WO2004028556A1 - 冠状動脈狭窄または閉塞治療用徐放性製剤 - Google Patents
冠状動脈狭窄または閉塞治療用徐放性製剤 Download PDFInfo
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- WO2004028556A1 WO2004028556A1 PCT/JP2003/012139 JP0312139W WO2004028556A1 WO 2004028556 A1 WO2004028556 A1 WO 2004028556A1 JP 0312139 W JP0312139 W JP 0312139W WO 2004028556 A1 WO2004028556 A1 WO 2004028556A1
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- gelatin
- bfgf
- gel
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1825—Fibroblast growth factor [FGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention relates to a sustained release formulation for treating coronary stenosis or occlusion. More specifically, the present invention relates to a sustained-release preparation containing an angiogenic factor for treating stenosis or obstruction of a coronary artery, which is a nutritional artery of the heart, a method for producing the same, and a new method for treating stenosis or obstruction of coronary artery using the same. Regarding treatment. Background art
- myocardial ischemia or angina caused by coronary artery stenosis and myocardial infarction resulting from lesion progression are serious diseases whose early detection and appropriate treatment can affect a patient's life. It is. Myocardial infarction is one of the three leading causes of death in Japanese adults, and the development of more effective treatments is urgently needed. Although the administration of circulatory agents such as antihypertensives and vasodilators can slow the progress of these diseases, this is only an adjunct and not a radical treatment.
- the new blood vessels only increase the traffic of the blood vessels in the native myocardium, and the increased blood volume is not sufficient to restore the reduced contractile cardiac function. It is enough. Therefore, there is a need in the art for the development of new therapies to provide sufficient blood to the coronary arteries.
- An object of the present invention is to provide a novel method for treating coronary artery stenosis or occlusion by promoting angiogenesis in a myocardial region, and a preparation for use in the method. Disclosure of the invention
- the present invention provides a pharmaceutical composition for treating coronary artery stenosis or occlusion, which comprises a sustained-release preparation containing an angiogenic factor or a gene encoding the same and a gelatin hydrogel.
- the present invention also provides a method for treating coronary stenosis or occlusion, which comprises using a sustained-release preparation containing an angiogenic factor or a gene encoding the same and a gelatin hydrogel.
- the angiogenic factor is bFGF.
- an angiogenic effect can be obtained by sandwiching a sheet impregnated with bFGF in a gelatin hydrated mouth gel between a myocardial ischemic site and a gastric omental artery having a large number of branches and releasing it slowly.
- New blood vessels are induced from blood vessels outside the heart, increasing blood flow and improving ischemia. That is, by using the sustained-release preparation of the present invention, blood vessels are induced from the outside of the heart. It became possible to form a so-called “bio-bypass” that connects the bypass without using a blood vessel of 5 mm or less, especially lmm or less.
- the present invention is particularly useful as a therapeutic agent for severe ischemic heart disease.
- the sustained-release preparation of the present invention can be used for bypassing (anastomosis) between the gastrointestinal artery (Gastroe piploicartery) or the greater omentum (greater omentum) and the coronary artery (coronary artery) or its branches or capillaries, left or right.
- Omentum which is a connective tissue rich in capillaries that exists to enclose the intestinal tract in the abdominal cavity, uses the right gastric omental artery as the main feeding artery.
- the right stomach omental artery is widely used as a graft (new blood supply route) for coronary artery bypass grafting, and is a high-quality blood vessel with an excellent patency rate in the late stage.
- the sustained release growth factor is placed so as to be sandwiched between the heart and the right gastric omental artery including the omentum, and a bio-bypass is formed to sprout blood vessels from the main artery to the myocardium. .
- the increase in blood flow due to bio-bypass is considered to be more abundant than the increase in blood flow only in collateral circulation in the myocardium, and a high therapeutic effect is expected.
- This could expand the indications for treating severe ischemic hearts, which were previously medically and surgically untreatable, and could bring a great gospel to patients suffering from heart failure and angina. In particular, it may be effective for patients with ischemic cardiomyopathy among patients eligible for heart transplantation.
- other arterial graft materials such as the internal thoracic artery, which is the highest quality in a blood vessel in a living body, and the radial artery having a large blood vessel diameter
- tissue engineering and genetic engineering Vein grafts can be applied to various types of artificial blood vessels, and a wide range of therapeutic strategies can be developed by combining them with conventional surgical treatment.
- the sustained-release preparation of the present invention comprises a vein graft (great saphenous vein or small saphenous vein or vein of the upper arm, or a tissue-engineered or genetically-engineered version thereof).
- a vein graft greater saphenous vein or small saphenous vein or vein of the upper arm, or a tissue-engineered or genetically-engineered version thereof.
- PTFE arterial graft or Gattex®
- Dacron Dacron
- biological grafts human arteries, veins, animal-derived arteries, veins, or those obtained by tissue-engineering or genetic engineering such as decellularization
- coronary arteries it is also useful for bypassing (anastomosis) with its branches or capillaries.
- angiogenic factors examples include basic fibroblast growth factor (bSGF) and other FGFs, vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF), growth factors such as angiovoietin, and hypoxia-inducible factor (HIF) having the activity of inducing the expression of VEGF; and , Site-inducing, chemokines, and adrenamedulin which have angiogenesis.
- bSGF basic fibroblast growth factor
- VEGF vascular endothelial growth factor
- HGF hepatocyte growth factor
- PDGF platelet-derived growth factor
- TGF transforming growth factor
- HGF hepatocyte growth factor
- HGF hepatocyte growth factor
- TGF transforming growth factor
- HGF hepatocyte growth factor
- HGF platelet-derived growth factor
- HGF transforming growth factor
- HGF transforming growth factor
- HGF
- bFGF is a growth factor that was first identified in the pituitary gland and brain as a factor that promotes the proliferation of fibroblasts (3T3) (Rifkin and Moscate 11 i, J. Cell Biol. 109, 1-6, 1989). bFGF has been found to have a wide variety of functions in various tissues and organs, such as angiogenesis, smooth muscle cell growth, healing of small foods, tissue repair, hematopoiesis, and differentiation of nerve cells (Bikfalvi, eta 1 , Endo crine Rev., 18, 26-45, 1997).
- b FGF is used in Europe and the United States at the clinical treatment level in angiogenesis therapy for ischemic heart disease.In Japan, it has already been commercialized as a skin ulcer treatment in the dermatology field and used in clinical trials in the orthopedic field. I have.
- Gelatin used in the present invention is selected from collagen that can be collected from all parts of the body, such as skin, bones and tendons of various animal species including cows, pigs, fish, etc., or a substance used as collagen. Alkaline hydrolysis, acid hydrolysis, And denatured by various treatments such as enzymatic degradation. Denatured gelatin of recombinant recombinant collagen may be used. The properties of gelatin vary depending on the material used and the processing method, but gelatin with any of these properties should be used as a hydrogel material for the sustained release of angiogenic factors such as bFGF in the present invention. Can be.
- Dielectric potential is a measure of the degree of electrostatic charge on a substance (gelatin).
- Particularly preferred gelatins for use in the present invention are the following physical properties: acidic gelatin obtained by an alkaline hydrolysis treatment from collagen, having a molecular weight of about 100 to about 200,000 daltons under non-reducing conditions of SDS-PAGE. And the potential in the aqueous solution is about 15 to about 12 OmV
- the gelatin hydrogel to be obtained is a hydrogel obtained by forming a chemical cross-link between various chemical cross-linking agents and gelatin molecules using the above-mentioned gelatin.
- Examples of the chemical cross-linking agent include a water-soluble carbodiimide such as dataraldehyde, for example, EDC, and a chemical bond between a propylene oxide, a diepoxy compound, a hydroxyl group, a carboxyl group, an amino group, a thiol group, and an imidazole group.
- the condensing agent that is made can be used.
- Preferred is Daltaraldehyde.
- Gelatin can also be chemically cross-linked by heat treatment, ultraviolet irradiation, radiation irradiation, electron beam irradiation, and the like. Further, these crosslinking treatments can be used in combination.
- hydrogels can be prepared by physical crosslinking using salt crosslinking, electrostatic interaction, hydrogen bonding, hydrophobic interaction, and the like.
- the degree of crosslinking of gelatin depends on the desired moisture content, It can be appropriately selected according to the bell.
- the preferred ranges of the concentration of gelatin and the cross-linking agent in preparing the gelatin hydrogel are a gelatin concentration of 1 to 20 wZw% and a crosslinking agent concentration of 0.01 to 1 wZw%.
- the cross-linking reaction conditions are not particularly limited, but are, for example, 0 to 40. Can be done in ⁇ 48 hours. In general, as the concentration of gelatin and the crosslinking agent and the crosslinking time increase, the degree of crosslinking of the hydrated gel increases and the bioabsorbability decreases.
- the shape of the gelatin hydrogel is not particularly limited as long as it is suitable for use in therapy, and examples thereof include a sheet, a column, a prism, a disk, a paste, a sphere, and a particle.
- an aqueous solution of a cross-linking agent for columnar, prismatic, sheet, and disk-shaped gelatin hide gels, add an aqueous solution of a cross-linking agent to an aqueous solution of gelatin, or add gelatin to an aqueous solution of the cross-linking agent and pour it into a mold having a desired shape. It can be prepared by a crosslinking reaction. Further, an aqueous solution of a crosslinking agent may be added to the molded gelatin gel as it is or after drying. To stop the crosslinking reaction, contact with a low molecular substance having an amino group such as ethanolamine or glycine, or add an aqueous solution having a pH of 2.5 or less.
- a low molecular substance having an amino group such as ethanolamine or glycine
- the obtained gelatin hydrid gel is washed with distilled water, ethanol, 2-propanol, acetone, etc., and used for preparation of the preparation. You.
- Spherical and particulate gelatin hydrated gels can be obtained, for example, by using a stirring motor fixed to a three-necked round-bottom flask (for example, Shinto Kagaku Co., Ltd., Three One Mo Yuichi, EYELA miniD. C. Stirrer, etc.) and Teflon ( A propeller for a registered trademark is attached, a gelatin solution is put into a device fixed together with a flask, an oil such as olive oil is added thereto, and the mixture is stirred at a speed of about 200 to 600 rpm. Then, an aqueous solution of a crosslinking agent is added thereto, or an aqueous solution of gelatin is pre-emulsified in olive oil (for example, a vortex mixer Advantec TME-21, a homogenizer,
- the average particle size of the obtained gelatin hydrogel particles varies depending on the gelatin concentration, the volume ratio between the aqueous gelatin solution and the olive oil, the stirring speed, and the like at the time of preparing the above particles.
- the particle size is 1 to 1000 / ⁇ m, and particles having a required size may be appropriately sieved and used according to the purpose. Further, by pre-emulsifying, a fine gelatin hydrogel having a particle size of 20 or less can be obtained.
- a spherical or particulate gelatin hydrogel As another method for preparing a spherical or particulate gelatin hydrogel, the following method can also be mentioned. Put olive oil in a device similar to the above method, stir at a speed of about 200 to 600 rpm, and add a gelatin aqueous solution dropwise to prepare a WZO-type emulsion. After cooling, acetone, ethyl acetate Add and stir, and recover the uncrosslinked gelatin particles by centrifugation. The collected gelatin particles are further washed with acetone, ethyl acetate, etc., then with 2-propanol, ethanol, etc., and then dried.
- the dried gelatin particles are suspended in an aqueous solution of a cross-linking agent containing 0.1% Tween 80, and subjected to a cross-linking reaction with gentle stirring, and 10 OmM containing 0.1% Tween 80 is used depending on the cross-linking agent used.
- the gel particles can be prepared by washing with an aqueous glycine solution or with 0.004N HC1 containing 0.1% Tween 80 and stopping the crosslinking reaction.
- the average particle size of the gelatin hydrogel particles obtained by this method is the same as in the above method.
- the gelatin hydrogel of the present invention can be used after appropriately cutting into a suitable size and shape, freeze-drying and sterilizing. Freeze-drying is performed, for example, by placing gelatin hydrated mouth gel in distilled water, freezing it in liquid nitrogen for 30 minutes or more, or 180 at least 1 hour, and then drying it for 1 to 3 days with a freeze dryer. be able to.
- bFGF used in the present invention
- those prepared by various methods can be used as long as they are purified to such an extent that they can be used as pharmaceuticals.
- bFGF can be obtained by culturing primary culture cells or cell lines that produce bFGF, and separating and purifying from a culture supernatant or the like.
- a gene encoding bFGF may be inserted into an appropriate vector by genetic engineering techniques, inserted into an appropriate host, and transformed to obtain the desired recombinant bFGF from the culture supernatant of the transformant. it can.
- the host cell is not particularly limited, and various host cells conventionally used in genetic engineering techniques, for example, Escherichia coli, yeast, insects, rice plants, or animal cells can be used.
- One or more amino acids in the amino acid sequence of the bFGF thus obtained may be substituted, deleted and / or added, as long as it has substantially the same action as the natural bFGF.
- the sugar chain may be substituted, deleted, Z- or added.
- the bFGF-containing sustained-release gelatin hide gel preparation of the present invention can be obtained, for example, by dropping bFGF into the freeze-dried gelatin hide gel and impregnating the hide mouth gel with bFGF. it can.
- This impregnation operation is usually completed in 4 to 37 for 15 minutes and 1 hour, preferably in 4 to 25 for 15 to 30 minutes, during which time the hydrogel swells with bFGF, and bFGF is combined with gelatin molecules.
- the weight ratio of bFGF to gelatin is about 5 times or less.
- the weight ratio of bFGF from about 5 to about 1 10 4 times the gelatin It is.
- the bFGF sustained release gelatin hydrogel preparation of the present invention has a sustained release effect and a stabilizing effect of bFGF, the function of bFGF can be exhibited in a small amount for a long time. Therefore, bFGF effectively exerts the angiogenesis-promoting function at the administration site, thereby forming a bio-bypass, and can effectively act as a therapeutic agent for coronary stenosis or occlusion. .
- the mechanism of this sustained release is based on the fact that bFGF is physically immobilized on gelatin in hide mouth gel.
- the present inventors have previously attempted sustained-release using a bioabsorbable polymer hydrate mouth gel such as a growth factor, a cytokinin, a monokinin, a lymphokine, and other physiologically active substances.
- a bioabsorbable polymer hydrate mouth gel such as a growth factor, a cytokinin, a monokinin, a lymphokine, and other physiologically active substances.
- the sustained release of an active ingredient having a physiological activity that cannot be achieved with the above materials and control of the sustained release period have been successful.
- it is considered that bFGF is gradually released from the hydrogel by a similar mechanism. When immobilized on a gelatin hydrate gel, bFGF is hardly released from the hydrogel.
- the gelatin molecules become water-soluble and, consequently, bFGF immobilized on the gelatin molecules is released. That is, the sustained release of bFGF can be controlled by the decomposition of the hide mouth gel.
- the degradability of the hide-mouth gel can be changed by adjusting the degree of crosslinking at the time of preparing the hide-mouth gel.
- the interaction of bFGF with gelatin improves the stability in vivo, such as resistance to enzymatic degradation.
- the water content of the gel of the gelatin hydrate according to the present invention greatly affects the sustained release property, and the water content showing a preferable sustained release effect is about 80 to 99 wZw%. Even more preferred are those of about 95-9 SwZw.
- An index that can measure the degree of crosslinking is water content. The higher the water content, the lower the degree of crosslinking and the easier it is to decompose. In other words, the value of this moisture content determines the sustained release (gradual release) of bFGF.
- the sustained-release preparation of the present invention may contain a gene encoding an angiogenic factor.
- a gene is used in such a form that the function can be expressed in the cell when introduced into the cell.
- the D It is used as a plasmid constructed so that NA is transcribed and the encoded angiogenic factor is expressed.
- a promoter region, an initiation codon: a DNA encoding a protein having a desired function, a termination codon, and a terminator region are arranged continuously.
- Such a plasmid can be prepared by inserting a gene encoding a desired angiogenic factor into various plasmids available in the art using an appropriate restriction enzyme site. It can also be prepared by synthetic or semi-synthetic means based on the nucleotide sequence of the gene to be introduced.
- a gelatin hydrogel containing a gene encoding an angiogenic factor can be prepared in the same manner as described above for an angiogenic factor which is a protein.
- a cross-linked gelatin gel prepared by directly adding a cross-linking agent to a 5 to 30% by weight aqueous solution of gelatin, or a cross-linked gelatin gel prepared by immersing an uncross-linked gelatin gel in an aqueous cross-linking agent solution in a solution containing a gene.
- it can be prepared by immersing the gel directly in the gel or drying the cross-linked gelatin gel and re-swelling it in a solution containing the gene. Since nucleic acids are negatively charged, it is preferable to use a positively charged gelatin hydrogel.
- the sustained-release preparation of the present invention can be placed in the vicinity of a coronary artery by surgery or administered by injection. Specifically, it can be placed or administered between the gastrocnemius artery or between the general rule and the coronary artery, between the left or right internal thoracic artery and the coronary artery, between the left or right radial artery and the coronary artery, and the like.
- As the sustained-release preparation of the present invention is gradually degraded in a living body, angiogenic factors are released, and angiogenesis factor acts to regenerate between these blood vessels and the coronary artery or its branches or capillaries. Blood vessels are induced and a bio-bypass is formed. This increases blood flow to the ischemic heart and can achieve effective treatment of coronary stenosis or occlusion.
- vein grafts large saphenous veins or small saphenous veins or brachial veins or those improved by tissue engineering and genetic engineering
- artificial vascular grafts Goretex (registered trademark) (PTFE) or Dacron)
- tissue-engineering and genetic engineering improvements and biological systems (human arteries, veins, animal-derived arteries and veins, or tissue-engineering or
- the sustained-release preparation of the present invention can be placed at or near a lesion site.
- sustained-release preparation of the present invention is gradually degraded in vivo, angiogenic factors are released, and these grafts and the coronary artery or its branches or capillaries are acted upon by the angiogenic factors. New blood vessels are induced between the blood vessels, and a bio-bypass is formed to increase blood flow.
- the sustained-release preparation of the present invention can be used for artificial blood vessel grafts and cell transplantation (cardiomyocytes, skeletal myoblasts, bone marrow cells or bone marrow-derived cells, bone marrow mononuclear cells, ES cells and cells differentiated therefrom, etc.). Can also be used effectively in bypass surgery using).
- the heart was exposed by median sternotomy under general anesthesia using 2.5-3.5 kg Japanese White Heron.
- a branch of the coronary artery (rotating branch) was ligated under administration of an antiarrhythmic agent, and a cardiomyocardial infarction model was prepared. Postoperative ventricular fibrillation may occur, and the patient was observed for about 20 minutes and waited for the condition to stabilize.
- these myocardial infarction heron models were treated with bFGF-containing gelatin hydrid gel.
- bFGF The administration of bFGF was performed by fixing a hydrogel sheet containing the same to the heart surface with a thin thread. Under these conditions, bFGF is released locally over a period of about 2 weeks.
- Cardiac function was evaluated by ultrasonography at 2 weeks and 4 weeks before operation. Body ultrasonography was performed under mild sedation. All groups had good preoperative cardiac function and no difference. At 2 and 4 weeks, group C showed significantly better cardiac contractility and maintained cardiac function.
- group B and group C were examined for omental arteries. Contrast examinations were performed on 6 mice each in groups B and C. Anticoagulation was performed under general anesthesia, and the abdomen was resumed. A 24 G catheter was inserted into the omental artery. The animals were sacrificed and the rope and heart were removed in one lump. A contrast agent was injected from a catheter that had been inserted in advance, and after photographing, the developed film was analyzed.
- heart specimens were removed and the extent of myocardial infarction was examined histologically.
- immunostaining was performed to examine and compare the number of capillaries at the infarct boundary area.
- the extracted heart is cut horizontally from the apical portion of the coronary artery at 2 mm from the apex to the long axis of the heart. Sliced into. This was stained with Masson's trichrome and the area of myocardial infarction occupying the entire left ventricle was calculated.
- group C was significantly smaller than A and B.
- the number of arterioles per unit area by immunostaining was significantly increased in group C compared to the other two groups.
- Angiogenic action of FGF-containing gelatin hydrogel connects extracardiac blood vessels to coronary arteries (bio-bypass) and improves blood circulation of ischemic heart, significantly improving cardiac function. Prevention of deterioration and reduction of myocardial infarction area.
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Abstract
Description
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/528,998 US20060148691A1 (en) | 2002-09-25 | 2003-09-24 | Sustained release preparation for therapy of coronary stenosis or obstruction |
AU2003268663A AU2003268663A1 (en) | 2002-09-25 | 2003-09-24 | Sustained release preparation for treating coronary stenosis or obstruction |
EP03748569A EP1555030A4 (en) | 2002-09-25 | 2003-09-24 | PREPARATION WITH DELAYED RELEASE FOR THE TREATMENT OF CORONARSTENOSIS OR OBSTRUCTION |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2002-279058 | 2002-09-25 | ||
JP2002279058A JP2004115413A (ja) | 2002-09-25 | 2002-09-25 | 冠状動脈狭窄または閉塞治療用徐放性製剤 |
Publications (1)
Publication Number | Publication Date |
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WO2004028556A1 true WO2004028556A1 (ja) | 2004-04-08 |
Family
ID=32040443
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/JP2003/012139 WO2004028556A1 (ja) | 2002-09-25 | 2003-09-24 | 冠状動脈狭窄または閉塞治療用徐放性製剤 |
Country Status (5)
Country | Link |
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US (1) | US20060148691A1 (ja) |
EP (1) | EP1555030A4 (ja) |
JP (1) | JP2004115413A (ja) |
AU (1) | AU2003268663A1 (ja) |
WO (1) | WO2004028556A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN100386431C (zh) * | 2005-03-31 | 2008-05-07 | 北京大学 | 人趋化因子的单克隆抗体 |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP4459543B2 (ja) * | 2003-03-17 | 2010-04-28 | 株式会社メドジェル | 徐放性ハイドロゲル製剤 |
US7429567B2 (en) * | 2005-01-04 | 2008-09-30 | The Brigham And Women's Hospital, Inc. | Sustained delivery of PDGF using self-assembling peptide nanofibers |
JP5025646B2 (ja) * | 2005-11-08 | 2012-09-12 | 公益財団法人先端医療振興財団 | 虚血性心疾患の治療方法 |
DE102005054937A1 (de) * | 2005-11-17 | 2007-05-24 | Gelita Ag | Angiogenese förderndes Substrat |
DE102007024239A1 (de) | 2007-05-16 | 2008-11-20 | Gelita Ag | Angiogenese förderndes Substrat |
US20150272874A1 (en) | 2012-10-29 | 2015-10-01 | Cardio Incorporated | Pulmonary disease-specific therapeutic agent |
CA2849472A1 (en) * | 2013-04-22 | 2014-10-22 | Nitto Denko Corporation | Crosslinked gelatin support and support for controlled release of physiologically active substance using the same |
JP6449166B2 (ja) | 2013-10-15 | 2019-01-09 | 小野薬品工業株式会社 | 薬剤溶出性ステントグラフト |
TW202016288A (zh) * | 2018-06-29 | 2020-05-01 | 國立研究開發法人量子科學技術研究開發機構 | 細胞培養用水凝膠、凝膠套組、細胞培養物之製造方法、及細胞培養用水凝膠之製造方法 |
Citations (3)
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WO1994027630A1 (fr) * | 1993-05-31 | 1994-12-08 | Kaken Pharmaceutical Co., Ltd. | Preparation de gel a base de gelatine reticulee contenant un facteur de croissance de fibroblaste de base |
JP2001316285A (ja) * | 2000-05-01 | 2001-11-13 | Yasuhiko Tabata | 細胞と細胞増殖因子とからなる組織器官の再生のための材料 |
JP2002145797A (ja) * | 2000-11-10 | 2002-05-22 | Seishi Yoneda | ヒドロゲルからなる細胞移植療法用材料 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5652225A (en) * | 1994-10-04 | 1997-07-29 | St. Elizabeth's Medical Center Of Boston, Inc. | Methods and products for nucleic acid delivery |
IL141688A0 (en) * | 1998-09-04 | 2002-03-10 | Scios Inc | Hydrogel compositions for the controlled release administration of growth factors |
DE60229399D1 (de) * | 2001-07-18 | 2008-11-27 | Medgel Corp | Hgf-hydrogel-zubereitungen mit verzögerter freisetzung |
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2002
- 2002-09-25 JP JP2002279058A patent/JP2004115413A/ja active Pending
-
2003
- 2003-09-24 US US10/528,998 patent/US20060148691A1/en not_active Abandoned
- 2003-09-24 WO PCT/JP2003/012139 patent/WO2004028556A1/ja active Application Filing
- 2003-09-24 AU AU2003268663A patent/AU2003268663A1/en not_active Abandoned
- 2003-09-24 EP EP03748569A patent/EP1555030A4/en not_active Withdrawn
Patent Citations (3)
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WO1994027630A1 (fr) * | 1993-05-31 | 1994-12-08 | Kaken Pharmaceutical Co., Ltd. | Preparation de gel a base de gelatine reticulee contenant un facteur de croissance de fibroblaste de base |
JP2001316285A (ja) * | 2000-05-01 | 2001-11-13 | Yasuhiko Tabata | 細胞と細胞増殖因子とからなる組織器官の再生のための材料 |
JP2002145797A (ja) * | 2000-11-10 | 2002-05-22 | Seishi Yoneda | ヒドロゲルからなる細胞移植療法用材料 |
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Title |
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IKEDA, T ET AL: "Experimental study of "Bio-CABG" : A new method to revascularize small coronary arteries", PROG. MED., vol. 23, no. 7, July 2003 (2003-07-01), pages 1768 - 1772, XP002973811 * |
See also references of EP1555030A4 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100386431C (zh) * | 2005-03-31 | 2008-05-07 | 北京大学 | 人趋化因子的单克隆抗体 |
Also Published As
Publication number | Publication date |
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AU2003268663A1 (en) | 2004-04-19 |
EP1555030A4 (en) | 2006-03-29 |
US20060148691A1 (en) | 2006-07-06 |
EP1555030A1 (en) | 2005-07-20 |
JP2004115413A (ja) | 2004-04-15 |
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