WO2010136819A2 - Dry powder fibrin sealant - Google Patents
Dry powder fibrin sealant Download PDFInfo
- Publication number
- WO2010136819A2 WO2010136819A2 PCT/GB2010/050910 GB2010050910W WO2010136819A2 WO 2010136819 A2 WO2010136819 A2 WO 2010136819A2 GB 2010050910 W GB2010050910 W GB 2010050910W WO 2010136819 A2 WO2010136819 A2 WO 2010136819A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- microparticles
- fibrin sealant
- fibrinogen
- thrombin
- dry powder
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/10—Polypeptides; Proteins
- A61L24/106—Fibrin; Fibrinogen
Definitions
- This invention relates to a dry powder fibrin sealant.
- Background of the Invention WO97/44015 describes a dry powder fibrin sealant based on micro- particles of fibrinogen and thrombin.
- the active agents are separately prepared, by spray-drying, to form hollow microspheres having a particle size less than 10 ⁇ m.
- the fibrin sealant, a blend of these components has been demonstrated to be an easy-to-use, stable and efficacious topical haemostat.
- the product can be used immediately, without reconstitution.
- a fibrin sealant according to the present invention is of the general type described in WO97/44105 (or its equivalent US6113948, the content of which is incorporated herein by reference), except that the microparticles of fibrinogen and/or those of thrombrin are larger, e.g. of 50 to 500 ⁇ m. They may be solid. This has the effect of providing greater density and thus momentum, thereby avoiding dusting upon application.
- the larger particle size will also enhance powder flow and thus enable automated filling at large scale.
- the greater density may also improve stability of the protein during and after sterilisation by irradiation.
- the novel fibrin sealant product has efficacy at low fibrinogen levels in severely bleeding wounds.
- Respective fibrinogen-containing and thrombin-containing soluble microparticles can be formulated together, in stable, dry form. This formulation can be subsequently activated, as desired, to give a fibrin sealant that is useful in wound therapy and surgical repair. It can meet the primary objectives of achieving good flow properties, enhanced, effective delivery to the active site, and dissolution only at the site, not in the delivery system.
- the content of fibrinogen in the microparticles containing it may be about 0.1 to 50% w/w, or about 0.5 to 20 w/w, or 5 to 10% w/w, or about 6.5% w/w.
- the content of thrombin in the microparticles containing it may be about 10 to 20,000 IU/g, or 100 to 500 IU/g, or about 25 to 100 IU/g, or about 270 IU/g.
- Microparticles comprising fibrinogen or thrombin that are solid may be prepared by use of a rotary atomiser. Typically, a 2-fluid nozzle is used which utilises compressed air during the atomisation process; this results in the production of hollow microparticles.
- the maximum particle size (X50) of microparticles that can be manufactured using this atomisation system on the Niro Mobile Minor spray dryer is ⁇ 30 ⁇ m.
- Preferred X50 values for the micoparticles of the invention are between 5 and 1000 microns, or between 10 and 500 microns, or between 30 and 200 microns.
- Suitable models and suppliers of such atomisers include the GEA Niro F15D, F160, F01A, Ledebuhr Industries single-stage, dual-stage, Penguin TM electric and PropTecTM hydraulic atomisers.
- Okhawara rotary disc atomisers particularly the Air Floating Atomiser (AFA), K-disc, Vn-disc, Vs-disc and the M- type disc are preferred, the M-type disc featuring a special spin shape that causes a uniform liquid film distribution and therefore a very sharp particle size distribution.
- AFA Air Floating Atomiser
- K-disc, Vn-disc, Vs-disc and the M- type disc are preferred
- the M-type disc featuring a special spin shape that causes a uniform liquid film distribution and therefore a very sharp particle size distribution.
- Most preferred are the Newland rotary atomisers, particularly the NT2 and electric atomisers.
- Such rotary atomisers not only produce solid particles according to the invention but have the advantage of being suitable for the drying of such sensitive proteins, whereby the mechanical droplet formation minimises interaction with the ambient air, or can even be operated in a controlled atmosphere. Also, the relatively low fluid velocities inside the atomiser preserve shear-sensitive fluids.
- Ultrasonic atomisers are also suitable for use in this invention. Suitable suppliers of such ultrasonic atomisers include SonoTek (non-clogging ultrasonic spray nozzle), Sonics, Nevoni, etc.
- Such processes enable the production of solid, soluble protein-containing microcapsules with a defined size distribution.
- Microparticles of the invention may be prepared from a solution of the active component with a saccharide.
- the fibrinogen or thrombin may be full-length or any active fragment thereof. Fragments are known; see Coller et al, J. Clin. Invest. 89:546-555 (1992).
- Fibrinogen raw material may be a frozen solution, although, lyophilised powder which requires reconstitution prior to spray-drying may be used.
- Suitable other proteins may be naturally occurring or recombinant. They may act as "wall-forming materials", as described in WO92/18164, where various examples are given.
- a preferred material is HSA (human serum albumin).
- fibrinogen is spray-dried alone or in the presence of varying amounts of excipients such as HSA (e.g. fibrinogen: HSA ratios of 1 :1 , 1 :3, 3:1 ) and trehalose.
- HSA e.g. fibrinogen: HSA ratios of 1 :1 , 1 :3, 3:1
- Other suitable substitutes for HSA include surfactants, such as Tween 20, Tween 80, Poloxamer 407 or Poloxamer 188.
- Calcium ion e.g. as calcium chloride
- calcium chloride may be added to the microcapsules after processing.
- Microparticles of the invention may be sterilised, if necessary or desired. Sterile processing, electron beam irradiation, ⁇ -irradiation and ethylene oxide are examples of suitable techniques.
- the components of the microparticles in a fibrin sealant of the invention are preferably water-soluble, and the microparticles are preferably obtained by spray-drying a suitable solution
- the microparticles that are obtainable may be free-flowing, discrete and substantially anhydrous, with a residual moisture content preferably no greater than 6% w/w, most preferably no greater than 3% w/w.
- the active components may therefore be delivered as a dry mixture, although separate application of the different microparticles is also envisaged.
- the microparticles are preferably amorphous so as to stabilise the entrapped protein as well as be such a rapidly- soluble state.
- the composition exhibits a glass transition temperature of greater than about 25°C, or about 30 0 C, or about 40 0 C, or about 50°C, as measured by Differential Scanning Calorimetry or modulated Differential Scanning Calorimetry.
- a dry powder fibrin sealant product may be of particular value where application to a large surface area is required. This includes surgery and repair of traumatic injuries to various organs such as the liver and spleen.
- a further advantageous application is in skin grafting for burns patients, and specifically where skin epidermal sheets are cultured in vitro and then transferred to the wound site.
- the use of fibrin sealant in the latter indication may be particularly effective in patients with extensive burns, providing a biocompatible anchorage for skin grafts. It may also be suitable in the treatment of topical ulcers.
- excipients are suitable for use in the invention. They include saccharides such as mono and di-saccharides, including lactose, mannitol and trehalose.
- Cellulose products such as microcrystalline cellulose (Avicel range), methylcellulose, carboxymethyl cellulose, microfine cellulose or hydroxy propyl cellulose, and other materials such as cross-linked polyvinyl pyrrolidone (PVP), used singly or in admixture.
- suitable carriers include include polyethylene glycol (PEG), preferably having a molecular weight of about 1000; polyvinylpyrrolidone (PVP), preferably having an average molecular weight of about 50,000; Poly(acrylic acid), PVA, Poly(methylvinylether co-maleic angydride), Poly(ethyleneoxide), and dextran, typically having an average molecular weight of about 40,000. Tablet disintegrants may be included.
- These materials will absorb moisture from the wound, expand rapidly and thereby enhance the wettability of the hemostatic components of the powder blend.
- An example of such materials is sodium starch glycolate (Explotab or Primojel) that typically has an average particle size in the range of 35-55 ⁇ m and in which about 25% of the glucose units are carboxymethylated.
- Further examples are cross-linked polyvinyl pyrrolidone (polyplasdone), alginates, alginic acid and cross-linked sodium carboxymethylcellulose (Ac-Di-SoI)
- Gums and gelling agents that can be used include tragacanth, karaya gum, soluble starch, gelatin, pectin, guar gum and gellan gum.
- a particularly preferred additive is Emdex, i.e., the hydrated form of dextrates (spray crystallized dextrose containing small amounts of starch oligosaccharides). It is a highly refined product composed of white, free-flowing, spray-crystallized macroporous spheres with a median particle size of 190- 220 ⁇ m.
- An especially preferred component is Non-Pareil Seeds® (Sugar
- Spheres are used in multiple drug units for improved content uniformity, consistent and controlled drug release and high drug stability, and have size ranges from 200 to 2000 ⁇ m.
- a preferred embodiment of the invention utilises a core material, particularly non-pareil seeds or any of the excipients described above, which are then coated with a solution comprising a glass-forming material (trehalose, PVP, etc) and either fibrinogen or thrombin, under conditions which leave the coat in a glassy state and with a low moisture content.
- a suitable coating apparatus includes a fluid-bed dryer and the like.
- the fibrinogen-coated cores are then admixed with the thrombin-coated cores to form a free-flowing dry powder fibrin sealant which presents the clot forming agents in a rapidly dissolving glassy state and a resultant improved time to clot formation.
- the core excipient can either dissolve, swell, or gel to form an adhesive matrix.
- Example 1 illustrates the invention.
- a Uni-Glatt laboratory spray-coater is charged with 800 grams non pareil seeds (mean particle size of 300 microns). Feedstock was prepared by dissolving 7.38 g human fibrinogen in 165 ml water containing 27.51 g trehalose dihydrate, which is then sprayed onto the fluidized cores at an inlet temperature of 50 0 C, an outlet temperature of 4O 0 C, and an atomization air pressure of 3.5 bar, to produce fibrinogen-coated cores. A Uni-Glatt laboratory spray-coater is charged with 800 grams non pareil seeds.
- Feedstock is prepared by dissolving 75,123 IU human thrombin in 165.3 ml water containing 1.15 g calcium chloride dihydrate and 50.73 g trehalose dihydrate, which is then sprayed onto the fluidized cores at an inlet temperature of 50 0 C, an outlet temperature of 40 0 C, and an atomization air pressure of 3.5 bar, to produce thrombin-coated cores.
- coated cores are then blended at the desired ratio using a tumble blender and then packaged in unit dose vials or similar packaging prior to administration.
- Spray dried solid fibrinogen:trehalose microparticles were prepared by dissolving 73.8g human fibrinogen in 1650 ml_ water containing 275.1g trehalose dihydrate. The resultant solution was spray dried on a Niro Mobile Minor spray dryer using the following operating parameters:
- Atomizer stainless steel Newland Rotary Atomizer
- the resultant powder had a particle size (X50, geometric diameter) of 47 ⁇ m and a moisture content (Karl Fisher) of 5.9%.
- Spray dried solid thrombinitrehalose microparticles were prepared by dissolving 751 ,230 IU human thrombin in 1653 ml_ water containing 11.5g calcium chloride dihydrate and 507.3 g trehalose dihydrate. The resultant solution was spray dried on a Niro Mobile Minor spray dryer using the same operating parameters.
Abstract
A fibrin sealant comprises a mixture of first microparticles that comprise fibrinogen, and second microparticles that comprise thrombin, wherein either or each of the microparticles is solid and has a particle size of at least 50 μm.
Description
DRY POWDER FIBRIN SEALANT
Field of the Invention
This invention relates to a dry powder fibrin sealant. Background of the Invention WO97/44015 describes a dry powder fibrin sealant based on micro- particles of fibrinogen and thrombin. The active agents are separately prepared, by spray-drying, to form hollow microspheres having a particle size less than 10 μm. The fibrin sealant, a blend of these components, has been demonstrated to be an easy-to-use, stable and efficacious topical haemostat. The product can be used immediately, without reconstitution. On contact with aqueous fluid such as blood, the exposed active thrombin converts the exposed fibrinogen into insoluble fibrin polymers. Summary of the Invention
A fibrin sealant according to the present invention is of the general type described in WO97/44105 (or its equivalent US6113948, the content of which is incorporated herein by reference), except that the microparticles of fibrinogen and/or those of thrombrin are larger, e.g. of 50 to 500 μm. They may be solid. This has the effect of providing greater density and thus momentum, thereby avoiding dusting upon application. The larger particle size will also enhance powder flow and thus enable automated filling at large scale. The greater density may also improve stability of the protein during and after sterilisation by irradiation.
The novel fibrin sealant product has efficacy at low fibrinogen levels in severely bleeding wounds. Description of Preferred Embodiments
Respective fibrinogen-containing and thrombin-containing soluble microparticles can be formulated together, in stable, dry form. This formulation can be subsequently activated, as desired, to give a fibrin sealant that is useful in wound therapy and surgical repair. It can meet the primary objectives of achieving good flow properties, enhanced, effective delivery to the active site, and dissolution only at the site, not in the delivery system.
The content of fibrinogen in the microparticles containing it may be about 0.1 to 50% w/w, or about 0.5 to 20 w/w, or 5 to 10% w/w, or about 6.5% w/w.
The content of thrombin in the microparticles containing it may be about 10 to 20,000 IU/g, or 100 to 500 IU/g, or about 25 to 100 IU/g, or about 270 IU/g.
Microparticles comprising fibrinogen or thrombin that are solid may be prepared by use of a rotary atomiser. Typically, a 2-fluid nozzle is used which utilises compressed air during the atomisation process; this results in the production of hollow microparticles. The maximum particle size (X50) of microparticles that can be manufactured using this atomisation system on the Niro Mobile Minor spray dryer is ~30 μm. Preferred X50 values for the micoparticles of the invention are between 5 and 1000 microns, or between 10 and 500 microns, or between 30 and 200 microns.
Suitable models and suppliers of such atomisers include the GEA Niro F15D, F160, F01A, Ledebuhr Industries single-stage, dual-stage, Penguin ™ electric and PropTec™ hydraulic atomisers. Okhawara rotary disc atomisers, particularly the Air Floating Atomiser (AFA), K-disc, Vn-disc, Vs-disc and the M- type disc are preferred, the M-type disc featuring a special spin shape that causes a uniform liquid film distribution and therefore a very sharp particle size distribution. Most preferred are the Newland rotary atomisers, particularly the NT2 and electric atomisers. Such rotary atomisers not only produce solid particles according to the invention but have the advantage of being suitable for the drying of such sensitive proteins, whereby the mechanical droplet formation minimises interaction with the ambient air, or can even be operated in a controlled atmosphere. Also, the relatively low fluid velocities inside the atomiser preserve shear-sensitive fluids. Ultrasonic atomisers are also suitable for use in this invention. Suitable suppliers of such ultrasonic atomisers include SonoTek (non-clogging ultrasonic spray nozzle), Sonics, Nevoni, etc.
Such processes enable the production of solid, soluble protein-containing microcapsules with a defined size distribution.
Microparticles of the invention may be prepared from a solution of the active component with a saccharide. The fibrinogen or thrombin may be full-length or any active fragment thereof. Fragments are known; see Coller et al, J. Clin. Invest. 89:546-555 (1992). Fibrinogen raw material may be a frozen solution, although, lyophilised powder which requires reconstitution prior to spray-drying may be used.
Suitable other proteins may be naturally occurring or recombinant. They may act as "wall-forming materials", as described in WO92/18164, where various examples are given. A preferred material is HSA (human serum albumin). For example, fibrinogen is spray-dried alone or in the presence of varying amounts of excipients such as HSA (e.g. fibrinogen: HSA ratios of 1 :1 , 1 :3, 3:1 ) and trehalose. Other suitable substitutes for HSA include surfactants, such as Tween 20, Tween 80, Poloxamer 407 or Poloxamer 188.
Calcium ion, e.g. as calcium chloride, may be incorporated in the thrombin feedstock. Alternatively, calcium chloride may be added to the microcapsules after processing.
Microparticles of the invention may be sterilised, if necessary or desired. Sterile processing, electron beam irradiation, γ-irradiation and ethylene oxide are examples of suitable techniques.
Although the components of the microparticles in a fibrin sealant of the invention are preferably water-soluble, and the microparticles are preferably obtained by spray-drying a suitable solution, the microparticles that are obtainable may be free-flowing, discrete and substantially anhydrous, with a residual moisture content preferably no greater than 6% w/w, most preferably no greater than 3% w/w. This means that the compounds of fibrin sealant in accordance with this invention are not activated until they are wetted, e.g. by coming into contact with liquid at a wound site. The active components may therefore be delivered as a dry mixture, although separate application of the different microparticles is also envisaged. The microparticles are preferably amorphous so as to stabilise the entrapped protein as well as be such a rapidly- soluble state. Preferably the composition exhibits a glass transition temperature of greater than about 25°C, or about 300C, or about 400C, or about 50°C, as measured by Differential Scanning Calorimetry or modulated Differential Scanning Calorimetry.
A dry powder fibrin sealant product may be of particular value where application to a large surface area is required. This includes surgery and repair of traumatic injuries to various organs such as the liver and spleen. A further advantageous application is in skin grafting for burns patients, and specifically where skin epidermal sheets are cultured in vitro and then transferred to the wound site. The use of fibrin sealant in the latter indication may be particularly
effective in patients with extensive burns, providing a biocompatible anchorage for skin grafts. It may also be suitable in the treatment of topical ulcers.
Various excipients are suitable for use in the invention. They include saccharides such as mono and di-saccharides, including lactose, mannitol and trehalose.
Cellulose products such as microcrystalline cellulose (Avicel range), methylcellulose, carboxymethyl cellulose, microfine cellulose or hydroxy propyl cellulose, and other materials such as cross-linked polyvinyl pyrrolidone (PVP), used singly or in admixture. Also, suitable carriers include include polyethylene glycol (PEG), preferably having a molecular weight of about 1000; polyvinylpyrrolidone (PVP), preferably having an average molecular weight of about 50,000; Poly(acrylic acid), PVA, Poly(methylvinylether co-maleic angydride), Poly(ethyleneoxide), and dextran, typically having an average molecular weight of about 40,000. Tablet disintegrants may be included. These materials will absorb moisture from the wound, expand rapidly and thereby enhance the wettability of the hemostatic components of the powder blend. An example of such materials is sodium starch glycolate (Explotab or Primojel) that typically has an average particle size in the range of 35-55 μm and in which about 25% of the glucose units are carboxymethylated. Further examples are cross-linked polyvinyl pyrrolidone (polyplasdone), alginates, alginic acid and cross-linked sodium carboxymethylcellulose (Ac-Di-SoI)
Gums and gelling agents that can be used include tragacanth, karaya gum, soluble starch, gelatin, pectin, guar gum and gellan gum. A particularly preferred additive is Emdex, i.e., the hydrated form of dextrates (spray crystallized dextrose containing small amounts of starch oligosaccharides). It is a highly refined product composed of white, free-flowing, spray-crystallized macroporous spheres with a median particle size of 190- 220 μm. An especially preferred component is Non-Pareil Seeds® (Sugar
Spheres). They are used in multiple drug units for improved content uniformity, consistent and controlled drug release and high drug stability, and have size ranges from 200 to 2000 μm.
A preferred embodiment of the invention utilises a core material, particularly non-pareil seeds or any of the excipients described above, which are then coated with a solution comprising a glass-forming material (trehalose, PVP, etc) and either fibrinogen or thrombin, under conditions which leave the coat in a glassy state and with a low moisture content. A suitable coating apparatus includes a fluid-bed dryer and the like. The fibrinogen-coated cores are then admixed with the thrombin-coated cores to form a free-flowing dry powder fibrin sealant which presents the clot forming agents in a rapidly dissolving glassy state and a resultant improved time to clot formation. The core excipient can either dissolve, swell, or gel to form an adhesive matrix.
The following Examples illustrate the invention. Example 1
A Uni-Glatt laboratory spray-coater is charged with 800 grams non pareil seeds (mean particle size of 300 microns). Feedstock was prepared by dissolving 7.38 g human fibrinogen in 165 ml water containing 27.51 g trehalose dihydrate, which is then sprayed onto the fluidized cores at an inlet temperature of 500C, an outlet temperature of 4O0C, and an atomization air pressure of 3.5 bar, to produce fibrinogen-coated cores. A Uni-Glatt laboratory spray-coater is charged with 800 grams non pareil seeds. Feedstock is prepared by dissolving 75,123 IU human thrombin in 165.3 ml water containing 1.15 g calcium chloride dihydrate and 50.73 g trehalose dihydrate, which is then sprayed onto the fluidized cores at an inlet temperature of 500C, an outlet temperature of 400C, and an atomization air pressure of 3.5 bar, to produce thrombin-coated cores.
The coated cores are then blended at the desired ratio using a tumble blender and then packaged in unit dose vials or similar packaging prior to administration.
Example 2
Spray dried solid fibrinogen:trehalose microparticles were prepared by dissolving 73.8g human fibrinogen in 1650 ml_ water containing 275.1g trehalose dihydrate. The resultant solution was spray dried on a Niro Mobile Minor spray dryer using the following operating parameters:
Atomizer: stainless steel Newland Rotary Atomizer
Inlet temperature: 160°C
Feed rate: 8g / minute
Atomizer voltage: 10.0 V
Outlet temperature: > 800C
The resultant powder had a particle size (X50, geometric diameter) of 47μm and a moisture content (Karl Fisher) of 5.9%.
Spray dried solid thrombinitrehalose microparticles were prepared by dissolving 751 ,230 IU human thrombin in 1653 ml_ water containing 11.5g calcium chloride dihydrate and 507.3 g trehalose dihydrate. The resultant solution was spray dried on a Niro Mobile Minor spray dryer using the same operating parameters.
Claims
1. A fibrin sealant comprising a mixture of first microparticles that comprise fibrinogen, and second microparticles that comprise thrombin, wherein either or each of the microparticles is solid and has a particle size of at least 50 μm.
2. A fibrin sealant as claimed in claim 1 , wherein said first microparticles contain 0.5 to 20% w/w fibrinogen.
3. A fibrin sealant as claimed in claim 1 or claim 2, wherein said second microparticles comprise 25 to 100 IU/g thrombin.
4. A fibrin sealant as claimed in any preceding claim, for use in wound treatment.
5. A method of treating a wound in a patient in need of treatment, comprising administering to the wound a fibrin sealant as claimed in any of claims 1 to 3..
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0909129A GB0909129D0 (en) | 2009-05-28 | 2009-05-28 | Dry powder fibrin sealant |
GB0909129.9 | 2009-05-28 |
Publications (2)
Publication Number | Publication Date |
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WO2010136819A2 true WO2010136819A2 (en) | 2010-12-02 |
WO2010136819A3 WO2010136819A3 (en) | 2011-01-20 |
Family
ID=40863062
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2010/050910 WO2010136819A2 (en) | 2009-05-28 | 2010-05-28 | Dry powder fibrin sealant |
Country Status (2)
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GB (1) | GB0909129D0 (en) |
WO (1) | WO2010136819A2 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2556842A1 (en) | 2011-08-11 | 2013-02-13 | Bioftalmik, S.L. | Composition in the form of film comprising fibrinogen and a fibrinogen activator and the applications thereof |
WO2014135689A3 (en) * | 2013-03-07 | 2014-10-30 | Profibrix Bv | Powder formulation comprising thrombin and fibrinogen |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE13810T1 (en) * | 1981-06-25 | 1985-07-15 | Serapharm Gmbh & Co Kg | ENRICHED PLASMA DERIVES TO ASSIST WOUND CLOSURE AND COVERAGE. |
AU702955B2 (en) * | 1996-05-17 | 1999-03-11 | Quadrant Healthcare (Uk) Limited | Microparticles and their use in wound therapy |
DE19849589C1 (en) * | 1998-10-27 | 2000-06-15 | Glatt Process Technology Gmbh | Fibrin tissue adhesive formulation and process for its manufacture |
-
2009
- 2009-05-28 GB GB0909129A patent/GB0909129D0/en not_active Ceased
-
2010
- 2010-05-28 WO PCT/GB2010/050910 patent/WO2010136819A2/en active Application Filing
Non-Patent Citations (1)
Title |
---|
COLLER ET AL., J. CLIN. INVEST., vol. 89, 1992, pages 546 - 555 |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2556842A1 (en) | 2011-08-11 | 2013-02-13 | Bioftalmik, S.L. | Composition in the form of film comprising fibrinogen and a fibrinogen activator and the applications thereof |
WO2013021066A1 (en) | 2011-08-11 | 2013-02-14 | Bioftalmik S.L. | Composition in the form of a film comprising fibrinogen and a fibrinogen activator and the applications thereof |
WO2014135689A3 (en) * | 2013-03-07 | 2014-10-30 | Profibrix Bv | Powder formulation comprising thrombin and fibrinogen |
AU2014224594B2 (en) * | 2013-03-07 | 2018-05-10 | Mallinckrodt Pharma Ip Trading D.A.C. | Powder formulation comprising thrombin and fibrinogen |
Also Published As
Publication number | Publication date |
---|---|
GB0909129D0 (en) | 2009-07-01 |
WO2010136819A3 (en) | 2011-01-20 |
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