CN106924722A - Medical composition with hemostatic function - Google Patents
Medical composition with hemostatic function Download PDFInfo
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- CN106924722A CN106924722A CN201511031669.8A CN201511031669A CN106924722A CN 106924722 A CN106924722 A CN 106924722A CN 201511031669 A CN201511031669 A CN 201511031669A CN 106924722 A CN106924722 A CN 106924722A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/38—Albumins
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Abstract
The present invention discloses a kind of medical composition with hemostatic function, and it includes consisting of composition：(A) the double-deck protein spherical particle of 16 22 weight %, the human albumin spheroid comprising internal layer and with covalently bonded together in the human albumin spherome surface fibrinogen；(B) surfactant of 0.8 2.3 weight %；(C) crosslinking agent of 12 16 weight %；And the solvent of (D) 45 75 weight %.The medical composition with hemostatic function is adapted for intravenous injection, and there is the diameter of the albumin spheroid of fibrinogen cladding to be less than l microns on surface in suspension, and agglomeration will not occur, therefore by the way that angiemphraxis will not be caused after intravenous injection, and help lend some impetus to wound healing and hemostasis.
Description
Technical field
The present invention relates to a kind of surgical hemostasis material, a kind of tool suitable for being injected intravenously is particularly related to
There is the medical composition of hemostatic function.
Background technology
It is well known that blood of human body abundance is health sheet, many operations (such as cancer operation) and internal medicine are controlled
Treatment process can cause loses blood, and for the patient of aleukia, excessive blood loss may have
Life danger；In addition, blood transfusion is again a very complicated process.Therefore, it is a kind of right to be needed badly at medical scene
The helpful material of blood coagulation, is used to shorten bleeding stopping period, or by blood loss control in minimum degree.
Effect of such blood coagulation substance can be reduced to operate on and lacked with patients after surgery and blood platelet such as blood platelet
The blood loss of weary patient；In general, such blood coagulation substance must coagulate with can allow for its participation blood
Solid surface molecular, such as fibrinogen.And such blood coagulation substance is to inject human body with injection system,
Therefore must meet claimed below：First, due to about 7 microns of the diameter of human microvascular, therefore blood coagulation substance
The diameter of (such as particulate) must be less than 7 microns；Second, such blood coagulation substance can not condense in blood, but
Can be condensed in wound, and such blood coagulation substance can not cause haemocyte to condense in blood, can but participate in
Haemocyte is promoted to be condensed in wound.
Now in the art, K.I.Widder et al. is in the document " development (V0l.16. of pharmacology and chemotherapy regimen
An article in 213-271) "《Magnetic active microspheres in antitumor and anticancer agent biophysics spike and other
Carrier》Disclose and " use protein aqueous solution and oil, and by heating or being polymerized, obtain emulsion synthesis egg
The technology contents of white matter microsphere "；However, needing in the blood vessel preserve at least one in actual therapeutic
Its above and the blood coagulation substance for undergoing no deterioration, the protein microsphere body are apt to deteriorate in building-up process,
Therefore its half-life period is very short.
Oppenhein et al. is in U.S. US4,107,288 patents " effective pole in injectable composition
A kind of method is disclosed in particulate and its production method ", mainly by using a kind of opposite solubilizer
To adjust the concentration of solvent agent, protein solution is reached one and go the solvent limit.However, this side
Method condition when reacting initial is extremely unstable, and often substantial amounts of along with cause spheroid to generate in the middle of reaction
Polymerization, and the diameter of coacervation spheroid generally can all be more than 7 microns, easily cause angiemphraxis and cause life
It is dangerous.
The content of the invention
It is a primary object of the present invention to provide a kind of medical composition with hemostatic function, it can be used for
The patient of aleukia is treated, is not only had no toxic side effect, anthemorrhagic speed is fast and effect is good.
It is that, up to above-mentioned purpose, the present invention uses following technical scheme：A kind of medical group with hemostatic function
Compound, be adapted for intravenous injection, the medical composition with hemostatic function comprising consisting of into
Point：(A) the double-deck protein spherical particle of 16-22 weight %, the human albumin spheroid comprising internal layer and
With covalently bonded together in the human albumin spherome surface fibrinogen；(B) 0.8-2.3 weight %
Surfactant；(C) crosslinking agent of 12-16 weight %；And the solvent of (D) 45-75 weight %；Its
In, relative to the human albumin of 100 weight portions, the content of the fibrinogen is 0.8-5.7
Weight portion.
Present invention tool has the beneficial effect that：In medical composition of the present invention, because fibrinogen can be by altogether
Valence link is incorporated into albumin spherome surface, therefore the quantity of the albumin spheroid in suspension will not be caused
Any loss, and the surface for being formed have fibrinogen coat albumin spheroid will not reunite
Phenomenon.
Furthermore, by selecting specific crosslinking agent, surface has the white egg that fibrinogen is coated to the present invention
The average diameter of Archon body is smaller than 1 micron, and coefficient of variation very little, so by after intravenous injection
Angiemphraxis will not be caused；Further, fibrinogen can be used as tracer molecule (tracer), and it is used to
Carry albumin spheroid and reach wound location, and make albumin spheroid agglomerated together, to reach hemostasis
Or reduce the effect of amount of bleeding.
Additionally, medical composition of the present invention can be used as hematoblastic substitute (Fibrinoplate, Platelet
Aggregation Substitute), it is used in wound, with the patient that performs the operation or bleed profusely when, will not
Antibody is produced, the problem of inadequate blood source and blood group incompatibility is not had, the disease of blood born can be avoided passing through.
For just auditor can to the object of the invention, technical characteristic and its effect, do further understanding with
Understand, hereby lift specific embodiment discussed below and be only used to explain the present invention, be not used to limit this hair
Bright scope, embodiment coordinates accompanying drawing, describes in detail as follows.
Brief description of the drawings
Fig. 1 is the schematic flow sheet of the manufacture method of the medical composition with hemostatic function of the invention.
Specific embodiment
Present pre-ferred embodiments provide a kind of medical composition, its manufacture method and purposes, the medicine
The characteristics of composition is that albumin spheroid will not reunite in suspension, albumin spheroid it is straight
Footpath is less than 1 micron, and surface has fibrinogen.
Next the manufacture method and its specific modus operandi of medical composition will be first illustrated, it is then in good time again
The weight proportion and its concrete example of each constituent in ground supplement medical composition；Although being in the present embodiment
Using human albumin, but human body other protein, such as immune protein, myoglobins, collagen,
Gelatin etc., equally also can be used and can form spheroid.
Those of ordinary skill in the art can understand advantages of the present invention and effect by this specification content.Should
Understand, described every details can be implemented or applied based on different viewpoints in this specification content,
Therefore various modifications and change are carried out under spirit of the invention, belongs to the intention model of equivalent structure of the present invention
In farmland.
Fig. 1 is referred to, is the manufacture of the medical composition with hemostatic function of present pre-ferred embodiments
The schematic flow sheet of method.The manufacture method mainly includes：
Step S100：Human albumin molecule is dissolved in a buffer solution, a human albumin solution is obtained,
The concentration of wherein described human albumin solution is 5-20wt%.In the present embodiment, the pH value of buffer solution
Scope is between 4-8, and preferably 5-7.3；The osmolarity ranges of buffer solution between 14-680mOsm, and
Preferably 250-400mOsm.
The concrete example of buffer solution includes one or more in following component：Tris, Tris-HCl, sodium acetate,
HEPES、HEPES-Na、ACES、ADA、AMPSO、BES、Bicine、Bis-Tris、Bis-Tris
Propane, CABS, CAPS, CAPSO, CHES, citric acid, DIPSO, EPPS, glycine,
HEPBS, HEPPSO, imidazoles, MES, MOBS, MOPS, MOPSO, PIPES, POPSO,
Dipotassium arsenic acid sodium, sodium citrate, glycine, TABS, TAPS, TAPSO, TEA and TES.
Step S102：In the human albumin solution surface-active is separately added into according to specific time sequence
Agent, a crosslinking agent and a solvent, obtain an albumin ball suspending liquid.Idealized conditions are, in shape
During into the albumin spheroid, the concentration of the surfactant is 0.1-10mg/ml, the crosslinking agent
Concentration be 0.625-2.5mg/ml, the concentration of the solvent is at least above 48wt%；Accordingly, formed
The average diameter of albumin spheroid be smaller than 1 micron, and albumin spheroid can be dispersed in suspension
In without occur agglomeration.
The surfactant that the present embodiment is used can be selected from Texapon K 14, TritonX-151 or
Tween80, also can be detergent.The crosslinking agent that the present embodiment is used includes the covalent small molecule of glutaraldehyde.
The concrete example of solvent includes one or more in following component：Chloroform, 2- propyl alcohol, toluene, benzene, benzyl
Base alcohol, dichloromethane, carbon tetrachloride, hexamethylene, cyclohexanone, trichloroethanes, methyl ethyl ketone, second
Acetoacetic ester, acetone, ethanol, methyl alcohol, tetrahydrofuran, 1,4- dioxanes, 1- propyl alcohol, phenol, pyridine,
Acetic acid, formic acid, hexafluoro -2- propyl alcohol, Hexafluoro acetone, N,N-dimethylformamide, N, N- dimethylacetamides
Amine, acetonitrile, METHYLPYRROLIDONE, N-methylmorpholine-N- oxides, 1,3- dioxolane,
And water；It is preferred that the solvent that the present embodiment is used can be alcoholic solution, particularly 2- propyl alcohol or ethanol.
Step S104：Fibrinogen, wherein fibrin are added in the albumin ball suspending liquid
Original, together in albumin spherome surface, forms double-deck protein spherical particle with covalently bonded.Idealized conditions
It is that fibrinogen is solution form, and fibrinogen is after step S102 is completed, to wait 10
Minute was added in the albumin ball suspending liquid to 1 hour；In this way, double-deck protein globules
The yield of shape particle can be more than 99%, hardly to the albumin spheroid in suspension in course of reaction
Quantity causes any loss.
After step S104 is completed, the manufacture method can further include step S106：To double-layer egg
The suspension of white matter spherical particle is post-processed, be for example diluted, filter, dialysis, refilter,
The programs such as centrifugation, electrophoretic separation and chromatogram post separation, then pass through vacuum freeze drying and freezing again
Powder reconstructization afterwards, freeze-dried type medical component (the i.e. protein of intravenous injection is adapted for be made
Grain constituent), wherein relative to the human albumin of 100 weight portions, the fibrinogen contains
It is 0.02-6 weight portions to measure, preferably 0.8-5.7 weight portions；Incidentally, needed during reconstructization
Add buffer solution or change the biological solutrope such as buffer solution and preservative, and the species and consumption of this kind of reagent
It is well known to the skilled artisan in the art, therefore will not be described here.
It is worth noting that, by reconstructization formed double-deck protein spherical particle (i.e. surface has fiber
The protein particulate of proteinogen cladding), its average diameter can be micro- much smaller than human body between 0.1 to 100 μm
The diameter of blood vessel, therefore by the way that angiemphraxis will not be caused after intravenous injection.
Do not damaging in the range of desired effect of the invention, in specific administration step S106, can
Add batroxobin, excipient (excipient) and/or other additives.Batroxobin can be any one
It is noncrosslinking fibrinous enzyme to plant fibrinogen catalysis；The addition without prejudice to double-layer egg of excipient
The performance of white matter spherical particle, and the uniformity and stability of medical component can be increased, while reducing doctor
Excitant and bad smell of medicine constituent etc., the concrete example of excipient include：Lactose, sucrose, sweet dew
Carbohydrate of sugar alcohol and mannitol etc.；Additive may include one or more in following component：
(1) glycine；
(2) ion concentration is the calcium ion of 1-200mmol；
(3) factor XIII；
(4) with antibacterial or bactericidal action composition；
(5) material of protein breakdown is suppressed；And
(6) Porcine HGF of cell growth is promoted.
The medical composition with hemostatic function made by manufacture method according to thing of the present invention, its bag
Include：(A) the double-deck protein spherical particle of 16-22 weight %, the human albumin spheroid comprising internal layer and
With covalently bonded together in the human albumin spherome surface fibrinogen；(B) 0.8-2.3 weight %
Surfactant；(C) crosslinking agent of 12-16 weight %；And the solvent of (D) 45-75 weight %；Its
In, relative to the human albumin of 100 weight portions, the content of the fibrinogen is 0.8-5.7
Weight portion.Idealized conditions are that composition (A) bilayer protein spherical particle contains in the medical component
It is 20 weight % to measure, and the content of composition (B) surfactant is 1.5 weight %, composition (C) crosslinking agent
Content is 14 weight %, and the content of composition (C) table solvent is 64.5 weight %.
Furthermore, not undermining in the range of the object of the invention, the medical composition can be further included：
The batroxobin of composition (E) 2-5 weight %；The additive of composition (F) 1-10 weight %；And composition (G)
The excipient of 0.4-1.3 weight %.
[embodiment 1]
There is no the method that fibrinogen forms particulate：
Human albumin powder is put into 0.9% sodium chloride solution, and adds concentration to exist
The surfactant of 0.05mg/ml-15mg/ml, such as Texapon K 14, Tween-80 or
TritonX-151, forms protein solution of the concentration in 5-20% w/vs.Then in containing difference
2ml is added in the serial test tube containing the above-mentioned protein solutions of 2ml of the surfactant of concentration with sodium chloride
What solution diluted, its concentration range is the glutaraldehyde of 0.01-3.0%.After 10 minutes, 10ml is added
Ethanol (being released to 80% (volume ratio) with water), at this moment solution becomes turbid at once.After 10 minutes,
Observe whether this suspension is clarified with 5 times of sodium chloride solution dilutions of volume, be as a result negative.This
Afterwards with this suspension of 1000 times of micro- sem observation, it is found that the diameter of particle in this suspension is micro- less than 1
Rice.
Simultaneously, it was also found that being 100-200mg/ml with the TritonX-151 and concentration that concentration is 1-2.5mg/ml
The mixture effect that is made of albumin it is best.In addition it has also been found that with the four decyl sulphur that concentration is 1-12mg/ml
The coefficient of variation of sour sodium is made mixture its mean particle dia is minimum.
[embodiment 2]
Fibrinogen is connected to the method as trace particle on albumen particle：
Using condition same as Example 1, the human albumin of the mark of 1-125 is used.By with
Centrifugal process precipitates spheroid, and measurement precipitation neutralizes the radioalbumin matter granule amount each contained in clear liquid,
It was found that the albumin particle for having 95% forms spheroid.If by the solute degree of solution by 0.9% sodium chloride
Solution concentration carries 2 times, that is, become 1.8% sodium chloride solution or drop to 0.9% sodium chloride solution
0.09% sodium chloride solution, finds do not have a significant impact to the yield of spheroid.If by cushioning liquid
PH drops to less than 4, then the amount of alcohol needed for when finding the amount of the required alcohol when spheroid is formed than pH for 8
Will it is many, and pH below 4 when the yield of spheroid has somewhat been declined.
[embodiment 3]
Embodiment 2 is repeated under the conditions of prepreerence, except that coating people with fluorescein isothiocyanate
Body albumin, using the optimum condition of embodiment 1, by fibre in different time intervals after becoming turbid
Fibrillarin original is added in ball suspension, as a result finds to add fibrin in 15 minutes after spheroid is formed
Proper energy enough makes spheroid stabilization and obtains best mixture.Further it is necessary to be carried out further to ball suspending liquid
Treatment, including being diluted, filter, dialysis, refilter, centrifugation, electrophoretic separation and color
Spectrum post separation, completes, wherein in the process by after the reconstruct of vacuum freeze drying and freezing powder
Need to add or change buffer solution or preservative.
According to McGill et al. in J.Lab.Clin.Med.1987,109：On 127-133 " blood is small
Template die chamber can reduce the bleeding time of the rabbit of aleukia " text, use the rabbit of aleukia
Pharmacological testing is carried out, the bleeding time of ten rabbits treated with the Busulfan methods of 70mg/kg is
697 seconds, (sodium chloride solution with 0.9% was molten for the spheroid coated by the fibrinogen for injecting 1ml/kg
Solve the powder of freezing), bleeding time is reduced to 115 seconds (standard deviation is 43 seconds).By rabbit ears injury
Fluorescence microscopy Microscopic observation is cut into slices and moved to, finds there are fluorescent particles in blood coagulation.If to aleukia
Rabbit injection not fibrinogen ball suspending liquid (1mg/ml), it is found that bleeding time does not shorten,
Fluorescent particles are not also found at ear blood coagulation, this explanation fibrinogen is by grain as guiding molecule
Son is directed at blood coagulation active regions, and causes to shorten bleeding time and reduce blood loss.
For those have wound or and aleucia may not be suffered from patient with operation for, the present invention
Particle equally there is curative effect, and the profit in clotting time faster and less blood loss can be experienced.
[effect that the embodiment of the present invention may be brought]
In medical composition of the present invention, because fibrinogen can be by covalently bonded together in albumin spheroid table
Face, therefore any loss, and the table for being formed will not be caused to the quantity of the albumin spheroid in suspension
The albumin spheroid that face has fibrinogen cladding will not occur agglomeration.
Furthermore, by selecting specific crosslinking agent, surface has the white egg that fibrinogen is coated to the present invention
The average diameter of Archon body is smaller than 1 micron, and coefficient of variation very little, so by after intravenous injection
Angiemphraxis will not be caused；Further, fibrinogen can be used as tracer molecule (tracer), and it is used to
Carry albumin spheroid and reach wound location, and make albumin spheroid agglomerated together, to reach hemostasis
Or reduce the effect of amount of bleeding.
Additionally, medical composition of the present invention can be used as hematoblastic substitute (Fibrinoplate, Platelet
Aggregation Substitute), it is used in wound, with the patient that performs the operation or bleed profusely when, will not
Antibody is produced, the problem of inadequate blood source and blood group incompatibility is not had, the disease of blood born can be avoided passing through.
Although the present invention is explained with embodiment, those skilled in the art can be from essence of the invention
God makes the change of various multi-forms with the scope of, and embodiment provided above is only used to illustrate the present invention,
Not it is used for limiting the scope of the invention, the invention is not restricted to above-mentioned each embodiment person, can be in claim
Various changes are carried out in scope shown in book, and the appropriately combined skill disclosed respectively in different embodiments
Embodiment obtained by art means, is also included in technical scope of the invention, i.e., all according to right of the present invention
The impartial change that claim is made and modification, all should still belong in patent covering scope of the invention.
Claims (10)
1. a kind of medical composition with hemostatic function, is adapted for intravenous injection, it is characterised in that
The medical composition with hemostatic function includes consisting of composition：
(A) the double-deck protein spherical particle of 16-22 weight %, the human albumin spheroid comprising internal layer and
With covalently bonded together in the human albumin spherome surface fibrinogen；
(B) surfactant of 0.8-2.3 weight %；
(C) crosslinking agent of 12-16 weight %；And
(D) solvent of 45-75 weight %；
Wherein, relative to the human albumin of 100 weight portions, the content of the fibrinogen is
0.8-5.7 weight portions.
2. the medical composition with hemostatic function as claimed in claim 1, further includes composition (E) 2-5
The batroxobin of weight %.
3. the medical composition with hemostatic function as claimed in claim 1, further includes composition (F) 1-10
The additive of weight %, the additive includes one or more of：
(1) glycine；
(2) ion concentration is the calcium ion of 1-200mmol；
(3) factor XIII；
(4) with antibacterial or bactericidal action composition；
(5) material of protein breakdown is suppressed；And
(6) Porcine HGF of cell growth is promoted.
4. the medical composition with hemostatic function as claimed in claim 1, further includes composition (G)
The excipient of 0.4-1.3 weight %, the excipient includes lactose, sucrose, mannitol, mannitol
Carbohydrate or its combination.
5. there is the medical composition of hemostatic function as claimed in claim 1, the scope of its osmotic pressure is
250-400mOsm。
6. there is the medical composition of hemostatic function as claimed in claim 1, wherein the composition (A) is double
A diameter of 0.01-100 μm of layer protein spherical particle.
7. there is the medical composition of hemostatic function as claimed in claim 1, wherein the composition (B) table
Face activating agent is detergent.
8. there is the medical composition of hemostatic function as claimed in claim 1, wherein the composition (B) table
Face activating agent is Texapon K 14, TritonX-151 or Tween80.
9. there is the medical composition of hemostatic function as claimed in claim 1, wherein the composition (C) is handed over
Connection agent includes the covalent small molecule of glutaraldehyde.
10. there is the medical composition of hemostatic function as claimed in claim 1, wherein the composition (D) is molten
Agent is chloroform, 2- propyl alcohol, toluene, benzene, benzyl alcohol, dichloromethane, carbon tetrachloride, hexamethylene, hexamethylene
Ketone, trichloroethanes, methyl ethyl ketone, ethyl acetate, acetone, ethanol, methyl alcohol, tetrahydrofuran, 1,4-
Dioxanes, 1- propyl alcohol, phenol, pyridine, acetic acid, formic acid, hexafluoro -2- propyl alcohol, Hexafluoro acetone, N, N-
Dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile, METHYLPYRROLIDONE, N-methylmorpholine
- N- oxides, 1,3- dioxolane, water or its combination.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201511031669.8A CN106924722A (en) | 2015-12-31 | 2015-12-31 | Medical composition with hemostatic function |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201511031669.8A CN106924722A (en) | 2015-12-31 | 2015-12-31 | Medical composition with hemostatic function |
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ID=59444069
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023119265A1 (en) * | 2021-12-21 | 2023-06-29 | Omrix Biopharmaceuticals Ltd. | Fibrinogen comprising formulation and uses thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1150047A (en) * | 1995-11-06 | 1997-05-21 | 徐家祥 | Protein granules suitable for intravenous injection |
| CN1150048A (en) * | 1995-11-06 | 1997-05-21 | 徐家祥 | Protein granule composition suitable for intravenous injection |
| EP1256804A1 (en) * | 2001-05-09 | 2002-11-13 | Bio Merieux | HBcAg expression and diagnostic and therapeutic uses |
-
2015
- 2015-12-31 CN CN201511031669.8A patent/CN106924722A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1150047A (en) * | 1995-11-06 | 1997-05-21 | 徐家祥 | Protein granules suitable for intravenous injection |
| CN1150048A (en) * | 1995-11-06 | 1997-05-21 | 徐家祥 | Protein granule composition suitable for intravenous injection |
| EP1256804A1 (en) * | 2001-05-09 | 2002-11-13 | Bio Merieux | HBcAg expression and diagnostic and therapeutic uses |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023119265A1 (en) * | 2021-12-21 | 2023-06-29 | Omrix Biopharmaceuticals Ltd. | Fibrinogen comprising formulation and uses thereof |
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