CN104254347B - Form dextran and the method for thrombin sheet material - Google Patents

Abstract

A kind of method forming hemostasis sheet material.Dextran and water are mixed to form dextran aqueous mixtures.Described dextran aqueous mixtures is formed the first support layer.Fibrinogen and thrombin are mixed to form Fibrinogen and Thrombin mixture.Described Fibrinogen and Thrombin mixture are dispersed in described first support on layer, to form hemostasis sheet material.

Description

Form dextran and the method for thrombin sheet material

Technical field

This invention relates generally to the product with haemostatic properties.Hemostasis is suitable to it is more particularly related to formed The dextran (dextran) used in application and the method for thrombin (thrombin) sheet material.

Background technology

For stoping from wound bleeding, the natural reaction of health is by being referred to as coagulation cascade (coagulation Cascade) complex process starts blood coagulation.Described cascade includes two approach, ultimately results in generation enzyme thrombin, and it is catalyzed fibre Fibrillarin former (fibrinogen) is converted into fibrin (fibrin).

Then, fibrin is cross-linked to form sludged blood (clot), causes hemostasis.For there is no antagonism situation The most serious individual internal wound of (countervening condition), health usually excessively loses from wound to stop The mode of blood carries out this process effectively.But, in the case of serious wounds, or the individual feelings that clotting mechanism is destroyed Under condition, this may be really not so.

But, individual for this type of, may be by directly using coagulation cascade composition, especially thrombin and fibre to wound Fibrillarin is former, and realizes hemostasis.Bleeding wounds wrapping is also common practice, isolates to a certain extent and protects wound district Territory, and also provide for executing stressed means to wound, this also can help to control hemorrhage.

Although at mild trauma or in the case of " controlled " injury (such as operation), these sides can be implemented satisfactorily Method, but the situation that many needs most this kind of process is also those situations being most difficult to provide this kind of process.The example of this kind of wound Including, such as, those are during the struggle or as the unexpected wound of thunder bolt result.In this case, injured individual Existence be likely to be dependent on prevention by the hemostasis reached in the hemorrhage and injured rear first few minutes of wound.Unfortunately, due to This kind of injured situation, possibly cannot use suitable medical intervention immediately.

Particularly, perforating wound (penetrating wound) such as bullet wounds or some wounds caused by shell fragment are processed It is problematic.This is that described injury site includes just owing to being difficult at accurate injury site placement binder and/or therapeutic agent Below good body surface, be difficult or impossible to use routine techniques arrive region.

It is right that Jiang et al. teaches Electrospun in Biomacromolecules, v. 5, p. 326-333 (2004) Rotation sugar acid anhydride fiber (electrospun dextran fibers).The most electric with the medicament that fiber (such as BSA, lysozyme) is combined Spinning enters in fiber.Described fiber is likely to include and other polymer of dextran Static Spinning spinning.

Jiang et al. is at Journal of Biomedical Materials Research Part B:Applied Biomaterials, p. 50-57 discloses electricity spinning fibre in (2006), and it is with polycaprolactone (poly (c- Caprolactone)) as shell with using dextran as the compositions of core.These fibers provide medicament, and (Sanguis Bovis seu Bubali is pure Albumen, BSA) slow release, described medicament is also entered in fiber by Electrospun.

The U.S. Patent No. of Smith et al. 6,753,454 discloses electricity spinning fibre, its comprise hydrophilic polymer and The substantially uniform mixture of the most weak hydrophobic polymer, it can be used for forming binder.Described binder can comprise activating agent (such as dextran).But, disclosed fiber is not easily dissolved in liquid.

The U.S. Patent No. of MacPhee et al. 6,762,336 teaches hemostasis multilamellar binder, and it comprises two fibrins Thrombin layer between former layer.Described binder can also contain other absorbable material, such as glycolic or based on lactic acid poly- Compound or copolymer.Either electricity spinning fibre or dextran fiber are not all taught as the constituent of binder.

The U.S. Patent No. of Smith et al. 6,821,479 teaches a kind of preservation life in dry protectiveness substrate The method of thing material, described substrate includes fiber such as electricity spinning fibre.A kind of composition of described fiber can be dextran, but Homogeneous dextran fiber is not described.

The U.S. Patent No. of Cochrum et al. 7,101,862 teaches for controlling hemorrhage hemostatic composition and side Method.Described compositions includes cellulose goods (such as gauze), covalency or ionomer polysaccharide on it.Described cross-linked polysaccharides is permissible It it is dextran.But, described compositions is not not comprise extrinsic coagulation agent in Electrospun, and described compositions.

The United States Patent (USP) of Wnek et al. discloses No. 2004/0018226, discloses by EDM Technology such as Electrospun raw The fiber produced.Described fibrous inside includes inner cover, for comprising not miscible with fiber material.Dextran is not taught as Fibre composition.

The United States Patent (USP) of Fisher et al. discloses No. 2007/0160653, teaches a kind of hemostatic textile, and it only comprises Blood factor (such as thrombin, Fibrinogen), but described fiber be by Electrospun glass add the second fiber (as silk, pottery, bamboo, Fiber crops, artificial silk etc.) formed.

The United States Patent (USP) of Carpenter et al. discloses No. 2008/0020015, teaches wound dressing, and it comprises various Biodegradable polymers and there is the allos being scattered in described polymer or the water of autologous precursor (such as stem cell) Gel.Described polymer can be prepared by Electrospun, and a kind of polymers compositions can be dextran.But, described poly- Compound can not contact with liquid one and i.e. dissolve, and provides scaffold, to the greatest extent owing to they are necessary for elapsing delivery cell over time Manage the final in situ biodegradation of described polymer.

The United States Patent (USP) of Li et al. discloses No. 2008/0265469, describes Electrospun nano-fibers, and it can comprise the right side Rotation sugar acid anhydride.But, do not describe described nanofiber and be soluble in liquid.

The United States Patent (USP) of Eskridge et al. discloses No. 2009/0053288, teaches a kind of braiding hemostatic textile, its Comprise the glass wire of about 65% and the bamboo fibre line of about 35%.Described fiberglass component with Electrospun, and can stop blooding The factor such as thrombin can be combined with fabric, such as by being immersed in thrombin solution by material.The document shows dextrose Acid anhydride can add as hygroscopic agent.

Need the ways and means that improvement is persistently provided to start the blood coagulation in wound, with stop or at least slow down mistake Blood.Particularly, sustained improvement easy way is needed to be prone to promote the ability of hemostasis in serious wounds, particularly by medical matters Personnel implement immediately treat limited or can not in the case of.

The United States Patent (USP) of Bowlin et al. discloses No. 2011/0150973, discloses a kind of to target location delivery one Or the method for plurality of target medicament.Described method includes target location application or delivers the hemostasia products stopped blooding.Described hemostasis Hemostasia products include contacting with liquid and the Electrospun dextran fiber that dissolves.The hemostasia products of described hemostasis also include with One or more target agent that described Electrospun dextran fiber is combined.Application or delivery cause described in target location Electrospun dextran fibrolysis is in liquid, thus discharges one or more target agent in liquid.

Summary of the invention

The method that one embodiment of the invention relates to forming hemostasis sheet material.Dextran and water are mixed to form dextrorotation Sugar acid anhydride-aqueous mixtures.Described dextran-aqueous mixtures is formed the first support layer (support layer).By fibrin Former and thrombin is mixed to form Fibrinogen and Thrombin mixture.Described Fibrinogen and Thrombin mixture are disperseed Support on layer, to form hemostasis sheet material described first.

Accompanying drawing explanation

Accompanying drawing is included to offer and is further appreciated by embodiment, and it is merged in and constitutes the part of this specification. Accompanying drawing explanation embodiment, and together with the description for explaining the principle of embodiment.Due to by with reference to following detailed Thin description better understood when them, and many expection advantages of other embodiment and embodiment will readily appreciate that.Attached Element in figure is not necessarily drawn in ratio relative to each other.Similar label represents corresponding similar portion.

Fig. 1. the schematic diagram of electric spinning device.The key element of electrospinning system includes high voltage power supply, for polymer Raw material bin and ground connection mandrel (grounded mandrel).This system uses cylindrical target mandrel；But, electrospinning process May be adapted to produce more complicated shape.Single and/or multiple polymer can be separately or simultaneously from one or more raw materials Bin is transported to electric field.Polymer different and unique from independent source Electrospun in chronological order can be used to produce lamination Structure.

Fig. 2 A and B. A, air brush base dextran process schematic representation；B, electric mist technique the dextran produced is fine Dimension.The quantity of material described is possible the amount of the most about 2 hemostasia products.Note the setting-out of material.Use electric field by dextran It is targeted to mandrel.

Fig. 3. the scanning electron micrograph of Electrospun dextran fiber.The nominal average cross sectional diameter of single fiber It it it is 1 micron, it is provided that substantial amounts of surface area.

Fig. 4 A-E. is formed the schematic diagram of exemplary hemostasia products by Electrospun dextran fiber.A, with the support of non-property Material is as the hemostasia products of backing (backing)；B, with the hemostasia products of netted support material；C, with non-property backing Hemostasia products with netted support material electricity spinning fibre maintained on backing；D, for hindering therapeutic agent delivery to deep layer The hemostasia products of mouth；E, for the optional embodiment by the hemostasia products of therapeutic agent delivery to deep layer wound.

Fig. 5 A and B. is exposed to the animal body based intracellular cvtokine of salmon Fibrinogen/thrombin hemostasia products (cytokine) change of level.(A) IL-1 β, IL-6, TNF-α, IFN-γ, the level of IL-4 and IL-10 are illustrated as The log ratio of the peak level after the Blood Cytokines level determined during initial surgery implantable intravascular mouth and exposure.Front Change is all shown in inflammatory reaction (IL-1 β, IL-6, TNF-α, IFN-γ) and humoral response (IL-4 and IL-10).(B) individual The change of body animal based intracellular cvtokine shows that first exposure (the first arrow) and venoclysis albumen (the second arrow) subsequently lure Deriving reaction, this reaction can detect in the upper sample once taking blood.

The immunoglobulin that Fig. 6 A-F. is produced by western blotting qualitative evaluation pig response salmon protein.(A) salmon Fish (Sal), people (Hu) and the fibrinogen preparation of pig (Sw) and with the corresponding albumen coming from two kinds of animal (B and C) serum The PAGE of matter trace.These groups show the serum profiles of the blood before exposure and after final euthanasia.By special Property HRP anti-pig IgG second antibody visualize the IgG occurring in serum according to the protein that is attached in gel sample of detection Isotype.IgG heavy chain and the position of light chain composition in arrow instruction pig albumen swimming lane, also can be by second antibody identification.Left side (kDal × 10^-3) show molecular weight.(D) salmon (Sal), people (Hu) and the thrombin preparation of pig (Sw) and with coming from (C and The PAGE of the corresponding Western blotting of the same animals serum D) illustrated.In these animals, E recognizes thrombin, but At F(arrow) salmon protein swimming lane in have faint reaction.Camera calibration in detecting system is to the heavy chain pig blood coagulation on film Pheron is the white ribbon in F.

Fig. 7 A-D. is exposed in the animal body of salmon thrombin/Fibrinogen hemostasia products via transdermal patches program The time course that antibody occurs.Anti-igg reagent is used to carry out ELISA.Following further antigens is used as the target in ELISA: (A) salmon is fine Fibrillarin is former, (B) salmon thrombin, (C) human fibrinogen and (D) human thrombin.Observe at sample sets A subsequently, B, C Absorbance increase betide venoclysis salmon protein after.Each curve represents the data from different animals.

Fig. 8 A-D. is exposed in the animal body of salmon thrombin/Fibrinogen hemostasia products via abdominal part paster program The time course that antibody occurs.Anti-igg reagent is used to carry out ELISA.Following further antigens is used as the target in ELISA: (A) salmon is fine Fibrillarin is former, (B) salmon thrombin, (C) human fibrinogen and (D) human thrombin.

Skin healing process after Fig. 9 A-D. through thickness wound.The is hindered from (B) of comparison (A) and the process of salmon hemostasia products The image of sampling in 7 days, display necrotic fibres concretion is filled with wound defect (*) and along with the wound after initial blood coagulation is healed The epithelial cell projection at the most oriented wound center in two cases of conjunction process.(H&E dyes, scale=100 um).From comparison (C) show competed by the generation of Hypertrophic and hyperkeratotic epidermis with (D) sampling hindered the 28th day that processes of salmon hemostasia products Property re-epithelialization.(H&E dyes, scale=100 um).

Figure 10. the schematic diagram of coagulation cascade.

Detailed description of the invention

The method that one embodiment of the invention relates to being formed hemostasia products by multiple sheet material hemostatic material.As formation The initial step of hemostasia products, prepares the sheet material of hemostatic material.

Sheet material has relatively uniform thickness and outward appearance.Form the sheet material enhancing standard with relatively uniform thickness and outward appearance Hemostasia products is really used to treat the ability of particular injury.

When hemostasia products is applied to injury site, discharge described material for manufacturing the material dissolving of hemostasia products To injury site, and provide haemostatic effect.

In one embodiment, action site is wound bed (wound bed), and the work delivered by this hemostasia products Property agent be to participate in the factor of coagulation cascade or medicament, such as thrombin and Fibrinogen.Use this hemostasia products to wound to cause Dissolving in dextran fiber blood in wound bed, this causes again activating agent release or is delivered to or enters this site.

The thrombin being combined with hemostasia products and fibrinogenic form are to have life when they touch blood Thing activity.Therefore, when dissolving, thrombin action, in Fibrinogen, is translated into fibrin, then shape in wound Become sludged blood, stop blood to flow out.

The present invention uses layer, and it makes the easy commercialization of product, and the composition in hemostasia products is more uniformly divided Dissipate.

The present invention provides dextran fiber, particularly Electrospun dextran fiber.Described Electrospun dextran is fine Dimension can make the various hemostasia products being applicable to various uses.Generally, by one or more targets (interest) material with Electrospun dextran fiber in described hemostasia products is combined, and for example, delivers one or more target substances to target liquid The purpose of body.When contacting with liquid, Electrospun dextran fiber dissolved within one relatively short period, and was connected The material closed is released to liquid environment.

In one embodiment of the invention, Electrospun dextran fiber is formed as hemostasia products.Hemostasia products Generally including the activating agent being combined with described Electrospun dextran fiber, inciting somebody to action by action site being used hemostasia products Described bioactive agent delivery delivers to action site (such as wound).

Action site contains maybe containing liquid, and will ought be applied to action site by hemostasia products, in hemostasia products Electrospun dextran fibrolysis is in liquid, and the activating agent that is combined with dextran fiber or be trapped in dextrose Acid anhydride fiber mat is interior or activating agent around is discharged in liquid.

In one embodiment, action site is wound bed, and the activating agent delivered by this hemostasia products is to participate in The factor of coagulation cascade or medicament, such as thrombin and Fibrinogen.Using this hemostasia products to wound causes dextran fine Dimension is dissolved in the blood in wound bed, and this causes again activating agent release or is delivered to or enters this site.

The thrombin being combined with hemostasia products and fibrinogenic form are to have life when they touch blood Thing activity.Therefore, when dissolving, thrombin action, in Fibrinogen, is translated into fibrin, then shape in wound Become sludged blood, therefore stop blood to flow out.

In some embodiments of the present invention, only use and spin dextran fiber, after therefore sludged blood is formed, just do not have Be necessary disturb sludged blood to remove hemostasia products composition because what not leaving in this site.In other embodiments, As described below, hemostasia products can include other material, as supported or back lining materials, initial quickly use hemostasia products after, can Can remove subsequently to process wound by conventional method further.

Electrospun is that a kind of on-mechanical processes strategy, and can extend to adapt to Large Copacity demand, meets at commercialization The needs of reason.Fig. 1 provides and arranges schematic diagram for a type of of Electrospun.In the process, electricity consumption stream injects polymerization Thing solution or melt are to set up charge unbalance.Then, charged solution is disposed adjacent to ground connection target (in FIG, the ground connection heart Axle).

At critical voltage, charge unbalance starts to overcome the surface tension of source of polymer, forms electrified jet.At electric field In, jet is directed to ground connection target and carrier solvent evaporation.As it is shown in figure 1, depend on reaction condition and used in this process Polymer, available Electrospun produces fine aerosol or the continuous print non-woven mat of fibrous material of material.

For many polymer, the character of electro-spinning process essentially provides the Altitude control to gained fibre diameter. It is present in the initial concentration of polymer in described Electrospun solution by regulation, simply choosing property can realize micron to nanometer The diameter of level.By controlling the motion of the ground connection target relative to described source solution, fibril can be deposited into random matrix or heavy Amass into along an array limiting axis orientation arrangement.

Fig. 2 A shows the second schematic diagram of electric spinning device.The key element of electrospinning system includes high voltage power supply, use Raw material bin and ground connection target center axle in polymer.The system described uses cylindrical target mandrel；But, electrospinning process can Be suitable to produce more complicated shape.

Single and/or multiple polymer separately or simultaneously can be transported to electricity from one or more raw material bins ?.Additionally, polymer different and unique from independent source Electrospun in chronological order can be used and produces laminated construction.Fig. 2 B Show the about 10 grams of dextrans being dissolved in deionized water of the Electrospun result to circular spindle target, as in following enforcement Described in example 1.Fig. 3 shows sweeping of the Electrospun dextran fiber of the average cross-sectional diameter about 1 micron of single fiber Retouch electron micrograph.

Those skilled in the art is not it will be recognized that Electrospun is the unique channel producing dextran fiber.Can lead to Other method crossing atomization (aerosolization) produces such fiber.But, electric field contributes to effective collection of fiber And Electrospun may produce fiber evenly.Can also be used for spinning other technology of dextran fiber, including those at Luo Et al. U.S. Patent No. 7,067,444, the U.S. of the U.S. Patent No. of Bogue et al. 6,116,880 and Fuisz et al. Those technology described in patent the 5th, 447,423, its respective full content is both incorporated herein by reference.

Especially, so-called " cotton candy machine (cotton-candy machines) " (electrostatic force with or without applying) The dextran fiber being suitably adapted for manufacturing the present invention uses.In following embodiment 2, it is provided that prepare dextrose of the present invention The more detailed description of the method for acid anhydride fiber.

Other method is included between two plates or other flat surfaces compression dextran solution, and by two plates or table Face is drawn apart from one another, generally repeats.Dextran fiber is formed between two surfaces.

In some embodiments, use other material rather than dextran to form fiber to produce for the hemostasis of the present invention In product, the when that especially (but not limited to) using cotton candy machine.The example of this kind of material includes but not limited to saccharide, such as Fructus Vitis viniferae Sugar, sucrose etc..

For producing the commercially available dextran of electricity spinning fibre of the present invention, can be by some lactobacillus cell surface Enzyme catalysis and from Sucrose synthesis, most notable lactic acid bacteria be Leuconostoc mesenteroides (Leuconostoc mesenteroides) and Streptococcus mutans (Streptococcus mutans).Dextran is that a kind of complexity, branched chain glucans (glucan) are (by being permitted The molecular polysaccharide of many D-Glucoses), it is made up of the chain of various length (such as from 10 to 200 kilodaltons).Straight chain is by Portugal α-1 between grape glycan molecule, 6 glycosidic bonds composition, and side chain by α-Isosorbide-5-Nitrae glycosidic bond (and in some cases also have α-1,2 and α- 1,3 glycosidic bonds) start.

The dextran being available commercially is in wide molecular weight ranges, such as from about 10 kilodaltons (kDa) to about 200kDa.Commercial formulation is the mixture of the dextran of different molecular weight, generally in narrower weight range and permissible According to such as, the dextran of " low " or " high " molecular weight provides.Such as, " Dextran 40 " has the mean molecule of 40 kDa Amount, " Dextran 75 " has the mean molecule quantity of 75 kDa, etc..

In an embodiment of the present invention, for the typical molecular weight ranges of dextran of Electrospun from about 10 to about 200kDa, or from about 25 to about 200kDa, or from about 50 to about 200kDa, or from about 75 to 200 kDa, and usually from about 60 to 90 kDa, or from about 100 to about 200kDa.

It addition, it will be appreciated by those skilled in the art that the median magnitude of dextran molecule in dextran preparation (median size) also has the effect that: if intermediate value weight is height by specified quantitative, can use less dextran shape Become the fiber of desired amount.

It is said that in general, as follows for the condition of Electrospun dextran: ambient temperature is from about 60 to about 75 °F, the wettest Degree is from about 30% to about 40%, and the most at least about 20%.Obtained by fiber be typically nanometer at cross-sectional diameter Or in the range of millimeter, generally from about 0.75 micron to about 1.25 micron.

Described electricity spinning fibre is " being dried ", should avoid exposure to humidity, to prevent Premature disintegration.But, some water It is combined with fiber, and fiber composition can containing the water from about 7 to about 8%, but be worked as by x-ray irradiation sterilizing fine During dimension, it is necessary to less than about 5%.

The hemostasia products of the present invention is generally formed by substantially uniform Electrospun dextran.The right side of each hemostasia products Rotation sugar acid anhydride amount can be extensively varied, and this depends on the size of the hemostasia products manufactured, and typical hemostasia products formula is every Individual hemostasia products uses from about 5-10 gram dextran (usual 100,000-200,000 Mr).

But, this scope can extend widely, such as paramount from the most about 0.5 gram or less (for little hemostasia products) Reach each hemostasia products 100 or more grams (for big hemostasia products).In some embodiments of the present invention, small amount is used The activating agent that will be delivered by hemostasia products of dextran (such as, each hemostasia products about 0.1 is to about 0.5 gram of dextran) It is useful for being concentrated into smaller size smaller.

The more important thing is in solution and be spun into the concentration of dextran of fiber by it.The solution being commonly used for Electrospun is right The concentration of rotation sugar acid anhydride be every milliliter of (ml) solvent from about 0.1 to about 10 gram in the range of, or every milliliter from about 0.5 to about 5 gram, and And usual such solution concentration be about 1 gram every milliliter ± about 0.15 milligram (mg).Preferred scope is every milliliter and to be spun The solution of silk is gram dextran from about 0.9 to about 1.1.

Those skilled in the art it will be recognized that due to the change of dextran preparation middle-molecular-weihydroxyethyl scope, and due to Claim the commercial preparations of specific molecular weight range criticize between intrinsic change, typically need to test every batch of dextran about electricity The performance of spinning.This test is within the general knowledge of those skilled in the art, and is usually directed to be dissolved in the one of suitable solvent The Electrospun test of the dextran of series concentration, to determine which concentration results has the most desired fiber properties, such as Stability (such as to hot, wet etc.), uniformity, cross-sectional diameter etc..

Those skilled in the art it will be recognized that when attempt new lot dextran time, successful important indicator right and wrong The most significantly.In spinning solution, dextran causes from pin " splash (spitting) " very little, but dextran is led too much Cause the generation of dry drop, or be difficult to spinning at all.

Equally, when humidity is too low, the result that can be similar to, i.e. can not form fiber and in some cases can not It is effectively targeted in ground connection mandrel.These characteristics can be assessed according to method known in those skilled in the art, but be not limited to regard Feel and observe that heat and/or irradiation, by electron microscope observation, dissolubility test, are resisted by fibre strength and flexible test Property, color and tendency of fading, etc..It should be understood by those skilled in the art that all these test can be in the heat of various conditions, humidity When carry out.It is used as zoopery assessment formula.

The area (length and width) of hemostasia products of the present invention can be extensively varied, and can be joined by regulation spinning Number is adjusted.Additionally, dextran fiber mat can cut into desired size after spinning.Generally, hemostasia products Length and/or width, from about 0.5 centimetre or less to about 30 centimetres or more, but it is also contemplated that greater or lesser chi Very little.

Depending on the desired use of hemostasia products, the height of hemostasia products or thickness can be very different equally.? In some embodiment, hemostasia products has the thickness of about 1 millimeter to about 5 centimetres.

The thickness (being correlated with volume) of hemostasia products may affect the rate of dissolution of dextran when contacting with liquid.Example As, under the conditions of fibrous face layer is comparable, thin hemostasia products (e.g., from about 2 millimeters) will compare thick hemostasia products and dissolve Obtain faster.

In most of embodiments, the dissolving of dextran fiber is extremely rapid, such as after being exposed to liquid, about 5 minutes or less, or about 4 minutes or less, or about 3 minutes or less, or about 2 minutes or less, or about 1 minute or less, Such as, hemostasia products the most only needs a little second (such as from about 1 to about 20 second) to dissolve.

Dissolve so rapidly and can be herein referred to as " instantaneous " or " immediately " dissolving.Can be by compression Electrospun dextrose Acid anhydride pad regulates rate of dissolution, and speed, i.e. compression degree described in the compression negatively influencing of higher level is the biggest, and rate of dissolution is the slowest.Fast The rate of dissolution of speed has superiority, particularly when delivering bioactivator (such as hemorrhage) to action site (such as wound) Wait.When disposing hemostasia products, the offer of dissolving rapidly of carrier dextran fiber delivers to wound hemorrhage extremely rapidly.

Those skilled in the art, it will be recognized that the existence of too much liquid flux, may dissolve dextran.But, use Realization typically solvent in the better result of Electrospun dextran be water, particularly deionized water or distilled water or go from Son, distilled water (ddH₂Or the purest water of other forms O).Additionally, there are seldom relevant to the use of water environmental effect.

Have been found that in general, solvent should be avoided the salt of high concentration.But, commonly used salt promotes some electricity The spinning of spinning polymer, this is unsuitable for dextran.The concentration of salt in spinning solution should be maintained at bottom line, with Have successfully formed dextran fiber.

One or more activating agents being combined with the dextran fiber of described hemostasia products can be any activating agent, Described activating agent is for being delivered to use or apply the site of Electrospun dextran fiber plant to be desirable or have superiority 's.In one embodiment of the invention, described Electrospun dextran fiber plant is hemostasia products and is used for delivering Beneficial agent, such as, to wound.

This wound includes health or the wound of tissue integrity or ruptures, and as wound, (such as accident trauma, by rushing for it The prominent wound caused such as gunshot wound, knife injury etc.) result and occur, also include the wound deliberately produced, such as operative incision, health Perforating wound, etc..

Generally, described medicament is to have the useful or bioactivator of therapeutic effect at wound site.An embodiment party In case, described site is bleeding wounds, needs to form blood clot to stop or to slow down hemorrhage.In the present embodiment, goal treatment Property material can include, such as, thrombin and Fibrinogen, although other medicine of active effect in promoting hemostasis Agent, includes but not limited to capscian, it is possible to be included.

Additionally, Electrospun or non-Electrospun collagen protein, absorb the medicament of moisture, incline when being placed in such as contacting blood To in absorb liquid various dry salt, engineering thrombin or thrombin Counterfeit Item, technical fiber proteinogen, cause vasospasm with Help shrink and seal bleeding vessel medicament (such as ADP, 5-hydroxy tryptamine (5-hydroxytryptamine, 5-HT) and coagulate Blood oxane (thromboxane, TXA-2)) etc., it is possible to it is included.

Additionally, to hemostasia products can be added other composition of coagulation cascade, such as: those be the most only expressed in impaired carefully Tissue factor on cellular surface and the tissue factor of startup normal coagulation cascade；Strengthen platelet aggregation and promote vasoconstrictive Serotonin；Be used for replacing in hemophilia other medicament of the coagulation cascade composition of disappearance, such as, factor 7(activate so-called outside Portion's extrinsic clotting cascade) and platelet crude extract.

These medicines are substantially by initiating the cascade in the remote downstream of reaction network and " jump open " blood coagulation, such as Figure 10 institute Show.In Fig. 10, the various factors (and their alternative terms and/or characteristic and/or activity) are as follows:

Factor Ⅴ II(Proconvertin, proconvertin): serine protease, in liver, vitamin K dependent closes Become；

Factor IX: the vWF of Glycoprotein binding, is produced by endotheliocyte and liver；

Factors IX (Christmas-Eve Factor, Christmas factor): serine protease；

The factor X(Stuart-Prowler factor, Stuart factor): serine endopeptidase, by prothombin be Thrombin；With

Factor XI, plasma thromboplastin antecedent (plasma throml oplastin antecedant): serine protease, plasma protein；

Factor XI, plasma thromboplastin antecedent I(Hageman factor, Hageman factor (HF)): serine protease, plasma protein incorporating collagen egg In vain；

FXIII (fibrin stablizes enzyme): stable fibers protein polymers, plasma protein, exists in blood little In plate and monocytic series.

In Fig. 10, italic path represents suppression, and shows thrombin core in activating blood coagulation and inactivation blood coagulation Heart effect, wherein:

VI=makes the cofactor of the Xa factor that thrombinogen changes to thrombin；

APC=activated protein C, extracellular signaling molecule, be equivalent to FVa by proteolytic event suppression FVI(, make The cofactor of the XA factor that thrombinogen is changed to thrombin) and FVIIIa；With

The fibrinolysis inhibitor of TAFI=thrombin activation, the inhibitor that sludged blood dissipates.

Additionally, may also comprise the activating agent that its effect is the final stage promoting wound healing, such as, to promote that cell moves Move and reinvent.The introducing of collagen protein (collagen) is the example of such activating agent.

In the embodiment of this invention, one or more these activating agents arbitrary can be used.Therapeutic agent must be adapted for being dried , and other composition with hemostasia products is combined in the dry state, because liquid may make in negative effect hemostasia products At least one composition.Such as, activating agent can be dehydration or lyophilizing, or anhydrated by some other means.

Typically, when they are combined with Electrospun dextran fiber, it is present in the water yield in described material below about 5%, and preferably less than about 2%.All or part of activity is kept during these materials rehydration the most in blood.With the present invention's The therapeutic substance that device is combined when contacting with liquid, general keep them to be dried or before dehydration at least about 25% or about 50% or the activity of the most about 75 to 100%, compared with the standard preparation of described material, use well known by persons skilled in the art Code test detects.

In some embodiments, by thrombin or Fibrinogen or the two, be combined with hemostasia products.Real at some Executing in scheme, thrombin and Fibrinogen are salmon thrombin and Fibrinogen.Use salmon as these material sources Advantage include but not limited to consider the propagation of pathogen (such as virus), when using the mankind or other mammals source Thrombin or during Fibrinogen (such as cattle), this propagation it may happen that.

When, in pig model (pig model), salmon thrombin and Fibrinogen are highly effective and do not have Harmful side effect, the animal model that pig model is well recognized as, it is considered the mankind are had predictive result.

The fibrinogenic amount adding hemostasia products to is typically in the range of about 10 milligrams to about 3 grams.At some In embodiment, in each hemostasia products, fibrinogenic amount is between about 20 milligrams to about 1 grams.

The amount of the thrombin adding each hemostasia products to is typically between about 10 to 10000 NIH units.At some In embodiment, in each hemostasia products, the amount of thrombin is between about 20 to 6000 NIH units.

In some embodiments, can independent Electrospun therapeutic agent itself.Such as, therapeutic agent is dissolved in solution and from molten Liquid spinning.In some embodiments, therapeutic agent can be electrospun to fiber.In other embodiments, can be by activating agent electricity It is spun to other forms, such as microdroplet (droplet), pearl (bead) etc..

In some implementations, activating agent such as thrombin electron spray together with sucrose can be formed sucrose microdroplet, this tends to steady Determine thrombin, and other target substance also " can be captured " be delivered to hemostasia products.

For thrombin and Fibrinogen, in most of embodiments, these (or other) activating agents are fine point The dry particles dissipated or particle form, as fine powder (fine powder) or dust (dust), being inclined to owing to Electrospun is possible In their activity of reduction.In other words, activating agent itself can not Electrospun.

Supply material provides the big contact surface being beneficial to dissolve when these materials contact with fluid in fine powder form Long-pending.Typically, such granule would have about 1 to 10, the average diameter of 000 micron, and, in certain embodiments, about Between 10 to 1000 microns.

Such dried solid particle can be formed by any one in several means, include but not limited to grind, pulverize, press Broken etc..But, those skilled in the art it will be recognized that these activating agents of other form also can be comprised in hemostasia products, Such as: thin slice, thin film, sheet material, line etc..Additionally, in some embodiments, when with excipient (excipient) or carrier phase During associating, thrombin and Fibrinogen are the forms of Electrospun microdroplet.

Can be by the suitable technology of many well known by persons skilled in the art, any one realizes target substance and figuration Agent or the associating of carrier, and will depend partially on exact form and the means on hand of described material.Such as, for pulverizing Microgranular thrombin and Fibrinogen, can by spilling, shake, air blast etc. is by described drug combination to excipient or carrier layer On.

Depend on the density of fiber mat, described target substance may relatively evenly be scattered in whole fiber wrought mat or Person may be mainly limited to the top part of fiber mat.Without the existence of backing, later embodiment is preferred, with Prevent target particles material permeance mat from dropping or dropping out mat.

The density of (such as increasing) fiber mat can be adjusted, such as, by adjusting its thickness and/or by pressing under stress Contract this pad, makes fiber be close together.There is also for other technology united, such as, dissolve in the material of liquid by being dried The sheet material of material or material strip is placed in carrier layer or carrier interlayer, adds as discontinuity layer or with the form Electrospun of discontinuity layer Material, etc., and any such technology can be used.

Can be either manually or mechanically to change to implement for assembling the technology of hemostasia products of the present invention, or available manual operations and The combination of mechanization.Especially for thrombin, the thrombin of 5000 NIH units is the powder of relatively small amount.Therefore, can add Enter inert carrier (inert carrier) or filler (bulking agent) such as glucose, to ensure that activating agent produces in hemostasis Product disperse more completely.

Combining of target substance and excipient can be carried out according to many different arrangements.Such as, excipient can be formed Ground floor, and one or more described materials can be combined with ground floor.Then can form another on target substance to compose The second layer of shape agent.And can identical or other target substance be combined with the second layer, the rest may be inferred.

Can be plus the last of excipient or outermost layer, to prevent target substance from being evicted from from following layer.The present invention's The variable amountsization of the figuration oxidant layer that hemostasia products uses is very big, from few to 1-2 to up to several, or the most hundreds of, depend on Desirable characteristics in hemostasia products.

Typically, hemostasia products will comprise 1-2 layer.In other embodiments, hemostasia products can include between 2-20 layer. The humidity of very slight amount is present in ready hemostasia products, can help to thrombin and Fibrinogen are captured and protected Hold on hemostasia products surface.

In some embodiments of the present invention, hemostasia products also includes that one or more combined wherein support structure Or support material.Such as, backing combination can be entered hemostasia products.

Can be from various Electrospun materials, such as polyglycolic acid (polyglycolic acid, PGA), polylactic acid (polylactic acid, PLA) and their copolymer (PLGAs) form support material；Also has charged nylon etc..One In individual embodiment, described support material is the Electrospun dextran fiber of compression.With " the Electrospun dextran of compression is fine Dimension " we refer to that Electrospun dextran fiber is pressed together under stress.

Such as, under the pressure between two plates (such as is secondary), carry out the compression of Electrospun dextran fiber, and The fiber mat of compressible about 3 inch height (thickness) is to about 0.5 inch height or even less (e.g., from about 0.1 to about 0.4 English Very little) sheet material.In some embodiments, by the Electrospun direct Electrospun of dextran fiber to previous Electrospun support material On material, but in other embodiments, respectively after Electrospun, support material and Electrospun dextran fiber are such as passed through Respective one or more layers is connected and joins together.

In other embodiments, support material is not Electrospun material, but the material of some other (the most lightweight) Material.So example of material includes but not limited to that gauze, various plastics, hydrogel and other promotion absorb blood and therefore formed The absorbent material of blood clot, etc..

Support material can be or can not be and dissolve in liquid, maybe can be slowly dissolve in liquid, and And can be or can not be liquid permeability.The material slowly dissolved includes that those are formed absorbable by it or dissolve (biodegradable) suture (stitche) or the material of suture (suture), including the polymerization of PGA, polylactic acid and caprolactone Thing.

In certain embodiments, support material can relatively rapid be dissolved, and within the most about 1 hour, dissolves.Implement at other In scheme, support material can from about 10 days to 8 weeks within dissolve.In either case, support material provides and is not required to remove hemostasis Product and the advantage that there is not destruction sludged blood risk.

But, under any circumstance, support material should not interfere with dissolving immediately and delivering associated conjunction of excipient Activating agent is in the liquid of excipient dissolving.Therefore, support material may only in the side of Electrospun dextran fiber plant, So that when this device is (such as) hemostasia products when putting on wound, and the orientation of hemostasia products is easy to excipient rather than support Material and the contacting blood in wound bed, i.e. when being placed on wound, support material is hemostasia products " top " or outermost Surface.

Such as, illustrating this embodiment in Figure 4 A, wherein Electrospun dextran fiber 10 is illustrated as being deposited on Non-porous, liquid impenetrability support material 20 on.When being applied to wound, excipient 10 will be down towards wound, and The support material 20 of non-porous will be away from wound.

This arrangement has an advantage, can apply pressure to wound by support material, be beneficial to interrupt hemorrhage.As choosing Selecting, support material can comprise liquid can be allowed to reach the hole of excipient, opening or space in hemostasia products, even if working as support material In the presence of.Such as, support material can be net (net) or netted (web) material, and it can not dissolve (or slowly dissolving) but allow Liquid freely reaches excipient and the target substance being combined.

Schematically illustrate this embodiment in figure 4b, wherein show that Electrospun dextran fiber 10 is deposited on On net 40 (or below possible, or above and below, or run through fabric), wherein net 40 is partly with diplopia (phantom) form Display, diplopia part is covered by Electrospun dextran fiber 10.The most in other embodiments, can exist in said device " backing " or " top " support material and the second netted support material.

Schematically illustrate this embodiment in figure 4 c, wherein show that Electrospun dextran fiber 10 is deposited on Cover in non-porous support material 50 and with Web materials 60, i.e. Electrospun dextran fiber 10 " is sandwiched " non-porous support Between material 50 and Web materials 60.

Those skilled in the art will can be contemplated to other combination and shapes of many figuration oxidant layer and support material, its Will be according to particularly setting offer advantage.Such as, excipient can be wound or wrapped around the holder such as filament or cord extended, or Hemostasia products, institute can may be placed in described cavity by excipient around a given configuration winding with empty shape State reciprocal of duty cycle such as shell hole etc..

In such embodiment, Fibrinogen is provided in the form of a powder and powder distribution is produced in hemostasis On the surface of a layer of product.In other embodiments, Fibrinogen is mixed with thrombin, then by Fibrinogen- Thrombin mixture scatters on a layer of hemostasia products.The concentration of 10 grams can be up to about by fiber egg according to each hemostasia products White former offer is on the surface of each hemostasia products.

In the present invention directly manufactures another embodiment of hemostasia products, dextran is mixed with water until preparing Go out full and uniform mixture.Can provide dextran in powder form, it has the microgranule of opposite fine.Optional relative Highly purified dextran and water, as being typically used in the purity of medical usage.The example of one this applicable water is distillation Water.

In a configuration, there are the dextran of about 3 grams to about 9 grams and about 6 milliliters of water.In other embodiment In, there are about 6 grams of dextrans and about 6 milliliters of water mixing.It will be apparent to one skilled in the art that and multiple technologies can be used dextrorotation Sugar acid anhydride and water mix, with the mixture full and uniform from dextran and aquatic product.One can be used for dextran The nonrestrictive example of the technology mixed with water is Electrospun.

The incorporation time needed for preparing the full and uniform mixture of dextran and water is likely to be dependent on various factors, Such as the device type used for carrying out mixing.In some configures, this mixing is performed for more than about 30 minutes.Described mixing can be Temperature between about 40 F to about 70 F is carried out.

Secondly, thrombin is mixed with dextran-aqueous mixtures.Thrombin is added dextran-aqueous mixtures, with Preparing hemostasia products from it, wherein the concentration of thrombin is about 20 to 6, between 000 NIH unit.

Can provide thrombin in the form of a powder, it has the microgranule of opposite fine.Optional the most highly purified solidifying Hemase, as being typically used in the purity of medical usage.

It is similar to prepare the method that dextran-aqueous mixtures uses, when mixing thrombin and dextran-aqueous mixtures When can use Electrospun.The mixing of thrombin and dextran-aqueous mixtures can temperature between about 40 F to about 70 F Degree is carried out.

The incorporation time needed for preparing the full and uniform mixture of thrombin, dextran and water is likely to be dependent on respectively The factor of kind, such as the device type used for carrying out mixing.In some configures, this mixing carries out about 10 to 30 minutes.At it In its configuration, this mixing carries out about 1 hour.

Once complete mixing, introduce a mixture in Electrospun machine.Electrospun machine is configured to production to be had up to The sheet material of about 1 meter of width.But, depend on needing size for hemostasia products, it is possible to use shorter width.

Being placed in below Electrospun machine by one releasing piece, fiber is placed on releasing piece.During processing and shearing, release Film releasing provides for fiber and supports.Should select not with the releasing piece manufacturing the interaction between component used in hemostasia products.Can will release Film releasing is configured to after shearing and/or other technique complete separate with product.

Owing to such as challenging such factor, described challenge with by Fibrinogen with forming its that utilize in hemostasia products Its composition merging is combined, and can provide in hemostasia products on the surface of a layer by Fibrinogen, without being merged in several layers In one or more layers in.

Pierce hinders the problem crux in site, and to be that wounded tissue is relatively difficult to close.Such as, for bullet wound (such as at lower limb Or in stock), will not occur as on surface many hemorrhage, but relatively deeply in tissue, be formed cavity by bullet it in, sky Hole is difficult to by being simply covered at exterior trauma that (such as the inlet point of bullet, cutter, shrapnel, sword, bayonet etc., or other is made Become wound) hemostasia products process.

This respect of the present invention solves and the pierce relevant problem of wound, and described pierce hinders cause in deep tissues a large amount of Hemorrhage, the present invention utilizes the characteristic of dextran hemostasia products highly dissoluble.Complicated factor in this wound types relate to by Highly dissoluble hemostatic material is delivered to the ability in this site.

Inlet point at wound may have hemorrhage and other mobility event, and this surface site is used hemostasia products Hemostasia products may be caused to be completely dissolved on surface, there is no delivery of active substances to hemorrhage source basic in wound cavity.This Bright by providing delivery of active agent to go deep into wound and solve this event.Existing hemostasia products can not fully solve this problem.

The present invention can be adapted to solve this problem for the hemostasia products of this wound by providing its shape and application.Example As, it is provided that cylindric " cigar shape " hemostasia products of extension, it contains thrombin and Fibrinogen, and can contain support material Material.

Hemostasia products can be stored in protectiveness overcover, packaging or pipe.This pipe protection hemostasia products departs from week Collarette border.The all preferably sterilizing of hemostasia products and pipe.These parts can be further affixed to (such as) paper, polymer, blister In the outer package of bag, it is similar to for disposable syringe such, to prevent from losing sterilizing state.

During use, tear outer package and obtain the hemostasia products that sterile tube comprises.In some embodiments, pipe is removed One end is placed in the accessible part of outermost of wound.Pipe may also include " piston " or similar device, and it makes user incite somebody to action Hemostasia products is discharged pipe and enters wound, and result is that " injection " hemostasia products enters wound.

Can use such as those for sheath deliver (vaginal delivery) such as cotton balls (i.e. " circle in cylinder Cylinder ") device, or syringe-like device can be used.Therefore in hemostasia products is in depth introduced tissue along wound track, And the therapeutic agent in hemostasia products is delivered to need most inside their place, i.e. wound.

In other embodiments, the most do not include piston, but the style of pipe is two ends all energy openings, and Hemostasia products can be pushed in wound from one end by applying pressure at the Rather, openings end of pipe, it is possible to use any applicable Object at least partially into pipe applies pressure, hemostasia products is released pipe fully and enters in wound.This type objects Example include finger and club.

This object can be included in the hemostasia products of the present invention.Those skilled in the art is it will be recognized that due to one The pliability that a little configurations are relatively high, the present embodiment of described hemostasia products can include support material in hemostasia products surrounding or inside Material (such as biocompatibility net, bar etc., it will be decomposed by biodegradation) so that when hemostasia products gos deep into wound, more Firm and less pliability.

Additionally, the outermost end of hemostasia products, i.e. apply pressure so that hemostasia products is discharged pipe (such as with piston) to it And entering that end of wound, available support material is strengthened, in order to for promoting the piston of hemostasia products or other objects to pass Pass enough power, to be removed from pipe by hemostasia products.

In fig. 4d, it is provided that an illustrative diagram of this embodiment of the present invention, wherein hemostasia products 100 figure Being shown as and be encapsulated in pipe 200, hemostasia products 100 includes spinning dextran fiber 110 and (optionally) support material 120, And there is the first end 130 and the second end 140.

Hemostasia products 100 is encapsulated in pipe 200, but for the sake of clarity, does not show with the form of diplopia.Pipe 200 have opening 210 and 220, use the first two opening all can cover (not shown lid) or all can open, if the most whole Individual instrument bag is wrapped in sterilization packaging 400.Before using, remove or break sterilization packaging 400, to take out described apparatus.In order to use Described apparatus, it is necessary to open opening 210 and 220.

In order to hemostasia products 100 being delivered to pierce wound, object such as piston 300 is inserted opening 210 end of pipe.Work as work Plug 300 touches device end 130, applies pressure to hemostasia products 100, hemostasia products 100 finally via opening 220(with by The direction of arrow instruction) it is pushed out pipe 200, and enter pierce and hinder (not shown).This hemostasia products is shown in Fig. 4 E The second schematic diagram.

In this schematic diagram, do not include support material, and dry, the hemostasia products material of sterilizing being combined with therapeutic agent Material (such as dextran fiber) is located in or is placed in cylinder little, that encapsulate, and there is lid one end of described cylinder, another End has piston.During use, abandon lid, the opening of cylinder is placed on the breach of wound and be can be inserted into wound, and oppress Piston, shifts or injects hemostasia products material and go deep into wound.

Similar designs delivery hemostasia products can be used to hole or passage, such as nasal passage, syrinx, vagina, anus, enter blood Pipe, etc..The parts used in this applications will be formed the most about 1 to about 6 inch long and from about inch to 1 inch The size of the shape of diameter, i.e. hemostasia products will be suitable for being inserted through outside opening and stretching in hole or wound cavity.

The invention is intended to include all such arrangement, shape and the embodiment party of carrier layer described here and support material Case.

Before using can hemostasia products described in sterilizing, generally by using electromagnetic radiation, such as, X-ray, gamma ray, purple Outside line etc..If described hemostasia products comprises thrombin, it may be necessary to reduce the moisture of hemostasia products (such as binder or gauze) Content is to less than about 5%, to protect thrombin activity during sterilizing.

Can be by the dry hemostasia products manufactured, the most under vacuo, or contain from beginning just reduction moisture by using The manufacture method of amount, it is achieved the reduction of moisture.Typically, X-is used with the dosage between about 5 to 25 kilograys (kGray) Hemostasia products described in ray sterilizing.Any do not destroy carrier or with fiber be combined material activity method be used equally to sterilizing The hemostasia products of the present invention.

When hemostasia products is binder, thrombin and fibre can be included with the target substance of the joint fiber of described hemostasia products Fibrillarin is former, and described hemostasia products can be used for stoping hemorrhage.But, the scope of active component can be along with the tool of hemostasia products Body is applied and is changed.

Such as, the hemostasia products only comprising thrombin can be used for little wound or is applied in combination with other intervention.Additionally, other is controlled The property treated benefit materials also can be combined with described hemostasia products, includes but not limited to: antibiotic, the medicine eased the pain, growth The factor, bone morphogenetic protein, vaso-active substance (such as causes angiospastic material), reduces the steroid of inflammation, and Combinations thereof.

In other embodiments, assembly of the invention does not comprise the medicament promoting blood coagulation.Those skilled in the art will Recognizing, assembly of the invention is highly suitable for delivering many target substances to the liquid environment needed or position.Such as, this dress Put any wet environment that can be designed to deliver treatment or benefit materials to health, as long as having enough liquid to dissolve electricity Spinning dextran fiber also discharges active substance, and wherein dissolving dextran is that there is no problem.

Oral administration, per nasal, include but not limited to through trachea, per anum, the example of material of transpulmonary and Transvaginal delivery, as Antimicrobial, analgesics, nutrient etc..Oral application includes delivering the material useful to tooth treatment, such as, antibiotic, Analgesic, whitening agent etc..The treatment can being used in combination with described device or the example of benefit materials include, antibiotic, alleviate The medicine of pain, somatomedin, bone morphogenetic protein, vaso-active substance (such as causing angiospastic medicine), inflammation subtract Few sex steroid and combinations thereof.

But, in some embodiments, there is no body fluid (or if there is leptochymia), used only Blood products can pass through moistening and " activate ", such as by spraying, or apply moisture source otherwise (such as, by stopping Blood products is exposed to moist material such as sponge), or hemostasia products is thrown in liquid (such as water body), fine with dextran to cause The release of the target agent that dimension is combined.

Due to the area of hemostasia products characteristic little, lightweight, they are the most valuable for space and the weight of equipment Situation is preferable.The example of this situation includes but not limited to: military operation, wherein the weight of soldier's equipment parts and chi Very little is major issue；In first-aid kit；Critical care (such as space flight, camping etc.) during travelling；Deng.

Described hemostasia products can be used for without the concern for space and the various situations of weight and various purpose.Such as, passing In the operating room of system, the hemostasia products of the present invention provides to be used thrombin and fibrinogenic facilitates hands surgical incision Section.

When needs are packed and finally discharge one or more dry matters, but wherein said dry matter is to be difficult to or be not required to Directly operate, wherein measuring minimum or material is poisonous situation, it is possible to be advantageously employed the hemostasia products of the present invention.

In this case, the Electrospun dextran fiber of the present invention may act as accommodating, store and/or transport point State " scaffold (scaffolding) " or the carrier of material, until use time, i.e. until with dissolve described Electrospun dextran The liquid contact of fiber is also with time in the described material of release to liquid.This kind of material can include, such as, and enzyme or their precursor (such as proenzyme (pro-enzymes) or proenzyme (zymogens)) and their substrate, i.e. activator protein or enzyme (such as albumen Enzyme, cofactor etc.) material, etc..

The invention still further relates to resist the use of the stabilizer of the composition premature breakdown that described hemostasia products utilizes.Described stable Agent can also improve the available shelf-life of described hemostasia products.In certain embodiments, described stabilizer provides hemostasia products tool There is the shelf-life of at least about 2 years.In other embodiments, described hemostasia products shows the shelf-life of at least 3 years.

As used herein, term can be meant that with the shelf-life, when not amplifying observation or amplifying observation such as magnifier or aobvious When micro mirror is observed, described hemostasia products does not show significantly degraded.

A kind of this stabilizer is suitable to be used in combination with thrombin.It is thought that thrombin stabilizer enters thrombin In structure, thus reduce the zymolytic speed of blood coagulation.Can by thrombin be used for manufacturing other composition of described hemostasia products Before mixing, at least one thrombin stabilizer is mixed with thrombin.

In one embodiment, described thrombin stabilizer contains sugar, such as sucrose.In certain embodiments, sucrose It is used in thrombin stabilizer being up to about the concentration of 5% based on thrombin weight.In other embodiments, sucrose concentration is pressed Thrombin weight is calculated as about 1%.

Before thrombin stabilizer is mixed with thrombin, thrombin stabilizer can be mixed with dextran.According to recognizing For, dextran strengthens sucrose and enters the ability of thrombin structure.

In certain embodiments, dextran is steady for thrombin to be up to about the concentration of 5% based on thrombin weight Determine in agent.In other embodiments, dextran concentration is calculated as about 1% by thrombin weight.

Similarly, stabilizer is used in combination with Fibrinogen.Fibrinogen is applied to tourniquet bandage, other becomes Before in Fen, Fibrinogen stabilizer is mixed with Fibrinogen.It is thought that Fibrinogen stabilizer enters fiber egg In the most former structure, thus reduce the speed of fibrinogenolysis.

In one embodiment, described Fibrinogen stabilizer contains sugar, such as sucrose.In certain embodiments, Sucrose is used in Fibrinogen stabilizer being up to about the concentration of 5% based on Fibrinogen weight.In other embodiment In, the concentration of sucrose based on Fibrinogen weight between about 2% to 3%.The most in other embodiments, sucrose concentration is by fibre Fibrillarin original weight gauge is about 1%.

Before composite fibre proteinogen stabilizer and Fibrinogen, Fibrinogen stabilizer can be mixed with solubilizing agent Close.It is thought that solubilizing agent strengthens sucrose enters the ability of fibrin original structure.In certain embodiments, solubilizing agent is Dirt agent.In other embodiments, solubilizing agent is general stream Buddhist nun gram (Pluronic).

In certain embodiments, solubilizing agent is used in fibrin by Fibrinogen weight with the concentration being up to about 1% In former stabilizer.In other embodiments, the concentration of solubilizing agent is calculated as about 0.002% by Fibrinogen weight.

In another embodiment of the present invention, Fibrinogen and thrombin be placed in dissolving film matrix surface and/or It is integrated in dissolving film matrix.Use Fibrinogen and thrombin that described hemostasia products can be placed with this structure At the hemorrhage of health and it is thus desirable on the position of hemostasis.

Can be configured to dissolving film when being exposed to liquid such as blood relatively quickly dissolve.In certain embodiments, Described film dissolved in less than about 30 seconds.In other embodiments, described film dissolved in less than about 5 seconds.A kind of suitable The example of dissolving film is sold by Hughes Medical Corp.

The example of another kind of dissolving film is dissolving paper, and it is by the material manufacture that patient will not cause after dissolving health hazard Form.In certain embodiments, described dissolving paper can be by reinforcing fiber proteinogen and at least one realization hemostasis energy of thrombin The material of power is fabricated by.The example of a kind of this dissolving paper is sold by Daymark Technologies.

In another embodiment, between two-layer soluble material, Fibrinogen and thrombin are provided.A kind of this The example of the suitable dissolving film of class is sold by Hughes Medical Corp, and it is as explained above.

Use the spirit of the present invention, Fibrinogen and thrombin can be provided with various configurations.This join at one In putting, at least one of Fibrinogen and thrombin is provided in powder form, holds it in the interlayer of soluble material.

Described soluble material should have enough structural intergrities Fibrinogen and thrombin to be remained at, Can not interact with Fibrinogen and thrombin simultaneously.When being exposed to liquid such as blood, described soluble material also should phase To dissolving rapidly, in order to make Fibrinogen and thrombin be released from out.

As used herein, " rapid solution " means that described soluble material decomposes sufficient degree so that fibrin The pith of former and thrombin is in less than about 30 seconds and contacting blood.In other embodiments, described soluble material Decompose in less than about 10 seconds.

Described soluble material also should be easy to easily engage, in order to two-layer soluble material can be connected to around its edge Together, to form the enclosure being suitable to remain at Fibrinogen and thrombin.

A kind of example for the applicable technology of the soluble material that is connected to each other is, to being intended to the material pieces that is bonded together At least one use a small amount of liquid.Water causes the slight degradation of soluble material so that when two-layer soluble material being placed in Time adjacent one another are, the layer of soluble material combines.

Described soluble material can be manufactured by multiple material.Described soluble material should be to Fibrinogen and blood coagulation The stability of enzyme adversely affects.Also should select not to the people being intended to use described product for manufacturing the material of dissolvable layer Or animal causes the material that any adverse health affects.

In certain embodiments, manufacture hemostasia products use material can individually or with Fibrinogen or thrombin In conjunction with and improve hemostasis speed.The example of the composition that can be used for soluble material includes cellulose derivative materials.

In one configures, use independent device that described hemostasia products is maintained the desired locations that patient is correlated with. The example of a kind of this kind of device is gauze, and it is wrapped in the bleeding part of health.

In another arrangement, described hemostasia products be coated with binding agent at least partially.Described binding agent can be around At least some of arrangement at hemostasia products edge.In an alternative configuration, table in described adhesive coverage hemostasia products The substantial portion in face.

In the configuration that this binding agent may contact with the bleeding sites of patient body, it should select bio-compatible bonding Agent, is contacted, by described binding agent, the potential patient experience complication caused to reduce with bleeding tissue.

In another embodiment, Fibrinogen and thrombin can be placed in shell inner and/or outer shell surface, work as institute State shell to be exposed to liquid such as blood and do not dissolve.This structure can be easy to be formed on blood clot so that can move from patient Except described blood clot.

This structure can be similar to traditional tea-bag, and its housing may connect on cord, described cord and shell group Close and use to realize being arranged in by described product closest to needing the region of hemostasis or removing described product from patient and be connected At least one in the blood clotting closed.

Described cord can be manufactured so that either when arranging that described product is still when removing from patient by sufficiently strong material The when of described product, cord is all without fracture.Also should be by being less likely to produce the material system interacted bad biology Make described cord.

Shell can be configured in the range of seclected time discharge Fibrinogen or thrombin.Fibrinogen or blood coagulation The speed that enzyme is discharged can speed based on the blood discharged from patient and/or volume and adjust.

In a kind of selectable configuration, shell can be configured in an elongated segment time range degraded.Outside described Shell is degraded, and Fibrinogen and thrombin can be discharged from described product.

The speed discharged from product by control Fibrinogen and thrombin and/or the speed of shell degraded, described product The formation with relatively large size sludged blood is preferably minimized by product, and may beneficially form the more blood coagulation with reduced size Block.If comparing to cause and forming relatively large sludged blood, this less sludged blood is easier to degraded in vivo.

This structure of hemostasia products may be suited especially for being used in combination with hemorrhage in patient, the most hemorrhage at health In hole, the hole of this health can be from the outside arrival of health.The reality of the surgery operating technology can being used in combination with described hemostasia products Example includes hole and operation on tonsils.

In another embodiment, Fibrinogen and thrombin are pressed into tablet.Except Fibrinogen and blood coagulation Enzyme, described tablet also can comprise at least one excipient.Described excipient not only should be beneficial to Fibrinogen and thrombin combines Together, also should promote that tablet relatively quickly dissolves.

As used herein, term " relatively quickly " means when being placed in tablet described in liquid molten in less than about 30 seconds Solve.In other configures, tablet dissolved in less than about 10 seconds.Solution tablet makes Fibrinogen and thrombin from sheet rapidly Agent discharges rapidly so that these materials can provide quick-acting haemostatic powder.

It addition, in certain embodiments, should not reduce Fibrinogen for preparing the excipient of described tablet and coagulate The stability of hemase and/or dissolubility.In certain embodiments, the excipient being used for preparing described tablet should increase fiber egg The most former stability with thrombin.

The example of one this excipient is Sorbitol (sorbitol), and it has formed little granule, such as by using It is spray-dried.In a this configuration, described granule has common spherical and has the most uniform size.

The Sorbitol granule being spray-dried not only provides the flow behavior of advantage, and when using direct compress technique shape During piece agent, show preferable compactingproperties.

Additionally, the Sorbitol granule being spray-dried provides good for discharging Fibrinogen and thrombin from tablet Dissolubility.SPI Pharmaceutical under the example of the Sorbitol granule of one this spray drying is specified by SORBITAB SD 250 goes out Sell.

The another kind of excipient that can use in manufacturing tablet is mannitol (mannitol), and it has formed little granule, example As spray drying can be used.Can form the granule with the distribution of narrow particle diameter, it is potential that its reduction composition when forming tablet is isolated Probability.

One advantage of mannitol be this material be nonhygroscopic so that described mannitol not to use in tablets its Its composition moisturizes, and do not contribute to formed tablet technique during or tablet formed after absorb moisture.Thus institute State Fibrinogen and the thrombin of mannitol protection water sensitivity.

The mannitol particles being spray-dried not only provides the flow behavior of advantage, and when using direct compress technique to be formed During tablet, show preferable compactingproperties.

The mannitol particles being spray-dried also promotes described tablet fater disintegration or dissolving so that Fibrinogen and blood coagulation Enzyme can discharge from tablet rapidly.The example of the mannitol particles of one this spray drying is specified by MANNOGEM EZ SPI Pharmaceutical is sold.

Other material that can be used as excipient when preparing tablet includes fructose and maltose.Be similar to discussed above its Its excipient, aforesaid excipient is formed as little granule before using, mixes with other composition used in tablets.

Another kind can be to be specified down by PHARMABURST 500 with the excipient that Fibrinogen and thrombin are used in combination SPI Pharmaceutical sell instant (platform).This material provides the ability that tablet dissolves rapidly, also provides for desired simultaneously Compacting and fragility characteristic.

Depend on the excipient used in tablets, be likely to when preparing described tablet need lubricant.Described lubrication Agent can improve the physical property of tablet.The example of this kind of physical property includes brittleness, frangible degree and hardness.One this lubricant Example be sodium stearyl fumarate (sodium stearyl fumarate), can from LUBRIPHARM specify SPI Pharmaceutical purchase ?.

The concentration of the lubricant used in manufacturing tablet is likely to be dependent on many factors, the class of excipient as used Type.In certain embodiments, the concentration by weight of described lubricant is up to about 5%.In other embodiments, described profit The concentration by weight of lubrication prescription is about 2% to 3%.The most in other embodiments, the concentration by weight of described lubricant is about 2.5%.

Once composition mixes, and is compressed by mixture, thus causes composition to form tablet.Some embodiment party In case, compression stress is at least 5000 pounds/square inch (psi).In other embodiments, compression stress is about 10, and 000 psi is extremely Between about 12,000 psi.

When using previous process to prepare tablet, it may not be necessary to include dextran.Even if dextran is probably not Necessary, but dextran may be used together with other composition being used for preparing tablet.

In another embodiment of the present invention, Fibrinogen and thrombin can be merged into rapid solution tablet, as By the technology using the Catalent company under being specified by Zydis to sell.

Described rapid solution tablet dissolves in less than 30 seconds, and in some configures, dissolves in less than about 5 seconds. Tablet described in rapid solution is important, because when tablet dissolved, Fibrinogen contained therein and thrombin are released, It is thus possible to generation anastalsis.

The Fibrinogen that can use in tablets based on amount of bleeding selection and the amount of thrombin.In some embodiment In, each tablet is up to about 1 gram of Fibrinogen and thrombin.In other embodiments, have in each tablet About 500 microgram Fibrinogen and thrombins.

In another embodiment of the present invention, Fibrinogen and thrombin it is applied to the surface of applicator or mixes Enter in applicator (applicator).This applicator makes Fibrinogen and thrombin be delivered exactly needs hemostasis Region.

In a this configuration, described applicator has the extension that can be grasped by the people just using hemostasia products. Described applicator can have the structure being similar to swab (swab).This structure of hemostasia products is particularly suitable for being difficult to directly arrive The position reached.The example of one situation that this hemostasia products can be used to process is epistaxis.

At least in Fibrinogen and thrombin can individually Electrospun or with another composition such as dextran one Play Electrospun.The fiber using this technique to produce can wind around the far-end of applicator.

Described applicator arrangement can become once hemostasia products run into blood and i.e. discharge Fibrinogen and thrombin.Use This method, Fibrinogen and thrombin will cause sludged blood to be formed.Described sludged blood can remove with patient.If Sludged blood is sufficiently small, can be allowed to be retained in and makes described sludged blood to be finally degraded in the patient.

In the another kind of configuration of this hemostasia products, can be by Fibrinogen and thrombin, at least one is configured to protect Hold and be in relatively close proximity to applicator or be limited to applicator so that when Fibrinogen and thrombin cause at least one sludged blood shape Cheng Shi, this sludged blood remains adhered on applicator.This structure is beneficial to remove sludged blood from patient, and can at sludged blood Can be sufficiently large so that being not intended to be maintained at internal place, need to remove from patient.

Do not discharged from applicator for ease of Fibrinogen and thrombin, can by Fibrinogen and thrombin also Enter in the material being attached to described applicator one end.The example of one this material is foam.Described foam can be perforate bubble Foam or closed-cell foam.Described foam should have sufficiently large hole to receive Fibrinogen and thrombin.Described foam should not Fibrinogen or thrombin had strong affinity, in order to when Fibrinogen and thrombin are exposed to water, these composition quilts Discharge from foam.

In another embodiment of the present invention, Fibrinogen and thrombin are mixed foam.One this properly The example of foam be absorbable gelatin sponge, as specified lower Novartis purchase from VETSPON.

Depend on the application needing to use sthptic sponge, it may be necessary to described sthptic sponge is being applied to needs hemostasis Before region, described sthptic sponge of prewetting.

The another advantage using foam is described foam construction can be become flexible so that described hemostatic foam can Be bent to suit the requirements the shape in region of hemostasis.The most described hemostatic foam is bent to required structure, and it just can be tieed up Hold at that structure, even if not using fixing device to maintain described hemostatic foam in required shape and/or position.

Similar in appearance to foam described above, this foam can be open celled foam or closed-cell foam.Described foam should be to fibre Fibrillarin is former or thrombin has strong affinity, in order to when Fibrinogen and thrombin are exposed to water, and these compositions are by from bubble Foam discharges.

Fibrinogen and thrombin can be mixed in the composition being used to manufacture foam so that be not by Fibrinogen With the surface that thrombin is applied to described foam, but Fibrinogen and thrombin are scattered in whole foam matrix.

This structure is beneficial to Fibrinogen and thrombin and discharges from foam duration, and when needing experience to go out again The when that the body region of blood forming sludged blood, it may be possible to particularly advantageous.

Rapid solution tablet is suitable for use in various application.The example of one this application is oral hemorrhage.If beaten Calculating is used in combination in oral hemorrhage by described product, and described tablet is probably the tablet of seasoning.

It is used in combination in various surgery operating technologies, it is necessary to form otch at patient body.Once completing operation, having must Stitching thread to be used (suture) or nail (staple) close described otch.Although stitching thread or nail are for protecting tissue It is effective for holding together, but these Guan Bi mechanism can not stop blood to be flowed out by described otch the most effectively.

Described hemostasia products can be placed in blood process stitching thread at least some of on.Described Fibrinogen is with solidifying Hemase contacts this blood, and therefore provides hemostasis.

With multiple medical treatment, as to patient delivery's chemotherapeutics, being used in combination vascular access device.A configuration In, vascular access device is that surgical operation is implanted in the big vein of patient's heart.Described vascular access device may Appropriate location a very long time can be stayed, such as the time more than a year.

It is to stop hemorrhage around vascular access device that surgical operation implantable intravascular enters a challenge of device.Such as, Blood may ooze out stitching thread or surrounding catheter.Seepage can not stoped in some cases, it is necessary to patient brought into Operating room is to make great efforts to stop seepage.

Hemostasia products can be placed around vascular access device, thus cause hemostasis.Depend on the shape of vascular access device Shape, hemostasia products is likely to be of multiple structure.

In other cases, the conduit being combined with vascular access device is probably porous.Hemostasia products may by with Hemostasis is provided, thus anti-Hemostatic Oral Liquid is through void channels.

One or more previous constructions of described hemostasia products are likely to be suited for stoping from patient's bleeding, as from patient The when that thigh tremulous pulse removing conduit.In such configuration, described hemostasia products may comprise binding agent, when hemostasis occurs Time, it maintains hemostasia products in position.

Aortic root operation is used to treat expansion or the expansion of aorta.Due to the character of aorta, hemostasis is in this journey The success of sequence plays an important role.Can use a structure of hemostasia products discussed above to provide hemostasis, without Causing aorta to shrink, described aorta shrinks and is caused by the medicament of prior art continually, and described medicament is used for and this kind The operation of type is used in combination to provide hemostasis.

For deeper into the wound in patient, it may be necessary to use described hemostasia products with the form of oakum, by it at least It is partially placed in wound, thus in wound, causes hemostasis.

The most in another arrangement, hemostasia products can be provided with the structure elongated, such as the shape of pad-type of stopping blooding.Can also Hemostasia products is provided with the shape of anthelmintic or rope.Such structure can be used for the hemostasis after vagina operation.Such structure also may be used It is used in combination in extension hole in the patient, as being probably the hole caused by gunshot wound.

The cylindrical structural of described hemostasia products is also suitable for having in the situation of big opening in the tissue.In this situation Under, multiple cylindrical hemostasia products can be inserted big opening, thus fill a part for this opening.

For the benefit of use the hemostasia products of elongation, it may be necessary to be stored in applicator by described hemostasia products, such as piston In.Described piston can be used in wound inserted into the patient for the hemostasia products of elongation.

In another structure of hemostasia products, hemostasia products every kind composition is individually packed, such as in syringe.This Structure make with the different each compositions of rate-allocation so that can according to specific patient or be certain types of wound customization stop Blood.Described applicator can allow selectively or simultaneously to deliver every kind of composition.

Described hemostasia products can be substantially by Fibrinogen, thrombin be suitable to be formed by the carrier of bio-absorbable. As selection, described Fibrinogen and thrombin can be placed in the outer surface of hemostasia products so that after completing hemostasis, hemostasis is produced Product will be by from taking out in the patient.

Again in another configures, deliver described Fibrinogen and thrombin by spray.Can be with microsphere (microsphere) form provides described Fibrinogen and thrombin, and it can use spray container to distribute.

It is likely to be used in combination described hemostasia products with robotic surgical.Although robot is by distant with patient location Remote surgeon provides the ability carrying out surgical procedure, but there is certain limitation in robot.Hemostasis can be produced Product are used in combination with described robotic surgery program, to provide hemostasis, thus overcome this limitation.

Except being used for producing hemostasis in the mankind, the spirit of the present invention is applicable to be used in combination with other animals.This The example of the bright this kind of animal that can be used for includes Canis familiaris L. and cat.

In another embodiment of the present invention, mix the water of effective dose with dextran to form aqueous dextrose Anhydride solution.Hereafter, aqueous dextran solution Electrospun is formed dextran sheet material.

Described dextran sheet material can be stored, until its needs are used for manufacturing hemostasia products.Such configuration In, dextran sheet material is rolled.Roll dextran sheet material and not only reduce the dextrose when storing described dextran sheet material The region that acid anhydride sheet material takies, and reduce and manufacture destroyed potentially possible of described dextran sheet material before described hemostasia products Property.

When rolling dextran sheet material, it should with caution, not by dextran sheet material overwind, because this process The density of dextran sheet material will be increased.As selection, may need before manufacturing described hemostasia products to roll up dextrose tightly Acid anhydride sheet material increases the density of dextran sheet material.

Only before needs manufacture described hemostasia products, by described thrombin and Fibrinogen by present patent application other The ratio discussed in part mixes.Described mixing should make thrombin in the mixture relative with Fibrinogen equal Even dispersion.

In certain embodiments, thrombin is dispersed on dextran sheet material, to provide square centimeter dextran Sheet material has the concentration of thrombin of 2 to 200 NIH units.

In certain embodiments, Fibrinogen is dispersed on dextran sheet material, to provide square centimeter dextrorotation Sugar acid anhydride sheet material has the fibrinogen concentration of 20 to 60 grams.

Dextran sheet material is untied, and thrombin and fibrinogen mixture are dispersed in the table of dextran sheet material On face.In certain embodiments, thrombin and fibrinogen mixture are dispersed in dextrorotation in a substantially even way On the surface of sugar acid anhydride sheet material.Need this uniform dispersion, be because it and make every part of hemostasia products have basic Styptic activity.

Repeat this process so that described sheet material is stacked, until the aequum of hemostasia products performance styptic activity.At some In embodiment, hemostasia products includes about 2 to 20 layers of dextran layer.

Thrombin and fibrinogen mixture are not placed in the superiors of described dextran sheet material.Use this joining Putting, thrombin and Fibrinogen are positioned in the interior location of hemostasia products.Manufacture hemostasia products by this way to enhance Thrombin and Fibrinogen are maintained at the ability within hemostasia products, even if thrombin and Fibrinogen are sprinkled upon dextrose On the surface of acid anhydride sheet material.

Although thrombin and Fibrinogen may be placed on the outside of described hemostasia products, before the use, thrombin It is likely to dissociate out from described hemostasia products with a fibrinogenic part.In view of thrombin with fibrinogenic become This, it is generally desirable to essentially all thrombin and Fibrinogen all keep being combined with described hemostasia products until needing to use Described hemostasia products, to maximize effect of described hemostasia products.

Although thrombin and Fibrinogen being mixed before thrombin and Fibrinogen are placed in dextran sheet material Together, described thrombin and Fibrinogen are sufficiently dispersed on dextran sheet material, so that being placed in by hemostasia products Before needing the position of hemostasis, thrombin and Fibrinogen do not react.

Then hemostasia products is cut into slices.In certain embodiments, can be formed with usual square shape described Sheet.Can intended application based on hemostasia products select sheet size.Such as, it is intended for surgical operation application when hemostasia products Time middle, if described can be intended for the application of wound than hemostasia products and have less size.

Can use cutter that hemostasia products cuts into required size.Except described hemostasia products is cut into slices, described cutter Tool may cause described dextran sheet material to be compressed in together adjacent to the layer of cutter.This compression causes dextran sheet material to be stayed Together.

In certain embodiments, hemostasia products sheet is vacuum-packed.Except keeping hemostasia products aseptic, vacuum packaging Also each layer in compressed tampon product, the ability of anti-interlaminar separation after taking out from the package before the use of this enhancement layer hemostasia products.

Therefore the method enhances the use ability of hemostasia products, because each layer resistant to separation in hemostasia products.Use One advantage of the method is, it is not necessary to extra step is to keep together each layer.Additionally, it need not use possibility Added ingredient and/or the additional process steps of hemostasia products effect can be affected.

Embodiment

The water of dextran Yu effective dose is mixed to form dextran aqueous solution.Dextran aqueous solution is electrospun to Electrospun dextran sheet material.

Thrombin and Fibrinogen are mixed, is then dispersed on Electrospun dextran sheet material.According to often The ratio dispersion thrombin of square centimeter Electrospun dextran sheet material about 1.3 to 2.7 NIH unit.According to every square centimeter of electricity The ratio dispersion Fibrinogen of spinning dextran sheet material about 3.6 to 7.4 milligrams.

Repeat this process, until there being the Electrospun dextran sheet material of 8 layers of stacking construction.Thrombin and Fibrinogen mix Compound is not dispersed on the surface of the superiors.The thickness of Electrospun dextran sheet material is of about 1 to 3 millimeter.

Then with cutter, hemostasia products is cut into width about 4.8 centimetres, the sheet of length about 4.8 centimetres.Required except being formed The sheet of size, cutting makes Electrospun dextran layer be pressed together.This process makes Electrospun dextran layer resistant to separation.Will Hemostasia products sheet is vacuum-packed to store until using.Except preventing the pollution of hemostasia products, vacuum packaging makes Electrospun Dextran is urged together.

What the Nycomed under using TACHOSIL to specify sold is purchased absorbable fibre protein blocking agent product and this patent The performance of the hemostasia products that application describes compares.

TACHOSIL product comprises and is coated in its side together with thrombin and Fibrinogen and starts collagen sponge. Containing human fibrinogen and every square centimeter of product of 3.6 to 7.4 milligrams on every square centimeter of product of TACHOSIL product The human thrombin of 1.3 to 2.7 NIH units is contained on product.

Utilize about thrombin on TACHOSIL product and the aforementioned information of fibrinogen concentration, by TACHOSIL product Cut into square sheets so that on every TACHOSIL product, thrombin and fibrinogenic amount approximate prepared above stopping Thrombin and fibrinogenic amount on blood products.

Use hemostasia products and the hemostasia effect of TACHOSIL product of pig liver damage model assessment present patent application, should Model had previously had been used for evaluating hemostasia effect.Pig liver damage model makes it possible to carry out multiple test on single animal.

The breeding adult, domestic, non-of weight about 50-70 kilogram, female pigs is used to test.At the beginning of every animal is carried out Step examines, to confirm that animal health condition is good.Before program, being isolated three days by animal, period optionally provides food for animal Thing and water.

Before start program, implement anesthesia to animal.During program, implement anesthesia and fluid maintenance to animal.The program phase Between, during animal heating cushion placed below is to help program, keep the body temperature of animal.

Carry out midline laparotomy to reach abdomen organ, carry out liver living tissue cut sections for microscopic examination (hepatic herein Biopsie).The biopsy punch using diameter about 8 millimeters creates the section of each liver living tissue.Each liver living tissue cuts Sheet width about 8 millimeters, the degree of depth about 4 millimeters.The section of cylindric liver living tissue surgically is removed with shears.

The most hemorrhage existence of about 20-25 second is observed in biopsy site.Hereafter, hemostasia products is executed Use biopsy site.The hemostasia products of hemostasis was maintained appropriate location in about 20 seconds by hand pressure.

Hemostasia products is stayed on biopsy site by the pressure then removing hands simultaneously.Obvious for active hemorrhage Sign, observes biopsy site about 2 minutes.

If hemorrhage sustainable existence, the hemostasia products that extra is placed on biopsy site.By hand pressure about Hemostasia products was maintained appropriate location in 20 seconds.Hemostasia products is stayed biopsy site by the pressure then removing hands simultaneously On.For the obvious sign of active hemorrhage, observe biopsy site about 2 minutes.Previously do not stopped if hemorrhage, repeated This process up to 4 times.

As comparison, biopsy punch is used to create liver living tissue's section of width about 8 millimeters, the degree of depth about 4 millimeters.See Examine biopsy about 2 minutes.During this period of time, biopsy does not stop hemorrhage.

Carry out using the hemostasia products of present patent application, TACHOSIL product and the detection of comparison with random order, to incite somebody to action It is preferably minimized by the potential impact using the order of hemostasia products to cause during assessment.

The order and the result obtained by this assessment that carry out hemorrhage assessment are listed in table 1 below.

Table 1

5 extra animals are used to repeat described assessment.The order using hemostasia products on 5 extra animals is also random 's.

The result of the first time assessment result being shown in Table 1 with 5 extra animals is combined.For from this specially Each of the sharp hemostasia products applied for and TACHOSIL product has 18 samples.

For these 18 samples, the hemostasia products from present patent application causes be 2.9 minutes the average time of hemostasis, tool There is the standard deviation of 1.7 minutes.For these 18 samples, TACHOSIL product causes be 4.7 minutes the average time of hemostasis, There is the standard deviation of 1.4 minutes.Therefore for realizing hemostasis, the hemostasia products from present patent application provides and connects in time The reduction of nearly 2 minutes.

Before biopsy and after realization hemostasis, have evaluated the change that animal blood is potential on hematology.For coming From hemostasia products and the TACHOSIL product of present patent application, Hematology results there is no obvious difference.

Use pathology compare present patent application hemostasia products provide sludged blood and TACHOSIL product provide Sludged blood.Fibrin is all can recognize that in the biopsy that the hemostasia products of all use present patent application processes.? On the other hand, use TACHOSIL product treatment 18 biopsies in 5 unidentified to fibrin.

For the hemostasia products of present patent application, the bioptic sum needing extra pressing is 5.For TACHOSIL product, the bioptic sum needing extra pressing is 17.Therefore, compared with TACHOSIL product, this is specially The hemostasia products of profit application shows the bioptic reduction more than 70% needing extra pressing.

For the hemostasia products of present patent application, the sum of the extra pressing needed for providing hemostasis is 8.For TACHOSIL product, the sum of the extra pressing needed for providing hemostasis is 24.Therefore compared with TACHOSIL product, this The hemostasia products of patent application shows and additionally presses the reduction more than 60%.

" basket (basketweave) " structure of the hemostasia products of present patent application allows to be scattered in whole biopsy The erythrocyte trapping in site.On the other hand, TACHOSIL product causes in biopsy site base portion or amorphous implantation Between material there is the trapping of erythrocyte sheet in region.

Thrombin and Fibrinogen owing to using in TACHOSIL product obtain, therefore from human plasma TACHOSIL product exists may be containing the risk of infectious pathogen.The hemostasia products of the present invention is better than of TACHOSIL Advantage is, the hemostasia products of the present invention shows more stable than TACHOSIL product keeps at relatively high temperatures.

Although the most directly comparing, but when contacting with fluid, hemostasia products produced according to the invention makes Electrospun dextrose anhydride group dissolve rapidly.Described dextran is inhaled in the relative short time section from several minutes to a couple of days In income health.The loss rapidly of dextran carrier provides the beneficial effect relevant to reduction inflammation and cicatrix risk.

In contrast, the collagen sponge used in TACHOSIL product was degraded, such as within one period of longer time period It is up to about 4 months.On the one hand this of TACHOSIL product be indicated as being a characteristic by manufacturer, because according to indicating that collagen sponge is tieed up Hold fibrin sludged blood in wound surface to realize hemostasis.Slowly absorbing of collagen can increase phase with inflammation and cicatrix risk Close.

The Electrospun dextran used in hemostasia products, compared to the collagen sea used in TACHOSIL product Silk floss, provides higher levels of pliability for hemostasia products.The pliability of this enhancing makes describe in the present patent application to stop Blood products is more easily adapted to conform to the surface of wound than TACHOSIL product.

In detailed description above, with reference to accompanying drawing, these accompanying drawings form one part, and concrete real by explanation The mode that scheme of executing illustrates wherein can also implement the present invention with this.In this, direction term, such as " top ", " end Portion ", "front", "rear", " first ", " tail " etc. use relative to the orientation of the figure being described.Due to can be with multiple different orientation The assembly of location embodiment, direction term is by no means limitative for explanatory purposes.It should be appreciated that do not taking off Under the scope of the present invention, other embodiment can be used and structure or logical changes can be made.Therefore, should not detailed by above Thin description is considered as in a limiting sense, and the scope of the present invention is defined by the appended claims.

It is contemplated that feature disclosed herein can be mixed and matched and those are incorporated by reference into described above Feature in application, to adapt to concrete condition.Other modification and transformation various will be apparent from for those of ordinary skill.

Claims (22)

1. the method forming hemostasia products, it is characterised in that including:

Mixing dextran and water form dextran-aqueous mixtures；

Described dextran-aqueous mixtures is formed the first support layer；

Composite fibre proteinogen and thrombin form Fibrinogen and the mixture of thrombin；

The mixture disperseing described Fibrinogen and thrombin is supported on layer described first to form hemostasis sheet material；With

Described hemostasis sheet material is placed around vascular access device.

Method the most according to claim 1, it is characterised in that with 3 to 9 grams of dextrans concentration to 6 milliliters of water, by the right side Rotation sugar acid anhydride mixes with water.

Method the most according to claim 1, it is characterised in that dextran-aqueous mixtures is being formed the first support layer Before, being mixed into thrombin at least partially in dextran-aqueous mixtures is also included.

Method the most according to claim 1, it is characterised in that described first supports that layer has relatively uniform thickness.

Method the most according to claim 1, it is characterised in that thrombin is salmon thrombin and wherein Fibrinogen It it is salmon Fibrinogen.

Method the most according to claim 1, it is characterised in that form the first support layer and include dextrose described in Electrospun Acid anhydride-aqueous mixtures forms fiber and deposits described fiber the most on top of each other.

Method the most according to claim 1, it is characterised in that also include compressing described first and support that layer is to less than described the One height supporting layer elemental height, wherein said compression makes the described first height supporting layer and described first support at the beginning of layer Begin highly to compare to be reduced at least 75%.

Method the most according to claim 1, it is characterised in that also include being placed on maintaining body being dispersed with fiber In the hemostasis sheet surface of proteinogen and Thrombin mixture, wherein said maintaining body is by described Fibrinogen and thrombin Mixture is maintained on the surface of described hemostasis sheet material.

Method the most according to claim 8, it is characterised in that described maintaining body is to have as described first supports layer Second support layer of structure.

Method the most according to claim 1, it is characterised in that also include distributing at least one bioactivator described On hemostasis sheet material.

11. methods according to claim 1, it is characterised in that described first supports that layer is formed in support material, And described support material includes selecting free gauze, the Electrospun dextran of compression, polyglycolic acid polymer, poly lactic acid polymerized The material of the group of thing, caprolactone polymers and charged nylon composition.

12. 1 kinds of methods forming hemostasia products, it is characterised in that including:

Mixing dextran and water form dextran-aqueous mixtures；

Thrombin is mixed into described dextran-aqueous mixtures and forms dextran-thrombin-aqueous mixtures；

Described dextran-thrombin-aqueous mixtures is formed the first support layer；

Dispersion Fibrinogen is supported on layer described first to form hemostasis sheet material；With

Described hemostasis sheet material is placed around vascular access device.

13. methods according to claim 12, it is characterised in that with 3 to 9 grams of dextrans concentration to 6 milliliters of water, will Dextran mixes with water.

14. methods according to claim 12, it is characterised in that dextran-aqueous mixtures is being formed the first support Before Ceng, also include being mixed into thrombin at least partially in dextran-aqueous mixtures.

15. methods according to claim 12, it is characterised in that described first supports that layer has relatively uniform thickness.

16. methods according to claim 12, it is characterised in that thrombin is salmon thrombin and wherein fibrin Former is salmon Fibrinogen.

17. methods according to claim 12, it is characterised in that form the first support layer and include dextrose described in Electrospun Acid anhydride-thrombin-aqueous mixtures forms fiber and deposits described fiber the most on top of each other.

18. methods according to claim 12, it is characterised in that also include that compressing described first supports that layer is to less than described First height supporting layer elemental height, wherein said compression makes the described first height supporting layer and described first support layer Elemental height is compared and is reduced at least 75%.

19. methods according to claim 12, it is characterised in that also include being placed on maintaining body being dispersed with fibre In the hemostasis sheet surface that fibrillarin is former, described Fibrinogen is maintained at described hemostasis sheet material by wherein said maintaining body On surface.

20. methods according to claim 19, it is characterised in that described maintaining body is to have as described first supports Second support layer of layer structure.

21. methods according to claim 12, it is characterised in that also include distributing at least one bioactivator described On hemostasis sheet material.

22. methods according to claim 12, it is characterised in that described first supports that layer is to be formed in support material , and described support material includes selecting free gauze, the Electrospun dextran of compression, polyglycolic acid polymer, polylactic acid The material of the group of polymer, caprolactone polymers and charged nylon composition.