CN113289051A - PEG powder capable of being rapidly crosslinked and degraded and application thereof - Google Patents
PEG powder capable of being rapidly crosslinked and degraded and application thereof Download PDFInfo
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- CN113289051A CN113289051A CN202110550673.4A CN202110550673A CN113289051A CN 113289051 A CN113289051 A CN 113289051A CN 202110550673 A CN202110550673 A CN 202110550673A CN 113289051 A CN113289051 A CN 113289051A
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- 230000002439 hemostatic effect Effects 0.000 claims abstract description 136
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- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 67
- 239000002131 composite material Substances 0.000 claims abstract description 58
- 150000002334 glycols Chemical class 0.000 claims abstract description 41
- 239000002245 particle Substances 0.000 claims description 27
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- 238000000034 method Methods 0.000 claims description 7
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0042—Materials resorbable by the body
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/04—Materials for stopping bleeding
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- C08J2471/00—Characterised by the use of polyethers obtained by reactions forming an ether link in the main chain; Derivatives of such polymers
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Abstract
The invention provides PEG powder capable of being rapidly crosslinked and degraded and application thereof, the composite hemostatic powder is formed by mixing polyethylene glycol derivatives 1 and 2 and commercially available hemostatic powder, and the polyethylene glycol derivatives 1 and 2 can react with each other to form gel in the presence of blood, so that the strength of the hemostatic powder and the interaction capacity with tissues are enhanced. The composite hemostatic powder can absorb a large amount of water, and the degradation time can be adjusted to be suitable for different bleeding positions and bleeding degrees.
Description
Technical Field
The invention relates to a composite hemostatic powder system, in particular to a composite hemostatic powder system based on PEG powder capable of being rapidly crosslinked and degraded and commercially available hemostatic powder, and a preparation method and application thereof.
Background
Trauma is the leading cause of death among individuals in the age of 1 to 44 years, and blood loss is a leading cause of death in both daily life and on the battlefield. Especially in the battlefield, timely intervention hemostasis is the key to improving the survival rate of individuals. The current hemostasis methods mainly comprise two methods, namely compression hemostasis and local application of a hemostatic material hemostasis, but the two methods have difficult effect on internal hemorrhage. In contrast, hemostatic powders have received attention because they can treat large blood flows and completely cover wounds. The hemostatic powder can absorb blood or adsorb blood cells to form colloid after being placed in a wound, and the blood cells and hemostatic factors are concentrated, so that the aim of hemostasis is achieved. However, the colloidal body formed by the hemostatic powder has low strength and is easy to break under the impact of blood flow at a wound; the hemostatic powder has no interaction with tissues at the wound, and special fixation is needed in the using process, so that the use is inconvenient.
Disclosure of Invention
The invention provides a PEG powder capable of being rapidly crosslinked and degraded on one hand, and a composite hemostatic powder system based on the PEG powder capable of being rapidly crosslinked and degraded and commercially available hemostatic powder on the other hand, and a preparation method thereof.
The PEG powder capable of being rapidly crosslinked and degraded consists of polyethylene glycol derivatives 1 and polyethylene glycol derivatives 2, wherein the polyethylene glycol derivatives 1 can be polyethylene glycol amine, and the polyethylene glycol derivatives 2 can be polyethylene glycol succinimidyl ester.
The composite hemostatic powder based on the PEG powder capable of being rapidly crosslinked and degraded and the commercially available hemostatic powder is formed by mixing the polyethylene glycol derivative 1, the polyethylene glycol derivative 2 and the commercially available hemostatic powder, wherein the polyethylene glycol derivative 1 and the polyethylene glycol derivative 2 can form chemical bond connection through chemical reaction in blood to form gel, so that the strength of the hemostatic powder and the interaction capacity with tissues are enhanced; the chemical bond is a beta-carbonyl amide bond.
In the composite hemostasis, the polyethylene glycol derivative 1 can be polyethylene glycol ammonia;
the polyethylene glycol derivative 2 can be polyethylene glycol succinimidyl ester;
in the PEG powder capable of being rapidly crosslinked and degraded, the polyethylene glycol derivative 1 can be any one of a formula I, a formula II, a formula III and a formula IV:
in the formula, m is 28 to 123.
In some embodiments, the polyethylene glycol derivative 1 may be any one of the following formulas 1) to 3):
1) as shown in formula II, wherein m is 56-112, in some embodiments 56, in other embodiments 112; or
2) As shown in formula III, wherein m is 28-56, in some embodiments 28, in some embodiments 56; or
3) As shown in formula IV, wherein m is 56.
In some embodiments, in the rapidly cross-linkable, degradable PEG powder, the polyethylene glycol derivative 2 may be any one of formula V, formula VI, formula VII, and formula VIII:
in each formula, n is 28 to 112.
A beta-carbonyl amide bond shown as a formula c is formed between the polyethylene glycol amino group and the polyethylene glycol succinimide ester:
the polyethylene glycol derivative 2 of the present invention may be any one of the following formulas 1) to 4):
1) as shown in formula V, wherein n is 28-56, in some embodiments 28, in another embodiment 56; or
2) As shown in formula VI, where n is 56-112, in some embodiments 56, in still other embodiments 112; or
3) As shown in formula VII, wherein n is 28;
4) as shown in formula VIII, wherein n is 56.
In the composite hemostatic powder based on the PEG powder capable of being rapidly crosslinked and degraded and the commercially available hemostatic powder, the polyethylene glycol derivative 1 and the polyethylene glycol derivative 2 are granular particles with the particle size of 0.01-100 μm, and in some embodiments, the polyethylene glycol derivative 1 and the polyethylene glycol derivative 2 are granular particles with the particle size of 0.01-10 μm.
In the composite hemostatic powder, the commercially available hemostatic powder may be regenerated cellulose hemostatic powder, chitosan hemostatic powder, starch hemostatic powder, collagen hemostatic powder, zeolite hemostatic powder, and the like, and specifically may be: fuhe and Tai degradable hemostatic powder, Meisiter quick-acting hemostatic powder, Languan hemostatic powder, Alista hemostatic powder, Aiwei Titing microfiber hemostatic collagen, QuikClot and the like.
The invention further provides a preparation method of the composite hemostatic powder based on the PEG powder capable of being rapidly crosslinked and degraded and the commercially available hemostatic powder, which comprises the following steps:
and uniformly mixing the polyethylene glycol derivative 1, the polyethylene glycol derivative 2 and the commercially available hemostatic powder according to a certain proportion to obtain the composite hemostatic powder based on the PEG powder capable of being rapidly crosslinked and degraded and the commercially available hemostatic powder.
In the preparation method, the mass ratio of the polyethylene glycol derivative 1, the polyethylene glycol derivative 2 and the commercially available hemostatic powder can be (0.5-2.0) to 1 to (0.4-5.0).
In some embodiments, the rapidly cross-linked, degraded PEG powder is composed of a compound of formula II and a compound of formula VI, wherein m is 36-123 and n is 46-112.
In other embodiments, the rapidly cross-linked, degraded PEG powder is composed of a compound of formula III and a compound of formula VII, wherein m is 28-38 and n is 28.
In still other embodiments, the rapidly cross-linking, degraded PEG powder is comprised of a compound of formula IV and a compound of formula VIII, a compound of formula V, or a compound of formula VI. Wherein m is 46 to 56, and n is 28 to 56.
The composite hemostatic powder based on the PEG powder capable of being crosslinked and degraded quickly and the commercially available hemostatic powder can be degraded quickly in a simulated body fluid environment and in vivo, and the degradation period is 1 hour to 10 days, preferably 3 days to 7 days.
The invention obtains the PEG powder which can be quickly crosslinked and degraded by selecting the structures (such as the arm number), the length (m, n numerical values) and the terminal substituent of the polyethylene glycol derivative 1 and the polyethylene glycol derivative 2 and combining different polyethylene glycol derivative molecules, and the PEG powder which can be quickly crosslinked and degraded is mixed with the commercially available hemostatic powder to form the composite hemostatic powder.
The composite hemostatic powder based on the PEG powder capable of being crosslinked and degraded quickly and the commercially available hemostatic powder provided by the invention has potential application in the following fields:
(1) medical sponge;
(2) a epidermal hemostatic sealant;
(3) organ hemostatic sealants;
compared with the prior art, the invention has the following beneficial effects:
(1) compared with the commercially available hemostatic powder, the composite hemostatic powder has higher water absorption capacity, can quickly absorb blood at a wound bleeding part, concentrates blood coagulation factors and blood cells, and quickly activates endogenous blood coagulation;
(2) the composite hemostatic powder can closely interact with tissues, can be closely attached to the position of a wound to form a physical barrier layer, prevents blood from continuously flowing out, and does not need an additional method to fix the composite hemostatic powder;
(3) the degradation time of the composite hemostatic powder can be regulated and controlled, and the hemostatic requirements of wounds at different positions and different degrees are met;
(4) the composite hemostatic powder has good biocompatibility.
Drawings
Fig. 1 shows that the composite hemostatic powder disclosed by the embodiment of the invention can be well attached to the surface of pigskin after absorbing water.
Detailed Description
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Examples 1,
Weighing 130mg of four-arm polyethylene glycol amino (shown as formula II, wherein m is 36) and the particle size is 1 μm, weighing 120mg of four-arm polyethylene glycol succinimidyl ester (shown as formula VI, wherein n is 46) and the particle size is 2 μm, and uniformly mixing the two PEG powders and 100mg of Fuhe and Tai degradable hemostatic powder to obtain the composite hemostatic powder.
And (3) degradation test: and (3) putting the absorbed composite hemostatic powder into a PBS (phosphate buffer solution) solution with the mass being 10 times that of the absorbed composite hemostatic powder, then putting the composite hemostatic powder into a constant-temperature shaking table at 37 +/-1 ℃, and observing the change condition of a gel sample in a buffer solution at the speed of 100r/min until no precipitate is seen after centrifugation, wherein the time is recorded as the gel in-vitro degradation time.
Absorption test: mixing a certain mass of hemostatic powder, then spreading the mixture in a culture dish, and adding ultrapure water immersed hemostatic powder into the culture dish. And taking out the gelatinized hemostatic powder every other hour, wiping off the residual water on the surface, weighing the gel, weighing for 5 times, and taking the average value as the weighing mass. The weighed gel is placed in a culture dish and water is added again to swell the gel. The final mass was recorded as the three consecutive weighed masses no longer changed. The water absorption capacity calculation method is as follows:
HE: water absorption expansion times;
wt: the final quality of the hemostatic powder after water absorption and expansion;
w0: initial quality of the styptic powder before water absorption.
The water absorption capacity of the composite hemostatic powder prepared in this example is 100 times, which is far higher than that (49 times) of the commercially available single Fuhe Tai degradable hemostatic powder, and after water absorption, the composite hemostatic powder becomes colloid and can be well attached to the surface of skin, as shown in fig. 1, and the in vitro degradation time is 5 days.
Examples 2,
Weighing 200mg of four-arm polyethylene glycol amino (shown as formula II, wherein m is 123) and the particle size is 0.2 mu m, weighing 200mg of four-arm polyethylene glycol succinimidyl ester (shown as formula VI, wherein n is 112) and the particle size is 0.5 mu m, and uniformly mixing the two PEG powders and 200mg of mester quick-acting hemostatic powder to obtain the composite hemostatic powder.
The water absorption capacity of the composite hemostatic powder prepared in the embodiment is 150 times, which is far higher than that (53 times) of the commercially available single mester quick-acting hemostatic powder, after water absorption, the composite hemostatic powder is gelatinous, can be well attached to the surface of skin, and the in vitro degradation time is 3 days.
Examples 3,
Weighing 100mg six-arm polyethylene glycol amino (shown as formula III, wherein m is 38) and the particle size is 0.2 μm, weighing 200mg two-arm polyethylene glycol succinimidyl ester (shown as formula V, wherein n is 46) and the particle size is 1.5 μm, and mixing the two kinds of PEG powder and 500mg arista (TM) hemostatic powder uniformly to obtain the composite hemostatic powder.
The water absorption capacity of the composite hemostatic powder prepared in the embodiment is 73 times, which is close to the water absorption capacity (70 times) of a single Arista TM hemostatic powder sold in the market, after water absorption, the composite hemostatic powder is gelatinous, can be well attached to the surface of skin, and the in vitro degradation time is 4 days.
Examples 4,
Weighing 200mg of six-arm polyethylene glycol amino (shown as formula III, wherein m is 28) and the particle size is 0.9 mu m, weighing 100mg of six-arm polyethylene glycol succinimide ester (shown as formula VII, wherein n is 28) and the particle size is 1.9 mu m, and uniformly mixing the two kinds of PEG powder and 400mg of QuikClot hemostatic powder to obtain the composite hemostatic powder.
The water absorption capacity of the composite hemostatic powder prepared in the embodiment is 98 times, which is higher than that (45 times) of the single QuikClot hemostatic powder sold in the market, after water absorption, the composite hemostatic powder is gelatinous and can be well attached to the surface of skin, and the in vitro degradation time is 4 days.
Examples 5,
Weighing 150mg of six-arm polyethylene glycol amino (shown as formula III, wherein m is 56) and the particle size is 1.9 μm, weighing 150mg of six-arm polyethylene glycol succinimidyl ester (shown as formula VII, wherein n is 56) and the particle size is 2.2 μm, and uniformly mixing the two kinds of PEG powder and 400mg of QuikClot hemostatic powder to obtain the composite hemostatic powder.
The water absorption capacity of the composite hemostatic powder prepared in the embodiment is 140 times, which is higher than that (45 times) of the single QuikClot hemostatic powder sold in the market, after water absorption, the composite hemostatic powder is gelatinous, can be well attached to the surface of skin, and the in vitro degradation time is 5 days.
Examples 6,
Weighing 150mg of eight-arm polyethylene glycol amino (shown as formula IV, wherein m is 46) and the particle size is 1.9 μm, weighing 150mg of eight-arm polyethylene glycol succinimidyl ester (shown as formula VIII, wherein n is 46) and the particle size is 2.2 μm, and uniformly mixing the two kinds of PEG powder and 300mg of Aiwei Dingting microfiber hemostatic collagen hemostatic powder to obtain the composite hemostatic powder.
The water absorption capacity of the composite hemostatic powder prepared in the embodiment is 200 times, which is higher than that (50 times) of the single commercially available Aiwei Ting microfiber hemostatic collagen hemostatic powder, and after water absorption, the composite hemostatic powder is gelatinous and can be well attached to the surface of skin, and the in vitro degradation time is 7 days.
Example 7,
Weighing 100mg of eight-arm polyethylene glycol amino (shown as formula IV, wherein m is 56) and the particle size is 0.03 μm, weighing 100mg of two-arm polyethylene glycol succinimidyl ester (shown as formula V, wherein n is 28) and the particle size is 0.02 μm, and uniformly mixing the two kinds of PEG powder and 500mg of Aiwei Dingting microfiber hemostatic collagen hemostatic powder to obtain the composite hemostatic powder.
The water absorption capacity of the composite hemostatic powder prepared in the embodiment is 290 times, which is higher than that (50 times) of the single commercially available Aiwei Ting microfiber hemostatic collagen hemostatic powder, and after water absorption, the composite hemostatic powder is gelatinous and can be well attached to the surface of skin, and the in vitro degradation time is 4 days.
Example 8,
Weighing 300mg of four-arm polyethylene glycol amino (shown as formula II, wherein m is 75) and the particle size is 0.6 μm, weighing 200mg of two-arm polyethylene glycol succinimidyl ester (shown as formula V, wherein n is 68) and the particle size is 0.2 μm, and uniformly mixing the two PEG powders and 500mg of arista (TM) hemostatic powder to obtain the composite hemostatic powder.
The water absorption capacity of the composite hemostatic powder prepared in this example is 146 times, which is far higher than that of a single Arista TM hemostatic powder sold in the market (70 times), after water absorption, the composite hemostatic powder is gelatinous, and can be well attached to the surface of skin, and the in vitro degradation time is 4 days.
Examples 9,
Weighing 450mg of eight-arm polyethylene glycol amino (shown as formula IV, wherein m is 56) and the particle size is 6 μm, weighing 300mg of four-arm polyethylene glycol succinimidyl ester (shown as formula VI, wherein n is 56) and the particle size is 0.5 μm, and uniformly mixing the two kinds of PEG powder and 270mg of Aiwei Ting microfiber hemostatic collagen hemostatic powder to obtain the composite hemostatic powder.
The water absorption capacity of the composite hemostatic powder prepared in the embodiment is 54 times, which is close to the water absorption capacity (50 times) of a single commercially available Aiwei Ting microfiber hemostatic collagen hemostatic powder, after water absorption, the composite hemostatic powder is gelatinous, can be well attached to the surface of skin, and the in vitro degradation time is 6 days.
Examples 10,
Weighing 50mg of hexa-arm polyethylene glycol amino (shown as formula III, wherein m is 28) and the particle size is 1.5 mu m, weighing 50mg of hexa-arm polyethylene glycol succinimide ester (shown as formula VII, wherein n is 28) and the particle size is 2 mu m, and uniformly mixing the two kinds of PEG powder and 100mg of Fujietai degradable hemostatic powder to obtain the composite hemostatic powder.
The water absorption capacity of the composite hemostatic powder prepared in this example is 150 times, which is far higher than that (49 times) of the commercially available single Fuhe Tai degradable hemostatic powder, and after water absorption, the composite hemostatic powder becomes colloid and can be well attached to the surface of skin, as shown in fig. 1, and the in vitro degradation time is 6 days.
And (3) hemostasis test: a wound with the length and width of 1cm and the depth of 0.3mm is made on the liver of a rabbit, the hemostatic powder is coated on the surface of the liver, the time required for observing the blood non-flowing is the hemostatic time, and the hemostatic effect graph of each example is shown in the table I.
Table one: comparison of hemostatic effects of the composite hemostatic powders prepared in examples
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A rapidly cross-linked, degradable PEG powder, which consists of polyethylene glycol derivatives 1 and polyethylene glycol derivatives 2, wherein the polyethylene glycol derivatives 1 are any one of formula I, formula II, formula III or formula IV:
in the formula, m is 28-123; the polyethylene glycol derivative 2 is any one of a formula V, a formula VI, a formula VII and a formula VIII:
in each formula, n is 28 to 112.
2. The rapidly cross-linking, degraded PEG powder of claim 1, characterized by: the polyethylene glycol derivative 1 is any one of the following formulas 1) to 3):
1) as shown in formula II, wherein m is 56-112; or
2) As shown in the formula III, wherein m is 28-56; or
3) As shown in formula IV, wherein m is 56.
3. The rapidly cross-linking, degraded PEG powder of claim 1, characterized by: the polyethylene glycol derivative 2 may be any one of the following formulas 1) to 4):
1) the formula is shown as a formula V, wherein n is 28-56; or
2) As shown in formula VI, wherein n is 56-112; or
3) As shown in formula VII, wherein n is 28; or
4) As shown in formula VIII, wherein n is 56.
4. The rapidly cross-linking, degraded PEG powder of claim 1, characterized by: the compound is composed of a compound shown in a formula II and a compound shown in a formula VI, wherein m is 36-123, and n is 46-112.
5. The rapidly cross-linking, degraded PEG powder of claim 1, characterized by: the compound is composed of a compound shown in a formula III and a compound shown in a formula VII, wherein m is 28-38, and n is 28.
6. The rapidly cross-linking, degraded PEG powder of claim 1, characterized by: the compound is composed of a compound shown in a formula IV, a compound shown in a formula VIII, a compound shown in a formula V or a compound shown in a formula VI. Wherein m is 46 to 56, and n is 28 to 56.
7. The rapidly cross-linking, degraded PEG powder of any one of claims 1-6, characterized by: the average particle size of the polyethylene glycol derivative 1 and the polyethylene glycol derivative 2 is 0.01-100 mu m, or: the polyethylene glycol derivative 1 and the polyethylene glycol derivative 2 are particles with the average particle size of 0.01-100 mu m.
8. The composite hemostatic powder based on the rapidly cross-linked and degraded PEG powder and the commercially available hemostatic powder of claim 1, which is prepared by mixing polyethylene glycol derivative 1, polyethylene glycol derivative 2 and the commercially available hemostatic powder in a mass ratio of (0.5-2.0) to 1 to (0.4-5.0).
9. The composite hemostatic powder according to claim 8, wherein the commercially available hemostatic powder is regenerated cellulose-based hemostatic powder, chitosan-based hemostatic powder, starch-based hemostatic powder, collagen-based hemostatic powder, or zeolite-based hemostatic powder.
10. The method for preparing a composite styptic powder based on rapidly crosslinkable, degradable PEG powder and commercially available styptic powder of claim 8, comprising the steps of: and uniformly mixing the polyethylene glycol derivative 1, the polyethylene glycol derivative 2 and the commercially available hemostatic powder according to a ratio to obtain the composite hemostatic powder based on the PEG powder capable of being rapidly crosslinked and degraded and the commercially available hemostatic powder.
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