JP2020050659A - 溶剤/界面活性剤処理された血漿(s/d血漿)を含む製剤及びその使用 - Google Patents
溶剤/界面活性剤処理された血漿(s/d血漿)を含む製剤及びその使用 Download PDFInfo
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Abstract
Description
a)細胞は、骨芽細胞分化、及び骨芽細胞分化中に多くの細胞外基質タンパク質遺伝子の発現を調節する多官能性転写因子であるRunx2の発現を含む。
b)細胞は、以下の:アルカリホスファターゼ(ALP)、特に骨−肝臓−腎臓型のALPのうちの少なくとも1つの発現を含み、より好ましくは、オステオカルシン(OCN)、プロコラーゲン1型アミノ末端プロペプチド(P1NP)、オステオネクチン(O)、オステオポンチン(OP)及び/又は骨シアロタンパク質(BSP)、及び/又はデクロシン及び/又はオステオプロテゲリン(OPG)のような1つ又は複数のさらなる骨基質タンパク質の少なくとも1つの発現を含む。
c)細胞は、CD45を実質的に発現しない(例えば、細胞の約10%未満、好ましくは約5%未満、より好ましくは約2%未満の細胞が、CD45を発現し得る)。
d)細胞は、外部周囲を石灰化するか、又はカルシウム含有細胞外基質を合成する能力の兆候を示す(例えば、骨形成性培地に曝露される場合;Jaiswal他 J Cell Biochem、1997、vol.64、295〜312頁を参照)。細胞内部でのカルシウム蓄積及び基質タンパク質への堆積は、例えば45Ca2+中で培養すること、洗浄すること及び再培養すること、続いて細胞内部に存在するか、又は細胞外基質へ堆積される任意の放射能を決定すること(米国特許第5972703号)、又はアリザンレッドベースの石灰化アッセイを使用することにより従来測定することができる(例えば、Gregory他 Analytical Biochemistry、2004、vol.329、77〜84頁を参照)。
e)細胞は、脂肪細胞系列(例えば脂肪細胞)又は軟骨細胞系列(例えば軟骨細胞)の細胞のいずれにも実質的に分化しない。そのような細胞系列へ分化しないことは、当技術分野で確立された条件を誘導する標準的な分化(例えば、Pittenger他 Science、1999、vol.284、143〜7頁)、及びアッセイ方法を使用して試験され得る(例えば、誘導されると、脂肪細胞は通常、脂肪蓄積を示すオイルレッドOで染色して、軟骨細胞は通常、アルシアンブルー又はサフラニンOで染色する)。脂肪生成性及び/又は軟骨形成性分化への実質的に欠如した傾向は、通常、試験した細胞の20%未満、又は10%未満、又は5%未満、又は1%未満が、各々の試験に適用されると脂肪生成性又は軟骨形成性分化の兆候を示し得ることを意味し得る。
例示的な製剤の組成上の特徴:
表1に示されるように、S/D血漿、すなわちOctapharma AG(ラチェン、スイス)からのオクタプラス(登録商標)の製品モノグラフは、S/D血漿及びヒト新鮮凍結血漿(FFP)の間の組成上の特徴の比較を提供する。この情報によれば、製品はほぼ同等の血漿タンパク質組成を大幅に有し、S/D血漿は有意に低いレベルのプラスミンインヒビターを示し得る。
保証実験は、下記のヒト血漿タイプ:S/D血漿、すなわちオクタプラス(登録商標)、ヘパリン処理されたチューブ中で加工処理された血漿、EDTAを含有するチューブ中で加工処理された血漿、又はクエン酸処理された(citrated)チューブ中で加工処理された血漿を用いた。血漿を次のように調製した。血液を、相当するチューブ、すなわちヘパリン処理されたチューブ、EDTAチューブ又はクエン酸処理されたチューブ中に直接収集して、チューブを室温において1500gで10分間遠心分離して、上清として血漿を収集した。S/D血漿が濾過により細胞を除去した血漿であるため、他の血漿タイプは、そのように示される場合、血小板又は細胞片のような細胞の不存在を保証するために0.2μmフィルターに通して濾過した。混合物反応の容量は250μl又は500μlであった。各構成物及び混合物は、37℃で維持した。凝固時間は、各々の血漿タイプ、10又は20%v/vの血清及び2.5又は5%v/v CaCl2(0.546M)を含有する混合物に関して37℃で決定した。凝固時間は、任意選択でチューブの撹拌中又は後に、目視観察により測定した。5個の試料を試験した。結果を表4に要約する。
オクタプラス(登録商標)及びHAによる血塊/ゲル形成:
ヒトS/D血漿、特にオクタプラス(登録商標)の挙動を、関節炎の患者由来の滑液と組み合わせて試験した(n=2)。滑液を、オクタプラス(登録商標)、ヒアルロン酸(10mg/ml ヒアルロン酸ナトリウム、分子量1.8〜2.106Da、Contipro、チェコ共和国により提供)及びCaCl2を含む本発明の実施形態による製剤と1:1の比で接触させた。CaCl2の3つの濃度、すなわち0、2及び4mg/ml CaCl2を試験した。ゲル形成は、タイマーを使用して異なる時点(20〜30分、1時間、2時間)で目視で評価した。粘性は、反応チューブが逆さまにした際に容器の壁上の規定スケールに達するのに、溶液が必要とする時間を測定することにより評価した。試験は、2人の関節炎患者由来の滑液に関して二度実施した。
ヒトS/D血漿、特にオクタプラスLG AB(登録商標)の挙動を、骨関節炎の患者由来の滑液と組み合わせて試験した(n=5)。これらの患者の滑液を、オクタプラスLG AB(登録商標)、HA(10mg/ml ヒアルロン酸ナトリウム、分子量2〜3.106Da、HTL Biotechnology、フランスにより提供)、クロニジン塩酸塩(HCl)(200μg/ml、PCAS laboratory、フィンランドから購入)及びCaCl2(4mg/ml カルシクロ(Calciclo)(登録商標)、Sterop Group、ベルギーにより提供)を含む本発明の実施形態による製剤と1:2(v/v)の比で混合して、臨床条件を模倣した。血塊/ゲル形成は、30分後に37℃(加湿インキュベーター、5%CO2)において目視で評価した。
健常なドナー(n=1)由来の全血と組み合わせてHAを伴うオクタプラスLG AB(登録商標)のゲル化効果を、血小板由来増殖因子を含む基質を形成するその可能性を評価するために研究した。この研究では、オクタプラスLG AB(登録商標)、HA(4mg/ml ヒアルロン酸ナトリウム、分子量2〜3.106Da、HTL Biotechnology、フランスにより提供)及びCaCl2(2mg/ml カルシクロ(登録商標)、Sterop Group、ベルギーにより提供)を含む製剤の挙動を、クエン酸処理されたチューブ(#VF054SBCS07、Venosafe、テルモ)中に収集した全血と組み合わせて試験した。凝固時間は、チューブ撹拌/溶液均質化後に目視観察により測定した。
いくつかの製剤の粘稠度を試験した。製剤は、ヒアルロン酸(ヒアルロン酸ナトリウム、分子量2〜3.106Da、HTL、フランスにより提供)、CaCl2及びオクタプラス(登録商標)又は同容量の次のヒト血漿タイプ(濾過されていない):ヘパリン処理されたチューブ中で加工処理された血漿、EDTAを含有するチューブ中で加工処理された血漿、又はクエン酸処理されたチューブ中で加工処理された血漿を含有した(製剤の組成に関しては表5を参照)。
* オクタプラス(登録商標)は、濾過血漿、すなわち細胞構成物/構成成分を含有しない血漿である。
** 撹拌後に得られる結果
オクタプラス(登録商標)、CaCl2、及び血清を含有する製剤について、ヒアルロン酸(ヒアルロン酸ナトリウム、分子量2〜3.106Da、HTL、フランスにより提供)を含有するものと含有しないものとの間で粘稠性を比較した。ヒアルロン酸を含有しない製剤は、37℃で下記構成成分:オクタプラス(登録商標)2ml、血清222μl及び30mg/ml CaCl2ストック溶液(水中でSigmaのCaCl2塩から調製)22μlを混合することによって調製した。ヒアルロン酸を有する製剤は、37℃で下記構成成分:オクタプラス(登録商標)2ml中にあらかじめ溶解されたHA 8mg、血清222μl及び30mg/ml CaCl2ストック溶液(水中でSigmaのCaCl2塩から調製)22μlを混合することによって調製した。凝固時間は、チューブの目視観察及び撹拌により測定した。試験は一度実施した。
ヒト対象への細胞の骨内送達に適した例示的かつ非限定的な製剤は、ヒトS/D血漿、特にオクタプラス(登録商標)と、20mg/ml HAと、ヒト骨髄から単離された自家性若しくはアロジェニック間葉系幹細胞(MSC)を含む細胞組成物又は骨芽細胞性細胞を含む細胞組成物と、20mg/ml CaCl2と、を含むか、それらから本質的になるか、又はそれらからなる。製剤は患者の骨欠損部位へ投与される。
オクタプラス(登録商標)及びCa2+含有細胞培養培地による血塊/ゲル形成:
血塊形成を、細胞を有さず、ヒトS/D血漿(特にオクタプラス(登録商標))と通常培地(CaCl2を含有)とヒト血清とを含むいくつかの製剤に関して試験した。種々の条件:種々の濃度(例えば、5%v/v、7.5%v/v、又は10%v/vでのオクタプラス(登録商標));種々の通常培地(例えば、DMEM、MEM、PBS、又はPBS+CaCl2);及び5若しくは10%v/v血清の不存在若しくは存在を試験して37℃での血塊形成を確証した。オクタプラス(登録商標)、通常培地(CaCl2を含有)、及び血清を細胞の不存在下で組み合わせた場合、血塊の形成は目視で観察された。
骨髄MSCは、5%v/v、10%v/v又は15%v/v SD血漿、特にオクタプラス(登録商標)を含有する通常培地(DMEM)中で、プラスチックフラスコで57000個の細胞/cm2で蒔いた。フラスコを37℃で5%CO2インキュベーター中に直接配置した。培地のゲル化が、37℃において1時間未満で観察された。ヒトS/D血漿、特にオクタプラス(登録商標)を含有する細胞培地は、接触後30分以内に液体からゲル化(ゲル)に粘稠性を変化させた。
種々のタイプのヒト血漿−オクタプラス(登録商標)、ヘパリン処理されたチューブ中で加工処理された血漿、EDTAを含有するチューブ中で加工処理された血漿、又はクエン酸処理されたチューブ中で加工処理された血漿を有する細胞培養組成物の粘稠性を評価した。
* オクタプラスは、濾過血漿、すなわち細胞構成物/構成成分を含有しない血漿である。
** 3つの細胞培養物は各血漿タイプに関して試験した。
哺乳動物対象への細胞の骨内送達に適した例示的かつ非限定的な製剤は、S/D血漿、特にオクタプラス(登録商標)と、骨髄から単離された自家性若しくはアロジェニック間葉系幹細胞(MSC)を含む細胞組成物又は骨芽細胞性細胞を含む細胞組成物と、2〜8mg/ml CaCl2と、を含むか、それらから本質的になるか、又はそれらからなる。製剤は、頭蓋冠骨切術のマウスモデルにおいて骨欠損部位へ投与される。
S/D血漿及び医薬活性成分を含む例示的かつ非限定的な医薬製剤(ここで、製剤は、骨欠損における治療上の使用に適している。)は、S/D血漿、特にオクタプラス(登録商標)と、増殖因子(30μg/mlでのIL−8)と、2〜8mg/ml CaCl2と、から本質的になるか、又はそれらからなる。製剤は、頭蓋冠骨切術のヌードマウスモデルにおいて骨欠損部位へ投与される。製剤の投与の4週後に、IL−8を含有しない対照と比較して処置マウスでは骨修復が明瞭に観察され得る(図1及び図2)。
Beeck H, Hellstern P. In vitro characterization of solvent/detergent−treated human plasma and of quarantine fresh frozen plasma. Vox Sang. 1998; 74 Suppl 1: 219−23.
Benjamin RJ, McLaughlin LS. Plasma components: properties, differences, and uses. Transfusion. 2012 May; 52 Suppl 1: 9S−19S.
Burgess WH, Maciag T. The heparin−binding (fibroblast) growth factor family of proteins. Annu Rev Biochem. 1989; 58: 575−606.
Cole,B.J., Seroyer,S.T., Filardo,G., Bajaj,S., Fortier,L.A., 2010. Platelet−Rich Plasma. Sports Health 2, 203−210.
Doyle S, O’Brien P, Murphy K, Fleming C, O’Donnell J. Coagulation factor content of solvent/detergent plasma compared with fresh frozen plasma. Blood Coagul Fibrinolysis. 2003 Apr; 14(3): 283−7.
Frescaline G, Bouderlique T, Huynh MB, Papy−Garcia D, Courty J, Albanese P. Glycosaminoglycans mimetics potentiate the clonogenicity, proliferation, migration and differentiation properties of rat mesenchymal stem cells. Stem Cell Res. 2012 Mar; 8(2): 180−92.
Gobbi,A., Bathan,L., 2009. Biological approaches for cartilage repair. J Knee Surg 22, 36−44.
Grimaud,E., Heymann,D., Redini,F., 2002. Recent advances in TGF−beta effects on chondrocyte metabolism. Potential therapeutic roles of TGF−beta in cartilage disorders. Cytokine Growth Factor Rev. 13, 241−257.
Hausser HJ, Brenner RE. Low doses and high doses of heparin have different effects on osteoblast−like Saos−2 cells in vitro. J Cell Biochem. 2004 Apr 1; 91(5): 1062−73.
Hellstern P, Solheim BG. The Use of Solvent/Detergent Treatment in Pathogen Reduction of Plasma. Transfus Med Hemother. 2011; 38(1): 65−70.
Horowitz B, Bonomo R, Prince AM, Chin SN, Brotman B, Shulman RW. Solvent/detergent−treated plasma: a virus−inactivated substitute for fresh frozen plasma. Blood. 1992 Feb 1; 79(3): 826−31.
Lyon M, Rushton G, Gallagher JT. The interaction of the transforming growth factor−betas with heparin/heparan sulfate is isoform−specific. J Biol Chem. 1997 Jul 18; 272(29): 18000−6.
Mast AE, Stadanlick JE, Lockett JM, Dietzen DJ. Solvent/detergent−treated plasma has decreased antitrypsin activity and absent antiplasmin activity. Blood. 1999 Dec 1; 94(11): 3922−7.
McCaffrey TA, Falcone DJ, Brayton CF, Agarwal LA, Welt FG, Weksler BB. Transforming growth factor−beta activity is potentiated by heparin via dissociation of the transforming growth factor−beta/alpha 2−macroglobulin inactive complex. J Cell Biol. 1989 Jul; 109(1): 441−8.
Park SH, Cui JH, Park SR, Min BH. Potential of fortified fibrin/hyaluronic acid composite gel as a cell delivery vehicle for chondrocytes. Artif Organs. 2009 Jun; 33(6): 439−47.
Sachs UJ, Kauschat D, Bein G. White blood cell−reactive antibodies are undetectable in solvent/detergent plasma. Transfusion. 2005 Oct; 45(10): 1628−31.
Svae TE, Frenzel W, Heger A, Romisch J. Quality differences between solvent/detergent plasmas and fresh−frozen plasma. Transfus Med. 2007 Aug; 17(4): 318−20.
本発明の実施形態は例えば下記実施形態1〜15を含む。
実施形態1:
溶剤/界面活性剤処理された血漿(S/D血漿)とグリコサミノグリカンとを含む医薬製剤。
実施形態2:
S/D血漿はヒトS/D血漿である、実施形態1に記載の医薬製剤。
実施形態3:
グリコサミノグリカンはヒアルロン酸又はその誘導体である、実施形態1又は2に記載の医薬製剤。
実施形態4:
1つ又は複数の医薬活性成分をさらに含む、実施形態1〜3のいずれかに記載の医薬製剤。
実施形態5:
血清、好ましくはヒト血清をさらに含む、実施形態1〜4のいずれかに記載の医薬製剤。
実施形態6:
全血又は全血の分画構成成分をさらに含み、好ましくは全血はヒト全血である、実施形態1〜4のいずれかに記載の医薬製剤。
実施形態7:
1つ又は複数の医薬活性成分は、各々独立して、細胞組成物、医薬活性化合物、タンパク質、ペプチド、及び小有機分子からなる群から選択される、実施形態4〜6のいずれかに記載の医薬製剤。
実施形態8:
細胞組成物は、間葉系幹細胞(MSC)、骨前駆細胞、骨芽細胞性細胞、骨細胞、軟骨芽細胞性細胞、及び/又は軟骨細胞を含む、実施形態7に記載の医薬製剤。
実施形態9:
医薬活性化合物はアルファ−2アドレナリン受容体アゴニストであり、好ましくは、アルファ−2アドレナリン受容体アゴニストはクロニジン及びその誘導体からなる群から選択される、実施形態7に記載の医薬製剤。
実施形態10:
医薬活性タンパク質又はペプチドは、増殖因子、好ましくは、線維芽細胞増殖因子(FGF)、トランスフォーミング増殖因子ベータ(TGFB)、血小板由来増殖因子(PDGF)、インターロイキン−8(IL−8)、骨形成タンパク質(BMP)、副甲状腺ホルモン(PTH)、副甲状腺ホルモン関連タンパク質(PTHrp)、及び幹細胞因子(SCF)からなる群から選択される増殖因子、より好ましくは、FGF−2、TGFB−1、PDGF、IL−8、BMP−2、BMP−4、BMP−6、BMP−7、PTH、PTHrp、及びSCFからなる群から選択される増殖因子である、実施形態7に記載の医薬製剤。
実施形態11:
非経口投与用、好ましくは、骨内、骨周囲、関節内若しくは関節周囲投与用又は腱内、腱周囲、靭帯内若しくは靭帯周囲投与用に構成されている、実施形態1〜10のいずれかに記載の医薬製剤。
実施形態12:
骨格筋疾患の処置における使用のための、実施形態1〜11のいずれかに記載の医薬製剤であって、好ましくは骨格筋疾患は骨疾患又は関節疾患である、医薬製剤。
実施形態13:
S/D血漿及びグリコサミノグリカンを含む製剤の、医薬添加剤としての使用。
実施形態14:
S/D血漿はヒトS/D血漿である、実施形態13に記載の使用。
実施形態15:
医薬製剤は、非経口投与用、好ましくは、骨内、骨周囲、関節内若しくは関節周囲投与用又は腱内、腱周囲、靭帯内若しくは靭帯周囲投与用に構成されている、実施形態13又は14に記載の使用。
Claims (15)
- 溶剤/界面活性剤処理された血漿(S/D血漿)とグリコサミノグリカンとを含む医薬製剤。
- S/D血漿はヒトS/D血漿である、請求項1に記載の医薬製剤。
- グリコサミノグリカンはヒアルロン酸又はその誘導体である、請求項1又は2に記載の医薬製剤。
- 1つ又は複数の医薬活性成分をさらに含む、請求項1〜3のいずれか一項に記載の医薬製剤。
- 血清、好ましくはヒト血清をさらに含む、請求項1〜4のいずれか一項に記載の医薬製剤。
- 全血又は全血の分画構成成分をさらに含み、好ましくは全血はヒト全血である、請求項1〜4のいずれか一項に記載の医薬製剤。
- 1つ又は複数の医薬活性成分は、各々独立して、細胞組成物、医薬活性化合物、タンパク質、ペプチド、及び小有機分子からなる群から選択される、請求項4〜6のいずれか一項に記載の医薬製剤。
- 細胞組成物は、間葉系幹細胞(MSC)、骨前駆細胞、骨芽細胞性細胞、骨細胞、軟骨芽細胞性細胞、及び/又は軟骨細胞を含む、請求項7に記載の医薬製剤。
- 医薬活性化合物はアルファ−2アドレナリン受容体アゴニストであり、好ましくは、アルファ−2アドレナリン受容体アゴニストはクロニジン及びその誘導体からなる群から選択される、請求項7に記載の医薬製剤。
- 医薬活性タンパク質又はペプチドは、増殖因子、好ましくは、線維芽細胞増殖因子(FGF)、トランスフォーミング増殖因子ベータ(TGFB)、血小板由来増殖因子(PDGF)、インターロイキン−8(IL−8)、骨形成タンパク質(BMP)、副甲状腺ホルモン(PTH)、副甲状腺ホルモン関連タンパク質(PTHrp)、及び幹細胞因子(SCF)からなる群から選択される増殖因子、より好ましくは、FGF−2、TGFB−1、PDGF、IL−8、BMP−2、BMP−4、BMP−6、BMP−7、PTH、PTHrp、及びSCFからなる群から選択される増殖因子である、請求項7に記載の医薬製剤。
- 非経口投与用、好ましくは、骨内、骨周囲、関節内若しくは関節周囲投与用又は腱内、腱周囲、靭帯内若しくは靭帯周囲投与用に構成されている、請求項1〜10のいずれか一項に記載の医薬製剤。
- 骨格筋疾患の処置における使用のための、請求項1〜11のいずれか一項に記載の医薬製剤であって、好ましくは骨格筋疾患は骨疾患又は関節疾患である、医薬製剤。
- S/D血漿及びグリコサミノグリカンを含む製剤の、医薬添加剤としての使用。
- S/D血漿はヒトS/D血漿である、請求項13に記載の使用。
- 医薬製剤は、非経口投与用、好ましくは、骨内、骨周囲、関節内若しくは関節周囲投与用又は腱内、腱周囲、靭帯内若しくは靭帯周囲投与用に構成されている、請求項13又は14に記載の使用。
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WO2016170112A1 (en) | 2015-04-23 | 2016-10-27 | Bone Therapeutics S.A. | In vitro preservation of therapeutic cells |
NZ747413A (en) * | 2016-04-27 | 2020-09-25 | Anika Therapeutics Inc | Compositions for use in treating tendon degeneration |
CN107789647B (zh) * | 2016-09-05 | 2021-02-02 | 上海赛伦生物技术股份有限公司 | 一种灭活动物血清或血浆中病毒的方法 |
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003511468A (ja) * | 1999-10-08 | 2003-03-25 | ブイ アイ テクノロジーズ インコーポレイテッド | 同種凝集素枯渇血液組成物および同種凝集素枯渇血液組成物の作製方法 |
JP2008505065A (ja) * | 2004-06-29 | 2008-02-21 | リライアンス ライフ サイエンシーズ ピーヴィーティー エルティーディー | ウイルス安全性生物学的流体の調製のための方法 |
JP2010057942A (ja) * | 2001-07-19 | 2010-03-18 | Prochon Biotech Ltd | 血漿タンパク質マトリックスおよびその製造方法 |
JP2010535188A (ja) * | 2007-08-02 | 2010-11-18 | バイオテクノロジー インスティチュート、アイ エムエーエス ディー、 エス.エル. | 関節疾患若しくは関節痛の治療用又は審美的な目的若しくは他の目的のための皮膚の治療用の方法及び化合物並びに化合物の調製方法 |
US20120171182A1 (en) * | 2010-12-31 | 2012-07-05 | Jae Woo Pak | Methods and compositions for the treatment, prevention, and alleviation of bone and cartilage diseases or injuries and hair loss |
Family Cites Families (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4764369A (en) * | 1983-07-14 | 1988-08-16 | New York Blood Center Inc. | Undenatured virus-free biologically active protein derivatives |
US4909940A (en) * | 1987-12-30 | 1990-03-20 | New York Blood Center, Inc. | Extraction of process chemicals from labile biological mixtures with organic alcohols or with halogenated hydrocarbons |
US5811094A (en) | 1990-11-16 | 1998-09-22 | Osiris Therapeutics, Inc. | Connective tissue regeneration using human mesenchymal stem cell preparations |
US5486359A (en) | 1990-11-16 | 1996-01-23 | Osiris Therapeutics, Inc. | Human mesenchymal stem cells |
US5837539A (en) | 1990-11-16 | 1998-11-17 | Osiris Therapeutics, Inc. | Monoclonal antibodies for human mesenchymal stem cells |
US5972703A (en) | 1994-08-12 | 1999-10-26 | The Regents Of The University Of Michigan | Bone precursor cells: compositions and methods |
US20020018777A1 (en) | 1995-01-05 | 2002-02-14 | Alfred M. Prince | Sterilization of virus infected plasma |
US5736396A (en) | 1995-01-24 | 1998-04-07 | Case Western Reserve University | Lineage-directed induction of human mesenchymal stem cell differentiation |
US5827740A (en) | 1996-07-30 | 1998-10-27 | Osiris Therapeutics, Inc. | Adipogenic differentiation of human mesenchymal stem cells |
US5981254A (en) * | 1997-10-30 | 1999-11-09 | Haemacure Corporation | Process for producing thrombin from plasma |
WO2000007639A1 (en) | 1998-08-07 | 2000-02-17 | Tissue Engineering, Inc. | Bone precursor compositions |
MXPA03000203A (es) * | 2000-06-29 | 2004-09-13 | Biosyntech Canada Inc | Composicion y metodo para la reparacion y regeneracion del cartilago y otros tejidos. |
MXPA01011542A (es) * | 2001-11-13 | 2003-05-22 | Alcon Inc | Regeneracion del cartilago articular da°ado por la osteoartritis de grado i y ii, mediante la aplicacion intra-articular de una mezcla de hialuronato de sodio y de condroitin sulfato en un vehiculo de gel. |
DE102004044429B4 (de) * | 2004-09-14 | 2009-04-30 | Biotest Ag | Verfahren zur Herstellung einer Zusammensetzung enthaltend von Willebrand Faktor |
ITPD20050056A1 (it) * | 2005-03-02 | 2006-09-03 | Fidia Farmaceutici | Derivati ammidici del'acido ialuronico in osteoartrosi |
KR20070113876A (ko) * | 2006-05-26 | 2007-11-29 | 메디제네스(주) | 혈장성분을 함유하는 창상 치료용 약학 조성물 |
US20090264477A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc., An Indiana Corporation | Beta adrenergic receptor agonists for treatment of pain and/or inflammation |
AT514675B1 (de) * | 2009-07-23 | 2019-05-15 | Baxalta Inc | Herstellung von faktor h (fh) und fh-derivaten aus plasma |
ES2578478T3 (es) * | 2009-09-17 | 2016-07-27 | Baxalta Incorporated | Coformulación estable de hialuronidasa e inmunoglobulina, y métodos de uso de la misma |
JP5737860B2 (ja) | 2010-04-30 | 2015-06-17 | テルモ株式会社 | ゲル状細胞組成物およびその製造方法 |
IL210162A0 (en) | 2010-12-21 | 2011-03-31 | Omrix Biopharmaceuticals | Viral inactivated platelet extract, use and preparation thereof |
US20120171169A1 (en) * | 2010-12-31 | 2012-07-05 | Jaewoo Pak | Compositions and methods for treating, preventing, or alleviating bone or cartilage diseases |
KR101038616B1 (ko) | 2011-03-16 | 2011-06-03 | 박재우 | 뼈 및 연골 질환의 치료, 예방, 또는 완화용 약제학적 조성물 |
-
2013
- 2013-09-26 AU AU2013322604A patent/AU2013322604B2/en active Active
- 2013-09-26 BE BE2013/0645A patent/BE1021755B1/fr active
- 2013-09-26 DK DK13780080.1T patent/DK2900247T3/en active
- 2013-09-26 PL PL13780080T patent/PL2900247T3/pl unknown
- 2013-09-26 NO NO13780080A patent/NO2900247T3/no unknown
- 2013-09-26 US US14/431,720 patent/US11458166B2/en active Active
- 2013-09-26 SG SG11201502402VA patent/SG11201502402VA/en unknown
- 2013-09-26 ES ES13780080.1T patent/ES2664694T3/es active Active
- 2013-09-26 CA CA2882317A patent/CA2882317C/en active Active
- 2013-09-26 EP EP13780080.1A patent/EP2900247B1/en active Active
- 2013-09-26 CN CN201380050163.4A patent/CN104703612B/zh active Active
- 2013-09-26 WO PCT/EP2013/070085 patent/WO2014049063A1/en active Application Filing
- 2013-09-26 PT PT137800801T patent/PT2900247T/pt unknown
- 2013-09-26 JP JP2015532472A patent/JP2015532919A/ja active Pending
- 2013-09-26 CN CN202110267878.1A patent/CN112999245A/zh active Pending
- 2013-09-26 KR KR1020157010195A patent/KR101848830B1/ko active IP Right Grant
-
2015
- 2015-03-16 IL IL237757A patent/IL237757B/en active IP Right Grant
- 2015-09-09 HK HK15108763.1A patent/HK1208157A1/xx unknown
-
2018
- 2018-07-06 JP JP2018129470A patent/JP2018184425A/ja active Pending
-
2019
- 2019-11-07 JP JP2019202677A patent/JP2020050659A/ja active Pending
-
2022
- 2022-01-04 JP JP2022000211A patent/JP2022061997A/ja active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003511468A (ja) * | 1999-10-08 | 2003-03-25 | ブイ アイ テクノロジーズ インコーポレイテッド | 同種凝集素枯渇血液組成物および同種凝集素枯渇血液組成物の作製方法 |
JP2010057942A (ja) * | 2001-07-19 | 2010-03-18 | Prochon Biotech Ltd | 血漿タンパク質マトリックスおよびその製造方法 |
JP2008505065A (ja) * | 2004-06-29 | 2008-02-21 | リライアンス ライフ サイエンシーズ ピーヴィーティー エルティーディー | ウイルス安全性生物学的流体の調製のための方法 |
JP2010535188A (ja) * | 2007-08-02 | 2010-11-18 | バイオテクノロジー インスティチュート、アイ エムエーエス ディー、 エス.エル. | 関節疾患若しくは関節痛の治療用又は審美的な目的若しくは他の目的のための皮膚の治療用の方法及び化合物並びに化合物の調製方法 |
US20120171182A1 (en) * | 2010-12-31 | 2012-07-05 | Jae Woo Pak | Methods and compositions for the treatment, prevention, and alleviation of bone and cartilage diseases or injuries and hair loss |
Non-Patent Citations (1)
Title |
---|
O. M. THEUSINGER, BRITISH JOURNAL OF ANAESTHESIA, vol. V106 N4, JPN5015009796, April 2011 (2011-04-01), pages 505 - 511, ISSN: 0004583822 * |
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EP2900247A1 (en) | 2015-08-05 |
HK1208157A1 (en) | 2016-02-26 |
CA2882317A1 (en) | 2014-04-03 |
CN104703612A (zh) | 2015-06-10 |
CA2882317C (en) | 2021-04-06 |
JP2018184425A (ja) | 2018-11-22 |
AU2013322604B2 (en) | 2018-01-18 |
US20150238528A1 (en) | 2015-08-27 |
NO2900247T3 (ja) | 2018-06-16 |
DK2900247T3 (en) | 2018-03-05 |
PL2900247T3 (pl) | 2018-05-30 |
ES2664694T3 (es) | 2018-04-23 |
CN112999245A (zh) | 2021-06-22 |
CN104703612B (zh) | 2021-03-19 |
PT2900247T (pt) | 2018-03-28 |
KR20150067209A (ko) | 2015-06-17 |
JP2015532919A (ja) | 2015-11-16 |
KR101848830B1 (ko) | 2018-04-16 |
AU2013322604A1 (en) | 2015-04-02 |
EP2900247B1 (en) | 2018-01-17 |
WO2014049063A1 (en) | 2014-04-03 |
BE1021755B1 (fr) | 2016-01-15 |
SG11201502402VA (en) | 2015-05-28 |
US11458166B2 (en) | 2022-10-04 |
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JP2022061997A (ja) | 2022-04-19 |
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