans from the cartilage matrix into the lubrication space, thus maintaining a normal cartilage matrix. In synovial fluid in the knee joints of osteoarthritis, the concentrations of hyaluronic acid, glycosaminoglycans, and keratan sulfate are lower than those in normal knee joints. Additionally, experiments with rabbit lubricating cells have suggested that the proinflammatory cytokines IL-1beta and TNF-alpha promote the expression of hyaluronic acid synthetase, which may contribute to the segmentation of hyaluronic acid under inflammatory conditions. . Exogenous hyaluronic acid can facilitate the production of newly synthesized hyaluronic acid. Hyaluronic acid and derivatives have been used as therapeutic aids in the treatment of osteoarthritis as part of reducing joint pain by increasing lubrication of the occlusal surface. Moreover, several in vitro culture studies have demonstrated that hyaluronic acid has a beneficial effect by inhibiting chondrocyte chondrosis mediated by fibronectin fragments. It has been shown that hyaluronic acid also has anti-inflammatory effects, as well as inhibitory effects on prostaglandin synthesis, and proteoglycan release and degradation.
본 발명에서는 상기와 같이 뼈 및 관절 질환으로서 공지된 지방줄기세포, 덱사메타손, 및 히알루론산을 사용하고 있으나, 이하에서 보는 바와 같은 주목할 만하며 성공적인 최초의 사례를 보인 것은 이들의 적량과 함께 CaCl2 및 혈소판 풍부 혈장을 본 발명에서와 같은 적량을 사용한 것 때문으로 생각된다.Although the present invention uses the fat stem cells, dexamethasone, and hyaluronic acid known as a bone and joint disease as described above, it is said remarkable merit as seen from below showing the first example of successful CaCl 2, and with them the appropriate amount It is considered that platelet rich plasma is used due to the same amount as in the present invention.
지방 줄기세포는 인체의 지방 조직에서 유래하는 줄기세포를 의미하는 것으로서, 자가 재생과 여러 가지 세포로의 분화 능력을 갖는다. 지방 줄기세포는 중간엽에서 발생하는 연골세포(chondrocytes), 지방세포(adipocytes), 조골세포(osteoblasts), 근세포(myocytes) 또는 내피세포(endothelial cells) 등으로 분화될 수 있다. 지방 줄기세포는 다른 줄기세포들에 비해 인체에서 얻을 수 있는 양이 충분하기 때문에 활용이 용이하다는 장점이 있다. 본 발명의 지방세포, 지방줄기세포 및 지방조직은 공지의 방법에 의해 얻을 수 있다. 예를 들어, 국제특허공개 제WO2000/53795호 및 제WO2005/042730호에 개시된 바와 같이, 지방조직(adipose tissue)으로부터 지방흡인(liposuction) 및 침강, 콜라게나제(collagenase) 등의 효소처리, 원심분리에 의한 적혈구 등의 부유 세포 제거 등의 과정을 통하여 지방세포 및 지방줄기세포를 분리할 수 있다.Adipose stem cells refer to stem cells derived from adipose tissue of the human body, and have the ability of self-renewal and differentiation into various cells. Adipose stem cells can be differentiated into chondrocytes, adipocytes, osteoblasts, myocytes, or endothelial cells that occur in the mesenchyme. Adipose stem cells have the advantage that they are easy to use because the amount that can be obtained from the human body compared to other stem cells. Adipose cells, adipose stem cells and adipose tissue of the present invention can be obtained by a known method. For example, as disclosed in WO2000 / 53795 and WO2005 / 042730, liposuction and sedimentation from adipose tissue, enzyme treatment such as collagenase, and centrifugation Adipose cells and adipose stem cells can be separated through a process of removing floating cells such as red blood cells by separation.
지방줄기세포는 본 발명에 따른 약학 조성물 중에 4-15중량부 포함될 수 있다. 지방 줄기세포의 함량은 이식이 필요한 환자의 상태, 목적, 성별, 나이 등에 따라 적절히 변경될 수 있다. Adipose stem cells may be included in the pharmaceutical composition according to the invention 4-15 parts by weight. The content of adipose stem cells may be appropriately changed according to the condition, purpose, sex, age, etc. of the patient in need of transplantation.
혈소판 풍부 혈장은 예컨대 환자의 몸에서 뽑은 혈액 20~40cc 정도를 원심분리기에 넣고 분리한 후 얻어진 혈소판을 특수 키트를 이용해 처리하면 2~4cc정도 얻어진다. 혈소판 풍부 혈장은 본 발명에 따른 약학 조성물 중에 1-10중량부 포함된다. 혈소판 풍부 혈장의 함량이 위 범위에 해당되지 않을 경우 지방줄기세포와의 함량비가 적절치 않아 상승적 재생 효과가 저하될 수 있다.Platelet-rich plasma is obtained by, for example, about 20 to 40 cc of blood drawn from the patient's body in a centrifuge, and then treated with a special kit to obtain 2 to 4 cc. Platelet rich plasma is included in the pharmaceutical composition according to the invention 1-10 parts by weight. If the content of platelet-rich plasma does not fall within the above range, the ratio of fat to stem cells may not be appropriate, which may lower the synergistic regeneration effect.
본 발명에 따른 약학 조성물은 상기 성분이외에 스캐폴드(scaffold)로 히알루론산을 추가 포함할 수 있다. 히알루론산은 식품의약품안전청으로부터 체내 주입이 허가된 생분해성 중합체로서, 생체에서 유래되는 물질이다. 본 발명의 조성물에 함유되는 히알루론산은 인간을 포함한 포유동물의 체액 또는 조직으로부터 정제된 것, 재조합 미생물 또는 세포를 배양하여 얻은 것, 또는 화학적 합성방법에 의해 얻어진 것 모두를 사용할 수 있다. 히알루론산의 중량평균분자량은 약 200,000 ∼ 400,000의 범위일 수 있다. 히알루론산은 지방 줄기세포 등이 적절한 분산될 수 있는 범위에서 포함될 수 있는데, 예컨대 본원의 약학 조성물 중에 0.5-2중량부가 포함된다.The pharmaceutical composition according to the present invention may further include hyaluronic acid as a scaffold in addition to the above components. Hyaluronic acid is a biodegradable polymer that is allowed to be injected into the body from the Food and Drug Administration. The hyaluronic acid contained in the composition of the present invention can be any of those purified from body fluids or tissues of mammals including humans, those obtained by culturing recombinant microorganisms or cells, or those obtained by chemical synthesis. The weight average molecular weight of hyaluronic acid may range from about 200,000 to 400,000. Hyaluronic acid may be included in the range in which fat stem cells and the like can be appropriately dispersed, such as 0.5-2 parts by weight in the pharmaceutical composition of the present application.
또한, 본 발명에 따른 약학 조성물은 혈소판의 활성화를 위한 1-5%의 염화칼슘(CaCl2)을 추가로 포함한다. 염화칼슘은 0.1-0.4중량부 포함된다. 효과면에서 가장 우수한 염화칼슘의 농도는 3%였다.In addition, the pharmaceutical composition according to the present invention further comprises 1-5% of calcium chloride (CaCl 2 ) for activation of platelets. Calcium chloride is included 0.1-0.4 parts by weight. In terms of effect, the best calcium chloride concentration was 3%.
본 발명자의 연구에 의하면, 상기와 같은 비율의 조성물이 무혈성 괴사로 인한 엉덩이 뼈의 치료에 가장 뛰어난 효과를 나타낸다는 것을 알 수 있었다.According to the research of the present inventors, it was found that the composition of the above ratio shows the most excellent effect on the treatment of the hip bone due to avascular necrosis.
본 발명의 또 다른 구현예에서, 본 발명은 상기 조성물에 소량의 덱사메타손을 추가하여 연골 상태의 치료, 예방, 또는 완화하는 방법을 제공한다. 덱사메타손(dexamethasone)은 스테로이드 호르몬의 당질코르티코이드 계열 합성 물질이다. 본 발명에서 이는 연골 세포 분화 유도제로 사용된다. 덱사메타손은 본 발명에 따른 약학 조성물 중에 0.05-0.2 중량부 포함된다. 덱사메타손이 위 범위를 넘어 과량 투여될 경우 부작용이 발생될 수 있다.In another embodiment of the present invention, the present invention provides a method of treating, preventing or alleviating cartilage conditions by adding a small amount of dexamethasone to the composition. Dexamethasone (dexamethasone) is a glucocorticoid family of steroid hormones. In the present invention it is used as an inducer of chondrocyte differentiation. Dexamethasone is included in the pharmaceutical composition according to the invention from 0.05 to 0.2 parts by weight. If dexamethasone is administered in excess of the above range, side effects may occur.
본 발명의 약학 조성물은 임상 투여 시에 주사 등과 같은 비경구로 투여가 가능하며 일반적인 의약품 제제의 형태로 사용될 수 있다. 즉, 본 발명의 치료제는 실제 임상 투여 시에 비경구의 여러 가지 제형으로 투여될 수 있는데, 제제화할 경우에는 보통 사용하는 충전제, 증량제, 결합제, 습윤제, 붕해제 및 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다.The pharmaceutical composition of the present invention can be administered parenterally, such as injection, during clinical administration and can be used in the form of general pharmaceutical preparations. In other words, the therapeutic agent of the present invention may be administered in various parenteral formulations during actual clinical administration, and when formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are commonly used. Can be prepared.
제제에는 멸균된 수용액, 비수용성용제, 현탁제, 유제, 동결건조제 등이 포함될 수 있다. 비수성용제와 현탁용제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세롤 및 젤라틴 등이 사용될 수 있다.Formulations may include sterile aqueous solutions, water-insoluble solvents, suspensions, emulsions, lyophilizers and the like. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol and gelatin may be used.
본 발명의 약학 조성물의 사용법에 있어서, 투여될 양에 영향을 미치는 인자들로는 이에 한정되는 것은 아니지만 투여 방식, 투여 빈도, 치료가 진행 중인 특정 질병, 질병의 심각성, 질병의 병력, 개체가 다른 치료제와 함께 협력 치료법이 진행중인지의 여부, 및 치료가 진행 중인 개체의 연령, 키, 체중, 건강, 및 신체 조건을 포함한다. 일반적으로 치료가 진행 중인 환자의 체중이 증가할수록 상기와 같은 비율의 약학조성물 제제를 더 많은 양으로 투약하는 것이 바람직하다.In the use of the pharmaceutical composition of the present invention, factors affecting the amount to be administered include, but are not limited to, the mode of administration, the frequency of administration, the specific disease under treatment, the severity of the disease, the history of the disease, and the individual with other therapeutic agents. Together whether or not a collaborative therapy is in progress, and the age, height, weight, health, and physical condition of the individual in whom the treatment is in progress. In general, as the weight of a patient undergoing treatment increases, it is desirable to administer a higher amount of the pharmaceutical composition formulation as described above.
본 발명의 약학 조성물은 연골 재생을 자극하기에 효과적인 양으로 투여할 수 있다. 반월상 연골판의 손상 또는 퇴행성 관절염의 치료를 위해서는 상기의 각 성분을 반으로 나누어 예컨대, 무릎의 앞부분 외부(anterior-lateral)에 한번, 내부(anterior medial)에 한번으로 나누어 투입한다.The pharmaceutical composition of the present invention may be administered in an amount effective to stimulate cartilage regeneration. For the treatment of meniscus damage or degenerative arthritis, the above components are divided in half, for example, once in the anterior-lateral area of the knee and once in the interior medial.
상기의 수치한정은 본 발명자의 클리닉에 내원하는 환자들을 대상으로 한 치료결과에 의한다. The numerical limitation is based on the results of treatment for patients who visit the clinic of the present inventors.
이하의 실시예에서 사례 1의 환자에게 3g의 ADSCs와 2g의 PRP, 0.2g의 염화칼슘 및 1g의 히알루론산을 주입하고 모든 방법을 동일하게 한 결과의 치료효과는 표 1에 나타낸 바와 같다.
In the following example, the therapeutic effect of the result of injecting 3 g of ADSCs and 2 g of PRP, 0.2 g of calcium chloride, and 1 g of hyaluronic acid to all patients in the following Examples and all the same methods is shown in Table 1.
따라서 상기의 조성비는 본 발명의 효과를 충분히 나타낼 수 없음을 알 수 있다.Therefore, it can be seen that the above composition ratio cannot sufficiently exhibit the effects of the present invention.
사례 1의 환자에게 4g의 ADSCs와 2g의 PRP, 0.2g의 염화칼슘 및 1g의 히알루론산을 주입하고 모든 방법을 동일하게 한 결과의 치료효과는 표 2에 나타낸 바와 같다.The therapeutic effect of the result of injecting 4 g of ADSCs, 2 g of PRP, 0.2 g of calcium chloride, and 1 g of hyaluronic acid to all patients in the case 1 was shown in Table 2.
이를 이하의 표 17과 비교하면 충분하지는 않지만 치료효과가 있음을 나타내고 있다.Comparing this with Table 17 below, it is not sufficient, but shows a therapeutic effect.
마찬가지로 사례 1의 환자에게 6g의 ADSCs와, 0.5g의 PRP, 0.2g의 염화칼슘 및 1g의 히알루론산을 주입하고 모든 방법을 동일하게 한 결과의 치료효과는 표 3에 나타낸 바와 같다.Similarly, the therapeutic effect of the result of injecting 6 g of ADSCs, 0.5 g of PRP, 0.2 g of calcium chloride, and 1 g of hyaluronic acid to all patients in the same case is shown in Table 3.
따라서 상기의 조성비는 본 발명의 효과를 충분히 나타낼 수 없음을 알 수 있다.Therefore, it can be seen that the above composition ratio cannot sufficiently exhibit the effects of the present invention.
마찬가지로 사례 1의 환자에게 6g의 ADSCs와, 1g의 PRP, 0.2g의 염화칼슘 및 1g의 히알루론산을 주입하고 모든 방법을 동일하게 한 결과의 치료효과는 표 4에 나타낸 바와 같다.Similarly, the therapeutic effect of the result of injecting 6 g of ADSCs, 1 g of PRP, 0.2 g of calcium chloride, and 1 g of hyaluronic acid to all patients in the same case and all the same methods is shown in Table 4.
이를 이하의 표 17과 비교하면 충분하지는 않지만 치료효과가 있음을 나타내고 있다.Comparing this with Table 17 below, it is not sufficient, but shows a therapeutic effect.
마찬가지로 사례 1의 환자에게 6g의 ADSCs와, 2g의 PRP, 0.05g의 염화칼슘 및 1g의 히알루론산을 주입하고 모든 방법을 동일하게 한 결과의 치료효과는 표 5에 나타낸 바와 같다.Similarly, the therapeutic effect of the result of injecting 6 g of ADSCs, 2 g of PRP, 0.05 g of calcium chloride, and 1 g of hyaluronic acid to all patients in the same case was shown in Table 5.
따라서 상기의 조성비는 본 발명의 효과를 충분히 나타낼 수 없음을 알 수 있다.Therefore, it can be seen that the above composition ratio cannot sufficiently exhibit the effects of the present invention.
마찬가지로 사례 1의 환자에게 6g의 ADSCs와, 2g의 PRP, 0.1g의 염화칼슘 및 1g의 히알루론산을 주입하고 모든 방법을 동일하게 한 결과의 치료효과는 표 6에 나타낸 바와 같다.Similarly, the therapeutic effect of the result of injecting 6 g of ADSCs, 2 g of PRP, 0.1 g of calcium chloride, and 1 g of hyaluronic acid to all patients in the same manner was shown in Table 6.
이를 이하의 표 17과 비교하면 충분하지는 않지만 치료효과가 있음을 나타내고 있다.Comparing this with Table 17 below, it is not sufficient, but shows a therapeutic effect.
마찬가지로 사례 1의 환자에게 6g의 ADSCs와, 2g의 PRP, 0.2g의 염화칼슘 및 0.3g의 히알루론산을 주입하고 모든 방법을 동일하게 한 결과의 치료효과는 표 7에 나타낸 바와 같다.Likewise, the therapeutic effect of the result of injecting 6 g of ADSCs, 2 g of PRP, 0.2 g of calcium chloride, and 0.3 g of hyaluronic acid to all patients in the same manner and the same method is shown in Table 7.
따라서 상기의 조성비는 본 발명의 효과를 충분히 나타낼 수 없음을 알 수 있다.Therefore, it can be seen that the above composition ratio cannot sufficiently exhibit the effects of the present invention.
마찬가지로 사례 1의 환자에게 6g의 ADSCs와, 2g의 PRP, 0.2g의 염화칼슘 및 0.5g의 히알루론산을 주입하고 모든 방법을 동일하게 한 결과의 치료효과는 표 8에 나타낸 바와 같다.Similarly, the therapeutic effect of the result of injecting 6 g of ADSCs, 2 g of PRP, 0.2 g of calcium chloride, and 0.5 g of hyaluronic acid to all patients in the same case and all the same methods is shown in Table 8.
이를 이하의 표 17과 비교하면 충분하지는 않지만 치료효과가 있음을 나타내고 있다.Comparing this with Table 17 below, it is not sufficient, but shows a therapeutic effect.
수치범위의 하한을 정한 이유는 상기의 결과에 근거한 것이다.The reason for setting the lower limit of the numerical range is based on the above results.
수치범위의 상한에 대해서 설명하면, 일반적인 이론에 의해 ADSCs와 PRP는 보다 많은 양을 주입하면 효과가 좋은 것으로 알려져 있지만, 본 발명에서 상기 두 성분의 상한을 넘는 양을 주입할 때는 환자에게서 불편함이 있다는 호소에 의해서 정한 것이다. 따라서 불편함을 감소하더라도 보다 빠른 치료를 원한다면 상기 두 성분의 중량비를 증가시킬 수 있다.When explaining the upper limit of the numerical range, according to the general theory, it is known that ADSCs and PRP are effective when injecting a larger amount, but in the present invention, when injecting an amount exceeding the upper limit of the two components, the patient is uncomfortable. It is determined by an appeal. Therefore, even if the discomfort is reduced, the weight ratio of the two components can be increased if a faster treatment is desired.
사례 1의 환자에게 6g의 ADSCs와, 2g의 PRP, 0.5g의 염화칼슘 및 1g의 히알루론산을 주입하고 모든 방법을 동일하게 한 결과의 치료효과는 표 9에 나타낸 바와 같다.The therapeutic effect of the result of injecting 6 g of ADSCs, 2 g of PRP, 0.5 g of calcium chloride, and 1 g of hyaluronic acid to all patients in Case 1 and all the same methods is shown in Table 9.
따라서 상기의 조성비는 본 발명의 효과를 충분히 나타낼 수 없음을 알 수 있다.Therefore, it can be seen that the above composition ratio cannot sufficiently exhibit the effects of the present invention.
사례 1의 환자에게 6g의 ADSCs와, 2g의 PRP, 0.2g의 염화칼슘 및 1g의 히알루론산을 주입하고 모든 방법을 동일하게 한 결과의 치료효과는 표 10에 나타낸 바와 같다.The therapeutic effect of the result of injecting 6 g of ADSCs, 2 g of PRP, 0.2 g of calcium chloride, and 1 g of hyaluronic acid to all patients in the case 1 was shown in Table 10.
이를 이하의 표 17과 비교하면 충분하지는 않지만 치료효과가 있음을 나타내고 있다.Comparing this with Table 17 below, it is not sufficient, but shows a therapeutic effect.
이하의 실시예에서 사례 3의 환자에게 6g의 ADSCs와 2g의 PRP, 0.2g의 염화칼슘, 1g의 히알루론산 및 0.04g의 덱사메타손을 주입하고 모든 방법을 동일하게 한 결과의 치료효과는 표 11에 나타낸 바와 같다.In the following examples, the therapeutic effect of the result of injecting 6 g of ADSCs and 2 g of PRP, 0.2 g of calcium chloride, 1 g of hyaluronic acid, and 0.04 g of dexamethasone to all patients in the following examples is shown in Table 11. As shown.
따라서 상기의 조성비는 본 발명의 효과를 충분히 나타낼 수 없음을 알 수 있다.Therefore, it can be seen that the above composition ratio cannot sufficiently exhibit the effects of the present invention.
이하의 실시예에서 사례 3의 환자에게 6g의 ADSCs와 2g의 PRP, 0.2g의 염화칼슘, 1g의 히알루론산 및 0.05g의 덱사메타손을 주입하고 모든 방법을 동일하게 한 결과의 치료효과는 표 12에 나타낸 바와 같다.In the following examples, the therapeutic effect of the result of injecting 6 g of ADSCs and 2 g of PRP, 0.2 g of calcium chloride, 1 g of hyaluronic acid, and 0.05 g of dexamethasone to all patients in the following examples is shown in Table 12. As shown.
이를 이하의 표 19와 비교하면 충분하지는 않지만 치료효과가 있음을 나타내고 있다.Comparing this with Table 19 below, it is not sufficient, but shows a therapeutic effect.
이하의 실시예에서 사례 3의 환자에게 6g의 ADSCs와 2g의 PRP, 0.2g의 염화칼슘, 1g의 히알루론산 및 0.3g의 덱사메타손을 주입하고 모든 방법을 동일하게 한 결과의 치료효과는 표 13에 나타낸 바와 같다.In the following examples, the therapeutic effect of the result of injecting 6 g of ADSCs and 2 g of PRP, 0.2 g of calcium chloride, 1 g of hyaluronic acid, and 0.3 g of dexamethasone to all patients in the following examples is shown in Table 13. As shown.
따라서 상기의 조성비는 본 발명의 효과를 충분히 나타낼 수 없음을 알 수 있다.Therefore, it can be seen that the above composition ratio cannot sufficiently exhibit the effects of the present invention.
이하의 실시예에서 사례 3의 환자에게 6g의 ADSCs와 2g의 PRP, 0.2g의 염화칼슘, 1g의 히알루론산 및 0.2g의 덱사메타손을 주입하고 모든 방법을 동일하게 한 결과의 치료효과는 표 14에 나타낸 바와 같다.In the following examples, the therapeutic effect of the result of injecting 6 g of ADSCs and 2 g of PRP, 0.2 g of calcium chloride, 1 g of hyaluronic acid, and 0.2 g of dexamethasone to all patients in the following examples is shown in Table 14. As shown.
이를 이하의 표 19와 비교하면 충분하지는 않지만 치료효과가 있음을 나타내고 있다.Comparing this with Table 19 below, it is not sufficient, but shows a therapeutic effect.
이하 실시예에 의해 본 발명을 보다 상세히 설명한다. 실시예는 본 발명을 예시하는 것일 뿐 특허청구범위를 제한하는 것이 아니다.The present invention will be described in more detail with reference to the following examples. The examples are illustrative only of the invention and do not limit the scope of the claims.
실시예Example
이하의 실험은 무혈성 괴사로 인한 환자들의 엉덩이에 자가 지방줄기세포(ADSC), 혈소판 풍부 혈장(PRP), 염화칼슘, 및 히알루론산을 포함하는 조성물을 주입하는 시술을 하였을 때 주목할만한 성공을 보여준 임상 사례 보고이다.The following experiments have demonstrated remarkable success when a composition containing autologous adipose stem cells (ADSC), platelet rich plasma (PRP), calcium chloride, and hyaluronic acid is injected into the hips of patients with avascular necrosis. It is a report.
본 실험의 지방 줄기세포(ADSC)에 요구되는 줄기세포들은 콜라게나제 효소를 가지고 지방 흡입 추출물(lipoaspirate)을 처리하는 과정을 통해 환자들의 복부 부분의 지방조직으로부터 얻었다. 분리작업(아래 더 자세히 설명됨) 후에 줄기세포들을 PRP, 염화칼슘 및 히알루론산과 함께 엉덩이에 주입하였다. 시술 전, 후를 MRI 이미지와 물리치료, 그리고 통증지수(pain score) 데이터를 통해 분석하였다.Stem cells required for the Adipose Stem Cells (ADSC) of this experiment were obtained from the adipose tissue of the abdomen of patients through the process of lipospirate with collagenase enzyme. After isolation (described in more detail below) stem cells were injected into the hip together with PRP, calcium chloride and hyaluronic acid. Before and after the procedure, MRI images, physical therapy, and pain score data were analyzed.
환자의 MRI 데이터 결과는 엉덩이 뼈의 크기에 큰 변화를 보여주었다. 또한 측정된 물리 치료 결과들과 통증지수, 기능 등급 지수가 모두 향상되었다. 따라서 PRP, 염화칼슘 및 히알루론산과 함께 자가 중간엽 줄기세포(MSC)의 주입은 엉덩이 뼈의 재생을 위한 촉망되는(외과수술에 의한 절개나 상처가 없는) 최소한의 외과시술이 될 것으로 전망된다.Patient MRI data showed a significant change in hip bone size. In addition, the measured physiotherapy results, pain index and functional grade index were all improved. Therefore, injection of autologous mesenchymal stem cells (MSC) with PRP, calcium chloride and hyaluronic acid is expected to be a minimal surgical procedure (without surgical incisions or wounds) for hip bone regeneration.
사례 1Case 1
첫 번째 환자는 29세의 한국 여성으로서 1년 이상 오른쪽 엉덩이에 고통을 느끼는 자였다. 병원에 내원하기 약 1년 전부터 환자는 어떠한 외상도 없는 상태인데도 엉덩이에 고통을 느끼기 시작하였다. 어떤 의사는 MRI 판독을 통하여 퇴행성 관절염으로 진단하였다. 오른쪽 무릎 앞에 방사선 치료를 하였지만 여전히 오른쪽 엉덩이에 고통을 느끼고 있었다. 일어서거나, 걷거나 또는 운동할 때 고통은 더욱 심했지만, 휴식을 취할 때는 고통이 경감되었다. 고통은 NSAIDS를 사용하여도 경감되지 않았다.The first patient was a 29-year-old Korean woman who suffered pain in her right hip for more than a year. About a year before he came to the hospital, the patient began to feel pain in the hips without any trauma. Some doctors diagnosed with degenerative arthritis through MRI readings. I had radiation in front of my right knee, but I still felt pain in my right hip. The pain was more severe when standing up, walking or exercising, but the pain was alleviated at rest. The pain was not alleviated with NSAIDS.
MRI를 몇 번 찍은 결과 대퇴골두의 무혈성 괴사 4단계였다. 이를 치료하기 위한 효과적인 비-수술적 방법이 없기 때문에 본 발명에 따른 시술을 받기로 결정하였다. 처음에 환자는 휴식시에 상대적으로 심각한 고통(VAS score 7)으로 평가되고, 일어서거나 걸을 때 고통은 증가되었다(VAS score 9).Several MRI scans revealed stage 4 of avascular necrosis of the femoral head. Since there is no effective non-surgical method for treating this, it was decided to receive the procedure according to the present invention. Initially, the patient was assessed with relatively severe pain at rest (VAS score 7) and increased pain when standing up or walking (VAS score 9).
지방흡인 절차Liposuction procedure
지방흡인(Liposuction) 시술 전 일주일 동안 환자는 코르티코스테로이드, 아스피린, NSAIDs, 그리고 동양 허브치료제 복용을 금지하였다.During the week prior to liposuction, the patient was prohibited from taking corticosteroids, aspirin, NSAIDs, and oriental herbal remedies.
지방흡인을 위해 환자를 수술실로 옮기고 환자를 반듯이 눕혔다. 그 후, 환자를 프로포폴(propofol) 2mg IV 주사와 20mg/hr 속도로 지속적인 주입을 통해 안정화시켰다.The patient was taken to the operating room for liposuction and the patient was laid flat. The patient was then stabilized via propofol 2 mg IV injection and continuous infusion at 20 mg / hr.
베타디엔(provodine-iodine)으로 복부 부분을 소독하고 살균된 천을 덮은 이후 배꼽 아래 5cm에 약 0.5cm를 절개하였다. 그리고 튬네센트 용액(500cc NS + 2% Lidocaine 40cc + 0.5% Marcaine 20cc + Epinephrine 1:1000 0.5cc)을 사용하여 아래 복부 부분을 마취시켰다. 그 다음 3.0 하트만 관을 사용하여 총 160cc의 지방추출물을 추출하였으며 중력에 의해 분리하였다. 그 결과 100cc의 지방조직을 3500 rpm으로 5분간 원심분리하였다. 이 과정을 통해 최종 40cc의 농축된 지방조직, 섬유조직, RBC 및 소수의 유핵세포들을 얻을 수 있었다.The abdomen was sterilized with betadiene (provodine-iodine), covered with a sterile cloth, and cut about 0.5 cm into 5 cm below the navel. And the lower abdomen was anesthetized using lithium Nescent solution (500cc NS + 2% Lidocaine 40cc + 0.5% Marcaine 20cc + Epinephrine 1: 1000 0.5cc). A total of 160 cc of fat extract was then extracted using 3.0 Hartmann tubes and separated by gravity. As a result, 100 cc of adipose tissue was centrifuged at 3500 rpm for 5 minutes. This process resulted in a final 40cc of concentrated adipose tissue, fibrous tissue, RBC and a few nucleated cells.
소화 효소인 콜라게네이스를 원심분리된 지방추출물들과 1:1 비율로 혼합하고 37℃에서 교반하면서 30분간 효소반응을 진행하였다(콜라게나제 A, 37℃에서 30-40분).Collagenase, a digestive enzyme, was mixed at a 1: 1 ratio with centrifuged fat extracts, followed by enzymatic reaction for 30 minutes with stirring at 37 ° C (collagenase A, 30-40 minutes at 37 ° C).
효소반응 후에 지방추출물과 효소를 분리하기 위하여 100g로 3분간 원심분리하였다. 그리고 분리된 효소를 제거하였다.After enzymatic reaction, centrifugation was performed at 100 g for 3 minutes to separate fat extract and enzyme. And the separated enzyme was removed.
이 후 500cc의 D5SR(Dextrose 5% Lactated Ringer)를 사용하여 세 번 와싱하여 효소를 제거하였다. 각각의 와싱 절차 후에 지방추출물은 100g에서 원심분리하였다. 마지막 원심분리 후에 대략 10g의 ADSCs를 획득하였다.After washing with 500cc D5SR (Dextrose 5% Lactated Ringer) three times to remove the enzyme. After each washing procedure, the fat extract was centrifuged at 100 g. Approximately 10 g of ADSCs were obtained after the last centrifugation.
PRP 준비PRP Preparation
ADSCs를 준비하는 동안 4.5cc의 항응고제인 ACD(ANTICOAGULANT ACID CITRATE DEXTROSE) 포뮬라를 가지고 30cc의 자가 혈액을 뽑아서 200g로 5분간 원심분리 하였다. 원심분리 후 상등액은 버리고 1000g으로 5분간 원심분리 하였다. 다시 상층액은 버리고 이 연막(방치한 혈액 표면에 생기는 백혈구, 혈소판의 얇은 막)을 수득하여 이중 2g을, 6g의 ADSCs와 혼합하였다.During the preparation of ADSCs, 30 cc of autologous blood was drawn with 4.5 cc of anticoagulant ACD (ANTICOAGULANT ACID CITRATE DEXTROSE) formula and centrifuged at 200 g for 5 minutes. After centrifugation, the supernatant was discarded and centrifuged at 1000 g for 5 minutes. Again, the supernatant was discarded to obtain this smoke (white blood cells on the surface of the blood left, a thin film of platelets), of which 2 g were mixed with 6 g of ADSCs.
이 혼합물에 스캐폴드로 히알루론산 1g을 첨가하였다. 이렇게 준비된 혼합물에 혈소판 활성화를 위해 0.2g의 CaCl2와 다시 혼합하였다. 1 g of hyaluronic acid was added to the mixture as a scaffold. The mixture thus prepared was mixed again with 0.2 g CaCl 2 for platelet activation.
조성물의 주입Injection of the composition
이렇게 준비된 조성물을 주입하기 위하여 환자를 오른쪽 엉덩이를 위로 향하게 눕게하였다. 베타디엔으로 소독하고 살균 천을 사용하여 청결하게 한 후, 2% 리도케인을 사용하여 엉덩이의 대퇴골부를 마취하였다. 22-게이지 3 1/2니들을 사용하여 이 조성물 9.2g을 초음파의 가이드하에서 대퇴골부에 주입하였다. 그 다음, 환자의 세포의 부착을 위해 다리를 높게하고 30분간 유지하게 하였다. 환자가 퇴원했을 때 가능한 활동을 자제하게 하였다. 1 달동안 이 환자에게 매주 4cc의 PRP와 염화칼슘 0.8cc(PRP: CaCl2=10:2)를 4번 주사하였다.The patient was allowed to lie down with his right hip up to inject the composition thus prepared. After disinfection with betadiene and clean with a sterile cloth, anesthesia was anesthetized with 2% lidocaine. 9.2 g of this composition was injected into the femur under the guidance of ultrasound using a 22-gauge 3 1/2 needle. The legs were then elevated and held for 30 minutes for the attachment of the cells of the patient. The patient was restrained from possible activities when discharged. For one month, the patient was injected with 4 cc of PRP and 0.8 cc of calcium chloride (PRP: CaCl 2 = 10: 2) four times a week.
결과result
이 조성물의 주입 4 주 후에 환자의 고통은 50% 가까이 향상되었고, 12 주 경과 후 환자의 고통은 70% 이상 향상되었다.After 4 weeks of infusion, the patient's pain improved nearly 50%, and after 12 weeks the patient's pain improved over 70%.
도 1에 12주 후에 MRI를 찍은 사진으로서, 상부 관골구에 뼈의 결함이 상당히 매꾸어지고 대퇴골두의 피질하부 부위에서 뼈 매트릭스가 형성될 수 있다는 것을 보여주고 있다. 도 1은 T1 관상 섹션으로서, 상부 관골구와 대퇴골두의 피질하부 부위의 크기가 감소되어 있다. 상부 관골구에서의 뼈 재생(↓) 및 대퇴골구의 피질하부 부위에서의 뼈 매트릭스 강화가 명확하다(↘,↑)A photograph taken after 12 weeks of MRI in FIG. 1 shows that bone defects in the upper tibial bone can be relieved considerably and a bone matrix can form in the subcortical region of the femoral head. 1 is a T1 coronal section with reduced size of the upper cortical and subcortical areas of the femoral head. Bone regeneration in the upper tibia (↓) and strengthening of the bone matrix in the subcortical region of the femur (↘, ↑)
사례 2Case 2
환자는 47세된 한국 남성으로서, 병원에 내원하기 3년 전까지 다이버로서 일해 온 사람이었다. 대락 3년 전부터 오른쪽 엉덩이 부분에 고통을 느끼기 시작하였고 오른쪽 엉덩이의 무혈성 괴사라고 진단되었다. 환자는 3년간 고통이 증가되어 엉덩이 관절 치환술(TKR)을 받을 것으로 권고되었다. 수술에 부담감을 느껴서, 환자는 본 발명의 줄기세포 치료를 받기로 하였다. 시술 전에 MRI를 찍을 결과, 대퇴골두의 무혈성 괴사, 단계 4로서 진단되었다. 지방흡인, PRP제조, 및 이들의 주입을 사례 1과 같이 시술하고 매주 1달간 내원하여 4cc의 PRP와 염화칼슘 0.8cc(PRP: CaCl2=10:2)를 4번 추가적으로 주입하였다.The patient was a 47-year-old Korean man who worked as a diver three years before coming to the hospital. He began to feel pain in his right hip three years ago and was diagnosed as avascular necrosis of his right hip. The patient was recommended to undergo hip arthroplasty (TKR) for three years with increased pain. Feeling burdened with the surgery, the patient decided to receive the stem cell treatment of the present invention. MRI was taken before the procedure, and was diagnosed as avascular necrosis of the femoral head, stage 4. Liposuction, PRP preparation, and their injection were performed as in Case 1 and visited for 1 month each week to inject 4 additional 4cc of PRP and 0.8cc of calcium chloride (PRP: CaCl 2 = 10: 2).
결과result
ADSC의 주입 4주 후에, 환자의 고통은 30%이상 경감되었다. 12주까지 환자의 고통은 약간 경감되었다. 하지만 12주째에 MRI를 수차례 찍은 결과 뼈 결함이 상당히 채워졌고, 대퇴골두의 괴사부위에서의 뼈 매트릭스의 형성 가능성이 보였다.After 4 weeks of infusion of ADSC, the patient's pain was reduced by more than 30%. By 12 weeks the patient's pain was slightly alleviated. However, multiple MRI scans at week 12 showed significant bone defects and the possibility of bone matrix formation at the necrotic site of the femoral head.
도 2에 12주 후에 MRI를 찍은 사진으로서, 시술 3개월 MRI를 보면 뼈 매트릭스 재생이 가능함을 명확히 알 수 있다As a photograph of MRI after 12 weeks in FIG.
사례 3Case 3
환자는 70세의 한국 여성으로서 오른쪽 무릎의 고통을 5년 이상 겪어왔다. 이 환자는 양쪽 무릎 관절을 심하게 사용하는 농장 노동자이다. 오른쪽 무릎의 퇴행성 관절염의 진단을 받고, 스테로이드와 히알루론산을 2, 3년간 여러번 주입받았지만 고통에 차도를 느끼지 못하였다. The patient is a 70-year-old Korean woman who has suffered pain in her right knee for more than five years. This patient is a farm worker with heavy use of both knee joints. He was diagnosed with degenerative arthritis of his right knee and had been injected with steroids and hyaluronic acid several times over the course of two or three years.
그녀는 정형외과에서 전체 무릎 교체(TKR : Total Knee Replacement) 시술을 제의했지만 부작용 때문에 꺼려했고 이후 별다른 상태 호전 없이 물리치료를 받아왔다. 초기 진단 시 환자는 심각한 통증(VAS 통증지수 7)을 나타냈으며, 보행 시 통증이 증가했었다. 또한 다소 부어 있다는 점을 불편하게 생각했다. 물리적 시험에서 다소의 관절 붓기가 있었고, 구부림 정도와 움직임이 감소되어 있는 상태였다. 애프리 및 맥머레이 테스트 결과는 네가티브였고 인대 이완은 없었다. 시술 전 1.5T MRI는 붓기 때문에 오른쪽 무릎의 반월상 연골판의 크기가 감소되었으며 변형된 윤곽을 나타내었다.She offered a total knee replacement (TKR) procedure in orthopedic surgery, but she was reluctant for side effects and has been following physical therapy without any improvement. At initial diagnosis, the patient developed severe pain (VAS pain index 7) and increased pain when walking. I also felt unwell that it was somewhat swollen. There were some joint swellings in the physical examination, and the degree of bending and movement was reduced. The results of the Apri and McMurray tests were negative and there was no ligament relaxation. Because of the swelling of the 1.5T MRI, the meniscus of the right knee was reduced in size and deformed.
사례 1 및 2에서 사용된, 10g의 ADSCs, 10g의 PRP, 2g의 히알루론산 및 2g의 CaCl2와 혼합(PRP:CaCl2=10:2)한 조성물에 1.0g의 덱사메타손을 추가로 첨가하여 혼합한 조성물을 준비하였다. 지방흡인, PRP의 준비는 사례 1에 나타낸 바와 같다.To the composition used in Examples 1 and 2, 10 g of ADSCs, 10 g of PRP, 2 g of hyaluronic acid and 2 g of CaCl 2 (PRP: CaCl 2 = 10: 2) was added and mixed with an additional 1.0 g of dexamethasone One composition was prepared. Liposuction, preparation of PRP is as shown in Example 1.
이 조성물을 주입하기 위하여 환자를 등을 바닥에 대고 반드시 눕히고 오른쪽 무릎을 90도 각도로 세우도록 하였다.. 주입부위를 베타디엔으로 소독하고 소독천으로 청결하게 한 이후에 2% 리도케인으로 슬개골을 마취하였다. 22-게이지 1인치 니들을 사용하여 상기에서 제조한 조성물 8.5cc를 반으로 나누어 무릎의 앞쪽 외측(anterior-lateral)과 앞쪽 내측(anterior-medial)에 주입하였다. 환자를 세포 부착을 위해 30분 동안 부동자세를 유지하도록 지시하였다. 퇴원 후에 가능한 활동을 줄이라고 지시하였다. 이 후 1개월 동안 매주 한 번씩 4주에 걸쳐 4cc의 PRP와 염화칼슘 0.8cc(PRP: CaCl2=10:2)를 주입하였다.In order to inject the composition, the patient should be placed on his back on the floor and his right knee angled at an angle of 90 degrees. After disinfection of the injection site with betadiene and cleaning with a disinfectant cloth, anesthesia was patted with 2% lidocaine. It was. Using a 22-gauge 1 inch needle, 8.5 cc of the composition prepared above was divided in half and injected into the anterior-lateral and anterior-medial of the knee. Patients were instructed to maintain a floating posture for 30 minutes for cell attachment. Instructed to reduce possible activities after discharge. After that, 4cc of PRP and 0.8cc of calcium chloride (PRP: CaCl 2 = 10: 2) were injected once a week for 4 months.
결과result
상기 조성물의 주입 7주 후에 환자의 고통은 80%이상 경감되었고 무릎의 구부림도 마찬가지로 향상되었다. 12주까지 환자의 고통은 90%이상 경감되었고 활동범위도 또한 더욱 향상되었다. Seven weeks after the injection of the composition, the patient's pain was alleviated by more than 80% and the knee flexion improved as well. By 12 weeks, the patient's pain was reduced by more than 90% and the range of activity was further improved.
도 3은 치료 12주 후에 MRI를 찍은 사진으로서, 오른쪽 무릎의 안쪽에 반월상 연골의 두께가 상당히 증대되었다는 것을 볼 수 있다. 도 3은 시상으로서 치료 전, 후에 무릎 안쪽의 반월상 연골 및 인공 연골의 높이가 증대었음을 보여주고 있다(화살표).3 is a photograph taken after 12 weeks of treatment MRI, it can be seen that the thickness of the meniscus cartilage on the inside of the right knee significantly increased. Figure 3 shows that the height of meniscus and artificial cartilage inside the knee increased before and after treatment as sagittal (arrow).
사례 4Case 4
환자는 79세의 한국 여성으로서 양쪽 무릎의 고통을 가지고 있었다. 왼쪽 무릎이 오른쪽 보다 훨씬 고통스러웠다. 그녀는 일생동안 가정주부였다. 양쪽 무릎의 퇴행성 관절염 진단을 받고 스테로이드와 히알루론산을 2,3년간 수차례 주 입받았다. 하지만, 고통에 차도는 없었다. 정형외과의는 전체 무릎 교체(TKR)을 제의했지만, 부작용이 염려되어 이를 거부하였다. 그 후 환자는 물리치료를 받아왔지만 별 차도가 없었다. The patient was a 79-year-old Korean woman who had pain in both knees. The left knee was much more painful than the right. She was a housewife for life. He was diagnosed with degenerative arthritis of both knees and received several injections of steroids and hyaluronic acid for a few years. But there was no pain. The orthopedic surgeon proposed full knee replacement (TKR), but refused because of concerns about side effects. Since then, the patient has had physical therapy but no difference.
시술초기 그녀는 휴식시에도 심한 고통을 가지는 것으로 평가되었고 (VAS점수 8), 걸을 때는 더욱 고통스러웠다.At the beginning of the procedure, she was assessed as having severe pain at rest (VAS score 8) and more painful when walking.
물리 검사에서 무릎의 기형, 관절의 붓기, 감소된 활동범위 및 구부리기의 민감성 등이 있었다. 애플리 및 맥머레이의 시험은 네가티브였고, 인대의 이완은 없었다. Physical examination included knee malformations, joint swelling, decreased range of motion and sensitivity to bending. Apple and McMurray's tests were negative, with no ligament relaxation.
시술 전 전처리 1.5T MRI는 왼쪽 무릎의 뒤쪽 반월상 연골의 크기가 감소되었고 변형된 윤곽을 나타내었다. Pretreatment 1.5T MRI showed a reduced contour and deformed posterior meniscal cartilage of the left knee.
사례 3에서와 같은 방법으로 본 발명의 약제학적 조성물을 시술하였다. The pharmaceutical composition of the present invention was performed in the same manner as in Example 3.
결과result
조성물 주입 4주 후 환자의 고통은 50%이상 개선되었고, 무릎의 구부리기도 마찬가지로 개선되었다. 12주에는 고통은 90%이상 개선되었고 구부리기도 훨씬 개선되었다. After 4 weeks of injecting the composition, the patient's pain improved over 50% and the knee flexion improved as well. At 12 weeks, the pain was improved by more than 90% and the bend was much better.
도 4는 치료 12주 후에 MRI를 찍은 사진으로서, 왼쪽 무릎 관절의 내부에(medial posterior region of meniscus) 반월상 연골의 높이가 상당히 증대되었다는 것을 볼 수 있다. 도 4는 시상으로서 치료 전, 후에 무릎 안쪽의 반월상 연골의 높이가 증대되었음을 보여주고, 인공 연골 또한 더 분명한 차이가 보여져, 연골이 재생되었음을 나타낸다(화살표).
FIG. 4 shows MRI 12 weeks after treatment, showing that the height of meniscus cartilage in the medial posterior region of meniscus is significantly increased. 4 shows that the height of meniscus cartilage inside the knee was increased before and after treatment as thalamus, and artificial cartilage also showed a clearer difference, indicating that cartilage was regenerated (arrow).
Claims (4)
상기 뼈 질환은 대퇴골두의 무혈성 괴사임을 특징으로 하는 조성물.The method of claim 1,
The bone disease is a composition characterized in that the avascular necrosis of the femoral head.
상기 연골 질환은 퇴행성 관절염임을 특징으로 하는 조성물.
The method of claim 3,
The cartilage disease is a composition characterized in that degenerative arthritis.
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| KR1020110023372A KR101038616B1 (en) | 2011-03-16 | 2011-03-16 | Pharmaceutical compositions for the treatment, prevention, or alleviation of bone and cartilage diseases |
| PCT/KR2011/007831 WO2012124873A1 (en) | 2011-03-16 | 2011-10-20 | Pharmaceutical composition for treatment, prevention or alleviation of bone and cartilage diseases |
| PCT/KR2012/001931 WO2012125007A2 (en) | 2011-03-16 | 2012-03-16 | Methods and compositions for the treatment, prevention, and alleviation of bone and cartilage diseases or injuries and hair loss |
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Cited By (5)
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| WO2013180431A1 (en) * | 2012-05-29 | 2013-12-05 | 서울대학교산학협력단 | Composition for enhancing cell engraftment and homing properties, containing prp as active ingredient |
| KR101521411B1 (en) * | 2015-02-05 | 2015-05-19 | 박재우 | Composition for the treatment of joint diseases including bone and cartilage and manufacturing method thereof |
| CN105748517A (en) * | 2016-02-16 | 2016-07-13 | 周滨 | Autogenous adipose-derived stem cell composition and application |
| KR101848830B1 (en) | 2012-09-26 | 2018-04-16 | 본 테라퓨틱스 소시에테아노님 | Formulations involving solvent/detergent-treated plasma (s/d plasma) and uses thereof |
| WO2020145491A1 (en) * | 2019-01-11 | 2020-07-16 | 서울대학교 산학협력단 | Pharmaceutical composition using endogenous cells for preventing or treating musculoskeletal disorders |
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| WO2014153614A1 (en) * | 2013-03-28 | 2014-10-02 | Cell-Innovations Pty Ltd | Improved methods for osteoarthritis therapy |
| PL426950A1 (en) * | 2018-09-07 | 2020-03-09 | Wasilczyk Cezary | Pharmaceutical composition and set of compositions, device for administration of the set of pharmaceutical compositions, method of administration of the set of compositions and use in regeneration of the locomotor system |
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| KR20060099232A (en) * | 2005-03-11 | 2006-09-19 | 양영일 | Composition of Adipose Tissue Therapeutic Agents, Their Preparation, and Their Delivery Methods |
| KR20100075827A (en) * | 2007-08-02 | 2010-07-05 | 바이오테크놀로지 인스티튜트, 아이 엠에이에스 디, 에스. 엘. | Method and compound for the treatment of articular diseases or articular pain, or for the treatment of skin for aesthetic or ohter purposes, and the method of preparation of the compound |
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| WO2016125960A1 (en) * | 2015-02-05 | 2016-08-11 | 박재우 | Composition for treatment of cartilage damage and method for preparing same |
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| WO2012124873A1 (en) | 2012-09-20 |
| WO2012125007A2 (en) | 2012-09-20 |
| WO2012125007A3 (en) | 2012-12-27 |
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