CN101618045A - Anti-adhesion gel containing polyhydroxyalkanoate - Google Patents
Anti-adhesion gel containing polyhydroxyalkanoate Download PDFInfo
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Abstract
The invention relates to an anti-adhesion gel containing polyhydroxyalkanoate and specifically the invention provides an anti-adhesion gel containing hydrophilic organic solvent and polyhydroxyalkanoate. The invention also provides an application of polyhydroxyalkanoate for preparing the medicament used for preventing postoperative adhesions.
Description
Technical field
The present invention relates to comprise the anti-adhesion gel of polyhydroxyalkanoate and hydrophilic organic solvent.The invention still further relates to polyhydroxyalkanoate and be used for preventing the purposes of the medicament of postoperative intestinal adhesion in preparation.
Background technology
Tissue adhesion's formation is the generally reaction of body to tissue injuries such as peritoneums, because the wound of tissue combines connective fiber band and adjacent tissue or organ, and the formation anomalous structure.The tissue adhesion is a kind of common pathological reaction (medical science general designation postoperative tissue adhesion), and major part occurs in (Menzies D, 1992 after the surgical operation; Dizerega GS, 1994; Holtz G, 1984; Ellis H, 1982).
The adhesion that forms between wound and nethike embrane, most of case can be involved organ around the intestinal etc., thereby cause severe complications, such as intestinal obstruction, and stomachache, female acyesis, endometriosis, operation back hyposexuality, pelvic pain etc.In addition, the compressing larynx anti-nerve that sticks together behind the thyroid operation causes hoarseness, and spinal operation can cause the postoperative root pain because of adhesion pressing spine nerve, operation of opening cranium stick together (Holmdahl L, 1997 such as can causing postoperative epilepsy; Young RL, 2001).Studies show that mechanical intestinal obstruction 90% is for due to the adhesion after the abdominal cavity operation on pelvis.Female acyesis patient about 20% is caused by pelvic adhesion.Secondly, the generation of tissue adhesion has also increased operating difficulty again.Once more, the tissue adhesion also can cause the part body function incomplete.Although the modern surgery surgical technic has greatly improved, tissue adhesion remains operation back common complication, and incidence rate is up to 90% (Menzies D, 1990).
How making surgical operation can reach the treatment disease and do not cause serious adhesion complication again, is current surgery problem demanding prompt solution.Surgeon are carrying out long-term and unremitting effort for this reason.People find that in reason that peritoneal adhesion is formed and Study on Mechanism the serous coat damage that mechanical injuries, tissue ischemia, foreign body stimulation and peritonitis etc. cause is the main inducing of peritoneal adhesion.Under the physiological status, the formation and the dissolving of the gluey thing of peritoneum fibrin are in dynamic balance state, and the fibrin that solidifies can be dissolved by fibrinolysin in 72-96h.Peritoneal injury, ischemia, inflammation all can make fibrinolytic reduce, and this is that peritoneal adhesion forms most important reason (Menzies D, 1992; Once strong, 2003).
Prevent that effectively the tissue adhesion from becoming operating key, once used various adhesion preventing methods clinically, anti-inflammatory agent is suppressed to the fibroblast proliferation medicine, the macromolecular substances of anti-peritoneal adhesion, therapies such as expanded PTFE isolation, but exist the side effect to normal structure, absorbability does not cause in vivo always existing with the form of foreign body, causes that easily patient does not accommodate other complication (Zhao Qiang, Cheng Guoxiang, 2003).Along with the mechanism of adhesion is revealed gradually, the product Film with Preventing Adhesion with the effect of lasting anti physical barriers that the degradable absorbing material is developed is used in the research extensively and profoundly of tissue adhesion prevention and the development of material science, is the method for normal employing in the world.The nineties in last century, multiple degradable absorbs anti product acquisition (the Food and Drug Administration of FDA (Food and Drug Adminstration) on the U.S. medical market, abbreviation FDA) permission, degradation material are extensive use of (table 1) clinically, such as: cellulose derivative (Cellulosederivatives), hyaluronic acid (Hyaluronic acid, be called for short HA), chitosan (Capsomere is called for short CS), polylactic acid (Polylactic acid is called for short PLA).(Saravelos HG, 1996; Yeo, Y.and Kohane, D.S, 2008) chitosan purity is not high enough, contacts easy gelation with body fluid, and preventing adhesiving effect is not ideal enough.The hyaluronate sodium degraded and absorbed is too fast, preventing adhesiving effect not ideal enough (Wiseman D, 1994; Zhu Xiaoming etc., 2002).In tissue engineering material, use more degradable synthetic material PLA at present many advantages are arranged, once be considered to a kind of promising material, but the PLA molecular weight of chemosynthesis is lower, its mechanical strength is relatively poor, and the too fast local overacidification that causes of degradation rate is in addition as synthetic family macromolecule material shortage cell recognition signal (Chen ﹠amp; Wu, 2005), adding characteristic owing to poly-lactic acid material itself, film fragility and hardness are bigger, tissue is produced sensation of pricking also limited its extensive use (Gao et al, 2006) in medical tissue engineering.
A kind of clinically good tissue adhesion's biomaterial that prevents must possess: good blood compatibility and histocompatibility; Good film property, the quality softness is to organizing not damaged, the penetrating mass exchange that is beneficial to of film porous; Broad-spectrum antibacterial action can effectively suppress post-operation inflammatory, reduces bacterial infection, inflammation generation; It is better to have haemostatic effect; The end product of biomaterial easily is absorbed by the body, and is difficult for causing untoward reaction; Also require characteristics such as physics and chemical property are stable, nontoxic, apyrogeneity, not carcinogenic, teratogenesis is not to consider yet; Random film forming need not sewed up in the body, and is easy to operate.This has proposed requirement (KloppLS et al, 2004 of intimate harshness for the main Material Used of clinical post-operation adhesion preventing; Dunn et al, 1994; Zhu Xiaoming etc., 2002; Xiong Chengdong etc., 2005; Shi Chunxia, 2005).
The anti barrier that table 1. has been developed or developed
Polyhydroxyalkanoate (Polyhydroxyalkanoates is called for short PHA) is a series of natural polymers that extensively are present in many microbial cells, (Chen et al, 2000) of a great variety.PHA is owing to have excellent biological compatibility, and biodegradability has more advantage in processing characteristics and mechanical properties simultaneously, has therefore determined its extensive use (Chen ﹠amp in organizational project; Wu, 2005).3-hydroxybutyric acid and 3-hydroxycaproic acid copolymer (Poly (3-hydroxybutyrate-co-3-hydroxyhexanoate), be called for short PHBHHx) be to occur as the substitute products that gather 3-hydroxybutyric acid (PHB) and 3-hydroxybutyric acid and 3-hydroxyl pentanoate copolymer (PHBV), its cell in vitro affinity is discovered, this material helps fibroblast (Yang et al after making film or three-dimensional rack, 2002), chondrocyte (Deng et al, 2002), bone marrow stroma stem cell (Yang et al, 2004) etc. stick and breed, and can promote the formation (Deng et al, 2003) of cartilage cell epimatrix.In addition, research worker finds that also new polyester PHBHHx has than better biocompatibility such as conventional medical material polylactic acid PLA, mechanical performance and processing characteristics (Gao et al, 2002).PHBHHx finally is degraded to 3-hydroxybutyric acid and 3-hydroxycaproic acid in vivo simultaneously, and wherein accounting for most 3-hydroxybutyric acid is the normal composition (Cheng et al, 2005) of blood and its hetero-organization.On February 12nd, 2007, FDA announces that the PHA suture that approval utilizes recombinant DNA technology to produce goes on the market in U.S.A, and claim this be first kind of absorbable suture that relies on high-new biotechnology to develop (
Http:// www.fda.gov), this has directly accelerated the research of PHA at medical instruments field.
Therefore, still need to have the anti-adhesion gel of good clinical effectiveness.
Summary of the invention
The present invention is based in part on following discovery: when the polyhydroxyalkanoate in being dissolved in absorbable hydrophilic organic solvent contacts with water, hydrophilic organic solvent and water exchange mutually, and the polyhydroxyalkanoate that is not dissolved in water begins gel solidification, forms one deck barrier film.
Therefore, the invention provides a kind of gel with the polyhydroxyalkanoate preparation, utilize it to meet MJPZ, coating animal tissue wound surface reaches the purpose that prevents tissue adhesion.
Particularly, the invention provides following embodiment.
[embodiment 1] a kind of anti-blocking compositions comprises: hydrophilic organic solvent, and formula (I) chemical compound,
Wherein: in the bracket is construction unit, and each construction unit can be identical or different; N represents the sum of construction unit; The m of each construction unit is independently selected from 1～3 integer; The R of each construction unit
1Be independently selected from by H, C
1-C
9The group that constitutes of alkyl.
[embodiment 2] is according to the compositions of embodiment 1, wherein R
1Be selected from by H, C
1-C
5The group that constitutes of alkyl.
[embodiment 3] is according to the compositions of embodiment 1, wherein R
1Be selected from by H, C
1-C
3The group that constitutes of alkyl.
[embodiment 4] according to the compositions of embodiment 1, wherein said formula (I) chemical compound is 3-hydroxybutyric acid-3-hydroxycaproic acid copolymer.
[embodiment 5] according to the compositions of embodiment 4, wherein the monomeric molar percentage of 3-hydroxycaproic acid is 1-30%.
[embodiment 6] according to the compositions of embodiment 4, wherein the monomeric molar percentage of 3-hydroxycaproic acid is 5-15%.
[embodiment 7] according to each the compositions of embodiment 4-6, the weight average molecular weight of wherein said 3-hydroxybutyric acid-3-hydroxycaproic acid copolymer is 50,000-2,000,000.
[embodiment 8] according to the compositions of embodiment 7, the weight average molecular weight of wherein said 3-hydroxybutyric acid-3-hydroxycaproic acid copolymer is 80,000-700,000.
[embodiment 9] according to the compositions of embodiment 1, wherein said formula (I) chemical compound is 3-hydroxybutyric acid-4 hydroxybutyric acid copolymer.
[embodiment 10] according to the compositions of embodiment 9, wherein the monomeric molar percentage of 4 hydroxybutyric acid is 1-50%.
[embodiment 11] according to the compositions of embodiment 9, wherein the monomeric molar percentage of 4 hydroxybutyric acid is 10-40%.
[embodiment 12] according to each the compositions of embodiment 9-11, the weight average molecular weight of wherein said 3-hydroxybutyric acid-4 hydroxybutyric acid copolymer is 50,000-2,000,000.
[embodiment 13] according to the compositions of embodiment 12, the weight average molecular weight of wherein said 3-hydroxybutyric acid-4 hydroxybutyric acid copolymer is 550,000-700,000.
[embodiment 14] is according to each the compositions of embodiment 1-13, wherein said hydrophilic organic solvent is selected from the group that is made of following member: N-Methyl pyrrolidone, N-ethyl pyrrolidone, ketopyrrolidine, N, N-dimethyl acetylamide, N, dinethylformamide, 1,4-dioxane, 1,4-butyrolactone, ethylene carbonate, methyl ethyl ketone, dimethyl sulfoxide, butanone caprolactam and two or more mixture in them.
[embodiment 15] according to each the compositions of embodiment 1-14, and the weight ratio of wherein said formula (I) chemical compound and described hydrophilic organic solvent is in 1: 5～1: 20 scope.
[embodiment 16] according to the compositions of embodiment 15, and the weight ratio of wherein said formula (I) chemical compound and described hydrophilic organic solvent is in 1: 10～1: 15 scope.
[embodiment 17] formula (I) chemical compound is used for preventing the purposes of the medicament of postoperative intestinal adhesion in preparation,
Wherein: in the bracket is construction unit, and each construction unit can be identical or different; N represents the sum of construction unit; The m of each construction unit is independently selected from 1～3 integer; The R of each construction unit
1Be independently selected from by H, C
1-C
9The group that constitutes of alkyl.
[embodiment 18] is according to the purposes of embodiment 17, wherein R
1Be selected from by H, C
1-C
5The group that constitutes of alkyl.
[embodiment 19] according to the purposes of embodiment 17, wherein said formula (I) chemical compound is 3-hydroxybutyric acid-3-hydroxycaproic acid copolymer.
[embodiment 20] according to the purposes of embodiment 19, wherein the monomeric molar percentage of 3-hydroxycaproic acid is 5-15%.
[embodiment 21] according to each the purposes of embodiment 19-20, the weight average molecular weight of wherein said 3-hydroxybutyric acid-3-hydroxycaproic acid copolymer is 80,000-700,000.
[embodiment 22] according to the purposes of embodiment 17, wherein said formula (I) chemical compound is 3-hydroxybutyric acid-4 hydroxybutyric acid copolymer.
[embodiment 23] according to the purposes of embodiment 22, wherein the monomeric molar percentage of 4 hydroxybutyric acid is 10-40%.
[embodiment 24] according to each the purposes of embodiment 22-23, the weight average molecular weight of wherein said 3-hydroxybutyric acid-4 hydroxybutyric acid copolymer is 550,000-700,000.
[embodiment 25] a kind of method that is used to prevent postoperative intestinal adhesion comprises each compositions from the embodiment 1-16 of effective dose to the experimenter that use.
Because the monomeric adding of HHx, the easy film forming of PHBHHx high resilience has mechanical strength again; P3HB4HB is owing to the monomeric adding high resilience of 4HB, and both show good performance aspect Antiadhesive film.Therefore, the most preferred polyhydroxyalkanoate of the present invention is PHBHHx, P3HB4HB.。
Anti-adhesion gel compositions of the present invention can be by being dissolved into polyhydroxyalkanoate in some water-miscible organic solvents, can stir in case of necessity or heat to be prepared from.
Anti-adhesion gel of the present invention has following characteristics: 1. good histocompatibility; 2. irregular position is coated with arbitrarily, the film forming according to actual needs at the position of need anti; 3. meet film forming formation physical barriers in the water short time; 4. degrade after a period of time in vivo, catabolite is nontoxic, and is not carcinogenic, not teratogenesis; 5. easy to operate.
Description of drawings
Fig. 1 has shown that the PHBHHx gel coating is at the lip-deep any filming performance of irregularly shaped object.
Fig. 2 shown the PHBHHx gel in the SD rat abdominal cavity with the position film-formation result.A.PHBHHx/ dioxane glue is coated film forming after the Rats Organs and Tissues; B.PHBHHx/N, N-dimethyl acetylamide glue coat back, rat peritoneum below film forming; C.PHBHHx/N, after N-dimethyl acetylamide glue is coated on the rat stomach surface, rapid film forming; D.PHBHHx/N, N-dimethyl acetylamide glue are coated on injection electrolyte solution in back on the rat stomach surface, make its rapider film forming.
Fig. 3 A has shown that the PHBHHx gel phase of different solvents preparation separates film forming surface topography.
(a) .NMP 12%PHBHHx. (b) .DMAC 12%PHBHHx. (c) .DIOX12%PHBHHx. (d) .1.4BL 12%PHBHHx. (e) .DMSO 12%PHBHHx. (f) .DMAC 7%PHBHHx. (g) .DMAC 3%PHBHHx. (h) .BL 7%PHBHHx. (i) .NMP PLA. (j) .DIOX 12%PHBHHx (volatilization film forming). (k) .BL 12%PHBHHx (volatilization film forming). (l). chloroform 12%PHBHHx (volatilization film forming).
Fig. 3 B has shown that the PHBHHx gel phase separates film forming side pattern under the different solvents condition.
(a) .NMP 12%PHBHHx. (b) .DMAC 12%PHBHHx. (c) .BL12%PHBHHx. (d) .DIOX 12%PHBHHx. (e) .DMSO 12%PHBHHx. (f). chloroform 12%PHBHHx (volatilization film forming). (g) .DMAC 7%PHBHHx. (h) .DMAC3%PHBHHx.
Fig. 4 has shown that the CTK-8 method is measured and has used different solvents to be separated the PHBHHx film of preparation to the influence of rabbit smooth muscle cell proliferation.
Fig. 5 has shown the influence of the film of the different PHBHHx preparations of CTK-8 method mensuration use to the rabbit smooth muscle cell proliferation.
The specific embodiment
Term used herein " alkyl " is meant and has to the side chain of the carbon atom of determined number and the radical of saturated aliphatic alkyl of straight chain.For example, " C
1-C
9Alkyl " be defined as the radical of saturated aliphatic alkyl group that has 1,2,3,4,5,6,7,8 or 9 carbon of straight or branched.For example, " C
1-C
9Alkyl " particularly including methyl, ethyl, just-propyl group, different-propyl group, just-butyl, tert-butyl, different-butyl, amyl group, hexyl, heptyl, octyl group, nonyl etc.
Term used herein " effective dose " refers to the amount of the medicament that is enough to cause biology that veterinary or clinicist seek or medical response in animal or human's body." effective dose " of anti-blocking compositions of the present invention can be determined according to factors such as route of administration, operative sites by those skilled in the art.For example, using the film thickness that forms behind the anti-blocking compositions of the present invention can be between 0.03mm～0.5mm.
Term used herein " experimenter " refers to any mammal, and for example, mice, rat, rabbit, Canis familiaris L., cattle, especially primate are as monkey and people." experimenter " can refer to ill mammal, particularly people, the people who for example suffers from appendicitis thereby need to perform the operation; The mammal that also can refer to not ill health.It will be understood by those skilled in the art that in some cases for example for cosmetic purpose or run into when emergency such as being buried by pressure, not ill experimenter also may need to carry out surgical operation and corresponding anti is handled.
" hydrophilic organic solvent " of the present invention should have following character: (1) is nontoxic and can absorb for human or animal body, promptly has biocompatibility; (2) can dissolve polyhydroxyalkanoates such as PHBHHx, dissolubility is high more good more; (3) can dissolve each other with water; (4) pharmaceutically acceptable.The higher hydrophilic organic solvent of boiling point is more preferred, because it is not easy volatilization.Those skilled in the art can select appropriate organic solvent according to above-mentioned requirements.Being particularly suitable for hydrophilic organic solvent of the present invention comprises: N-Methyl pyrrolidone (N-Methyl pyrrolidone, be called for short NMP), N-ethyl pyrrolidone (N-Ethyl-2-pyrrolidinone, be called for short NEP), ketopyrrolidine (2-Pyrrolidone, be called for short 2-P), N, N-dimethyl acetylamide (N, N-Dimethylacetamide, be called for short DMAC), N, dinethylformamide (N, N-dimethylformamide is called for short DMF), 1,4-dioxane (1,4-dioxane, be called for short DIOX), 1, and the 4-butyrolactone (1,4-butanolide, be called for short BL), ethylene carbonate (glycol carbonate), methyl ethyl ketone (2-Butanone), dimethyl sulfoxide (Dimethyl sulfoxide is called for short DMSO), caprolactam (Caprolactam) etc.Most preferred " hydrophilic organic solvent " is N-Methyl pyrrolidone, 1,4-dioxane, N,N-dimethylacetamide, dimethyl sulfoxide.
Polyhydroxyalkanoate of the present invention, its structure is suc as formula shown in (I).Polyhydroxyalkanoate of the present invention had both comprised poly butyric ester (Poly (hydroxybutyrate), be called for short PHB), poly-hydroxyl valerate (Poly (hydroxyvalerate), be called for short PHV), poly-Hydroxycaprylic acid ester (Poly (hydroxyoctanoate), be called for short PHO) etc. PHA class homopolymer, also comprise hydroxybutyric acid valeric acid copolymer (Poly (hydroxybutyrate-co-hydroxyvalerate), be called for short PHBV), 3-hydroxybutyric acid-3-hydroxycaproic acid copolymer (Poly (3-hydroxybutyrate-co-3-hydroxyhexanoate), be called for short PHBHHx), the mixture that 3-hydroxybutyric acid-4 hydroxybutyric acid copolymer pha copolymers such as (Poly (3-hydroxybutyrate-co-4-hydroxybutyrate) are called for short P3HB4HB) and several PHA thereof form.
The weight average molecular weight of polyhydroxyalkanoate of the present invention (PHA) has no particular limits, and preferable range is 50, and 000-2 is between 000,000.Weight average molecular weight is less for example to be lower than at 50,000 o'clock, and the film-strength that is become is less, and film-forming speed can reduce to some extent; Weight average molecular weight more for example is higher than at 1,000,000 o'clock, and degradation cycle can extend, and the flowability of gel can reduce to some extent.Particularly preferred molecular weight ranges is 100,000-700,000.Those skilled in the art can determine suitable molecular weight according to the factors such as flowability of the kind of polymer, the solvent that is adopted, formed gel.
Polyhydroxyalkanoate material of the present invention preferably has certain elasticity, suitable hot strength (preferably below the 30Mpa) and elongation at break (preferred more than 100%).For example, PHB hot strength 43Mpa, elongation at break 5%, the crisp easy fracture of material; And PHBHHx (10%HHx) hot strength 21Mpa, elongation at break 400%, P3HB4HB (16%4HB) hot strength 26Mpa, elongation at break 444%, these materials are rich in certain elasticity.The polyhydroxyalkanoate material also will possess suitable degree of crystallinity, this and material filming performance, and histocompatibility, degradation properties etc. have very big relation.For example, PHB (W
M50W) degree of crystallinity is 65%, though film forming speed is very fast, causes the big frangible and damaged tissue of film material rigidity, and it is also slow to degrade.PHBHHx (7%HHx, W
M300,000) and PHBHHx (12%HHx, W
M500,000) degree of crystallinity is respectively 28%, 20%, and is more suitable on degree of crystallinity.Therefore, PHBHHx and P3HB4HB are the particularly preferred polyhydroxyalkanoates of the present invention.
Dissolubility PHA preferably in solvent, the film material mechanical strength of formation is also better.Can be particularly preferred by the rapid dissolved PHA class of solvent under the normal temperature condition, in 5 minutes, be dissolved in the N,N-dimethylacetamide such as PHBHHx.The PHA class that some side chains are long, for example the free carbon atomic number surpasses 8 PHA, and the dissolubility in water-miscible organic solvent can descend to some extent.
Because enough mechanical strengths of PHBHHx, good histocompatibility, its catabolite 3-hydroxy fatty acid, it itself is the part of blood and its hetero-organization, nontoxic non-stimulated, add the gel of this semi-liquid stage to make it can handle the irregular position of health, compare with anti product in the market, have an enormous advantage.
Concrete polyhydroxyalkanoate material 3-hydroxybutyric acid used in the present invention and 3-hydroxycaproic acid copolymer p HBHHx comprise following several: HHx molar percentage 12%, weight average molecular weight (weight-average molecular weight or Mw) is respectively 80,000,310,000 and 400,000; HHx molar percentage 3%, weight average molecular weight are 540,000; HHx molar percentage 7%, weight average molecular weight are 650,000.
3-hydroxybutyric acid used in the present invention-4 hydroxybutyric acid copolyesters P3HB4HB comprises following several: the 4HB molar percentage is respectively 12% and 40%, and corresponding weight average molecular weight is respectively 590,000 and 700,000.
In the anti-adhesion gel of the present invention, the consumption of polyhydroxyalkanoate PHA and hydrophilic organic solvent has no particular limits, as long as can form the gel liquid that is suitable for using, having by modes such as for example injections good fluidity.Usually, the weight ratio of PHA and hydrophilic organic solvent is in 1: 5～1: 20 scope, preferably in 1: 10～1: 15 scope.The consumption of organic solvent can easily be determined according to the factors such as character of the PHA that is adopted by those skilled in the art.
The organization of human body complexity, the wound surface of postoperative also is not quite similar, and is also incomplete same to the shape and the thickness requirement of film at different parts, though can prepare the film of different size, can not address this problem fully.By the degradable anti-adhesion gel of PHA preparation, gel is the water white transparency shape before use, has flowability, is easy to sprawl film forming, can be at the position that needs anti according to the practical situation film forming, and shape and the thickness that can regulate film according to the wound surface situation.For example, using the film thickness that forms behind the anti-blocking compositions of the present invention can be between 0.03mm～0.5mm.
Be not subjected to the constraint of any particular theory, think that the mechanism of anti-adhesion gel Film with Preventing Adhesion of the present invention is to form barrier, fibroblast is to the invasion of surgical wound surface in the prevention surrounding tissue.The film that anti-adhesion gel of the present invention forms is loose structure, the quality softness, and permeability is good, is beneficial to the both sides mass exchange.After the surgical wound surface healing, polyhydroxyalkanoate is degraded to the hydroxy aliphatic acid monomers gradually, participates in the metabolism of body, finally excretes; Easy to use, determined curative effect, applied range are nontoxic, harmless, have no side effect.With Antiadhesive film relatively, easy and simple to handle without sutured, and be not subjected to the influence of patient's Body Position Change; Can be conveniently used in endoscope-assistant surgery; Its preparation technology is simple and reliable, easy to use simultaneously, cost is low, and good prospects for application is arranged clinically.Absorption portion moisture when being separated film forming owing to it simultaneously, preliminary experimental result confirms that it has hemostatic function.
Polyhydroxyalkanoate gellike of the present invention is applicable to postoperative tissue adhesions such as general surgery, orthopaedics, department of obstetrics and gynecology and Urology Surgery.
During use, can be packaged in polyhydroxyalkanoate gel of the present invention directly to release in the syringe and use, easy to use, save operating time.
If desired, the pharmaceutical field technical staff can also add other compositions in polyhydroxyalkanoate gel of the present invention, for example medicine such as anti-inflammatory agent, and solubilizing agent, antiseptic etc.
In order to explain the present invention in further detail, will provide embodiments of the invention below.These embodiment only are for explaining and illustrative purposes, should not being understood that to limit the scope of the present invention.
Embodiment 1:
The PHBHHx of molecular weight 310,000 HHx content 12mol%, the N-Methyl pyrrolidone of 12 times of weight joins PHBHHx with N-Methyl pyrrolidone, and stirring can obtain.
Embodiment 2:
The PHBHHx of molecular weight 310,000 HHx content 12mol%, the N,N-dimethylacetamide of 12 times of weight joins PHBHHx with N,N-dimethylacetamide, and stirring can obtain.
Embodiment 3:
The PHBHHx of molecular weight 310,000 HHx content 12mol%, the ketopyrrolidine of 12 times of weight joins PHBHHx with ketopyrrolidine, and stirring can obtain.
Embodiment 4:
The PHBHHx of molecular weight 310,000 HHx content 12mol%, 1 of 12 times of weight, the 4-dioxane, with 1, the 4-dioxane joins PHBHHx, and stirring can obtain.
Embodiment 5:
The PHBHHx of molecular weight 310,000 HHx content 12mol%, 1 of 12 times of weight, the 4-butyrolactone, with 1, the 4-butyrolactone joins PHBHHx, and stirring can obtain.
Embodiment 6:
The PHBHHx of molecular weight 310,000 HHx content 12mol%, the butanone of 12 times of weight joins PHBHHx with butanone, and stirring can obtain.
Embodiment 7:
The PHBHHx of molecular weight 310,000 HHx content 12mol%, the dimethyl sulfoxide of 12 times of weight joins PHBHHx with dimethyl sulfoxide, and stirring and dissolving can obtain.
Embodiment 8:
The PHBHHx of molecular weight 310,000 HHx content 12mol%, the dimethyl sulfoxide of 12 times of weight joins PHBHHx with dimethyl sulfoxide, stirring and dissolving, the bubble that ultrasonic removal contains can obtain.
Embodiment 9:
The PHBHHx of molecular weight 310,000 HHx content 12mol%, the mixed solvent of 1: 1 ratio of the N-Methyl pyrrolidone of 12 times of weight and N,N-dimethylacetamide joins PHBHHx with mixed solvent, stirs or heat to obtain.
Embodiment 10:
The PHBHHx of molecular weight 310,000 HHx content 12mol%, the N-Methyl pyrrolidone of 8 times of weight joins PHBHHx with N-Methyl pyrrolidone, and stirring can obtain.
Embodiment 11:
The PHBHHx of molecular weight 400,000 HHx content 12mol%, 1 of 10 times of weight, the 4-dioxane, with 1, the 4-dioxane joins PHBHHx, and stirring can obtain.
Embodiment 12:
The PHBHHx of molecular weight 540,000 HHx content 3mol%, the N,N-dimethylacetamide of 12 times of weight joins PHBHHx with N,N-dimethylacetamide, and the agitating heating dissolving can obtain.
Embodiment 13:
The PHBHHx of molecular weight 650,000 HHx content 7mol%, the N,N-dimethylacetamide of 12 times of weight joins PHBHHx with N,N-dimethylacetamide, and the agitating heating dissolving can obtain.
Embodiment 14:
The PHBHHx of molecular weight 80,000 HHx content 12mol%, the N,N-dimethylacetamide of 6 times of weight joins PHBHHx with N,N-dimethylacetamide, and stirring and dissolving can obtain.
Embodiment 15:
The P3HB4HB of molecular weight 590,000 4HB content 12mol%, the N-Methyl pyrrolidone of 12 times of weight joins P3HB4HB with N-Methyl pyrrolidone, and high-temperature stirring can obtain.
Embodiment 16:
The P3HB4HB of molecular weight 700,000 4HB content 40mol%, 1 of 15 times of weight, the 4-dioxane, with 1, the 4-dioxane joins P3HB4HB, and high-temperature stirring is spent the night and can be obtained.
Embodiment 17:
The gel coating that the foregoing description 1 is made is inserted in the water 30 seconds rapid film forming at the bottom of clean culture dish.
Embodiment 18:
The gel coating that the foregoing description 4 is made is inserted in the water 40 seconds rapid film forming at the bottom of clean culture dish.
Embodiment 19:
The gel coating that the foregoing description 5 is made is inserted in the water 30 seconds rapid film forming at the bottom of clean culture dish.
Embodiment 20:
The gel coating that the foregoing description 1 is made is inserted 0.9% normal saline, 40 seconds rapid film forming at the bottom of clean culture dish.
Embodiment 21:
The gel coating that the foregoing description 4 is made is inserted in 0.9% the normal saline 40 seconds rapid film forming at the bottom of clean culture dish.
Embodiment 22:
The gel that the foregoing description 12 is made is by syringe, inserts on a small quantity in 0.9% the normal saline, and solution surface formed one deck barrier film in 10 seconds rapidly.
Embodiment 23:
The gel coating that the foregoing description 2 is made is in clean test tube outer surface, inserts in 0.9% the normal saline, is close to the test tube outer surface and forms a skim in 50 seconds rapidly.(Fig. 1)
Embodiment 24:
The gel coating that the foregoing description 2 is made is in clean microscope slide outer surface, inserts in 0.9% the normal saline, is close to the microscope slide outer surface and forms a skim in 40 seconds rapidly.(Fig. 1)
Embodiment 25:
The liquid gel that the foregoing description 2,4 is made is inserted in the SD rat abdominal cavity on a small quantity by syringe, and organ surface forms one deck barrier film rapidly.(Fig. 2)
Embodiment 26:
The gel that the foregoing description 1 is made is by syringe, inserts on a small quantity in 0.9% the normal saline, and solution surface formed one deck barrier film in 10 seconds rapidly.
Embodiment 27:
The gel that the foregoing description 9 is made is by syringe, inserts on a small quantity in 0.9% the normal saline, and solution surface formed one deck barrier film in 10 seconds rapidly.
Embodiment 28:
With the film that the foregoing description 1-7 makes, air-dry final vacuum drying utilizes electronic scanner microscope to observe the surface topography and the side pattern of film, and the result shows in the middle of film a lot of apertures, not of uniform size.(see Fig. 3 A, it is soft that 3B) appearance in these holes makes membranous ground, and have permeability to be beneficial to mass exchange.
Embodiment 29:
With the foregoing description 1,2,4,5 gels of making are got 0.5ml and are dropped in the glass dish (diameter 2.1cm, high 1.2cm), rotation makes it to cover whole bottom, becomes membranaceous, immerses 1min in the 0.9% sodium chloride normal saline solution, take out natural drying, the sterilization of 75% soak with ethanol after the film forming, under the gnotobasis, the went out PBS cleaning and dipping three times of bacterium was changed one time PBS every 1 hour, standby.The rabbit smooth muscle cell that the phase of taking the logarithm cultivates in DMEM culture medium (10% hyclone).Each sample well adds 1ml, and promptly 1 * 10
4Cell, 37 ℃, 5%CO
2Cultivate.Cell proliferation test group: phase separation membranes such as 1.NMP; 2. chloroform film forming material contrast; (3.TCP the contrast of 12 hole tissue culturing plates).Used Cell Counting Kit-8 test kit (BeyotimeInstitute of Biotechnology) to detect in 48 hours.48h takes out all culture medium, adds 1000ul culture medium (serum-free adds the CTK-8 solution of 10% volume, lucifuge) recently, and 37 ℃, 5%CO
2Cultivate 3h, back supernatant is transferred in 96 orifice plates, and each hole 150ul uses microplate reader (the vigorous MK3 microplate reader of Finland's thunder, Thermo Labsystems company) 450nm, and the 630nm dual wavelength optical filter detects, deal with data.
The rabbit smooth muscle cell is using NMP, DMAC, DIOX, the BL solvent by on the PHBHHx film that is separated into the growth 48h after, the vigor of cell is respectively 63.5 ± 7.0%, 63.7 ± 4.1%, 64.0 ± 4.1% of TCP control wells (TissueCulture Plate), 63.6 ± 7.0%, and cell viability is 66.8 ± 3.1% (Fig. 4) of control wells on the film that the volatilization by chloroform (lv) forms.These several different solvents of this description of test are separated and are unfavorable for the growth of smooth muscle cell on the film that forms.
Embodiment 30:
With the foregoing description 2,12,13 gels of making, get 0.5ml and drop in the glass dish (diameter 2.1cm, high 1.2cm), rotate and make it to cover whole bottom, become membranaceous, immerse 1min in the 0.9% sodium chloride normal saline solution, take out after the film forming, natural drying, the sterilization of 75% soak with ethanol, under the gnotobasis, the PBS cleaning and dipping of the bacterium of going out three times, changed one time PBS every 1 hour, standby.The rabbit smooth muscle cell that the phase of taking the logarithm cultivates in DMEM culture medium (10% hyclone).Each sample well adds 1ml, and promptly 1 * 10
4Cell, 37 ℃, 5%CO
2Cultivate.Cell proliferation test group: 1.DMAC phase separation membrane; 2. chloroform (LV) film forming material contrast; (3.TCP the contrast of 12 hole tissue culturing plates).Used Cell Counting Kit-8 test kit (BeyotimeInstitute of Biotechnology) to detect in 48 hours.48h takes out all culture medium, adds 1000ul culture medium (serum-free adds the CTK-8 solution of 10% volume, lucifuge) recently, and 37 ℃, 5%CO
2Cultivate 3h, back supernatant is transferred in 96 orifice plates, and each hole 150ul uses microplate reader (the vigorous MK3 microplate reader of Finland's thunder, Thermo Labsystems company) 450nm, and the 630nm dual wavelength optical filter detects, deal with data.
The rabbit smooth muscle cell contains 3% respectively what use DMAC solvent formed by being separated, 7%, on the PHBHHx film of 12%HHx the growth 48h after, the vigor of cell is respectively 24.5 ± 2.0% of control wells, 79.5 ± 5.8%, 34.5 ± 4.2%, and cell viability is 70.9 ± 3.9% of a TCP control wells (Tissue Culture Plate) on the film that the volatilization by fluoroform forms, 71.1 ± 5.9%, 71.7 ± 7.5%.(Fig. 5) a kind of solvent of these several uses of this description of test but different materials is separated film forming and TCP contrast (Tissue Culture Plate) compare, be unfavorable for the cell growth, wherein 3%, cell viability has only 24.5 ± 2.0% of matched group on 12% the film, 34.5 ± 4.2%, with the contrast of 100% TCP control wells (Tissue Culture Plate) significant difference (P＜0.05) is arranged.
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Claims (24)
1. anti-blocking compositions comprises:
Hydrophilic organic solvent, and
Formula (I) chemical compound,
Wherein:
In the bracket is construction unit, and each construction unit can be identical or different;
N represents the sum of construction unit;
The m of each construction unit is independently selected from 1～3 integer;
The R of each construction unit
1Be independently selected from by H, C
1-C
9The group that constitutes of alkyl.
2. according to the compositions of claim 1, R wherein
1Be selected from by H, C
1-C
5The group that constitutes of alkyl.
3. according to the compositions of claim 1, R wherein
1Be selected from by H, C
1-C
3The group that constitutes of alkyl.
4. according to the compositions of claim 1, wherein said formula (I) chemical compound is 3-hydroxybutyric acid-3-hydroxycaproic acid copolymer.
5. according to the compositions of claim 4, wherein the monomeric molar percentage of 3-hydroxycaproic acid is 1-30%.
6. according to the compositions of claim 4, wherein the monomeric molar percentage of 3-hydroxycaproic acid is 5-15%.
7. according to each the compositions of claim 4-6, the weight average molecular weight of wherein said 3-hydroxybutyric acid-3-hydroxycaproic acid copolymer is 50,000-2,000,000.
8. according to the compositions of claim 7, the weight average molecular weight of wherein said 3-hydroxybutyric acid-3-hydroxycaproic acid copolymer is 80,000-700,000.
9. according to the compositions of claim 1, wherein said formula (I) chemical compound is 3-hydroxybutyric acid-4 hydroxybutyric acid copolymer.
10. according to the compositions of claim 9, wherein the monomeric molar percentage of 4 hydroxybutyric acid is 1-50%.
11. according to the compositions of claim 9, wherein the monomeric molar percentage of 4 hydroxybutyric acid is 10-40%.
12. according to each the compositions of claim 9-11, the weight average molecular weight of wherein said 3-hydroxybutyric acid-4 hydroxybutyric acid copolymer is 50,000-2,000,000.
13. according to the compositions of claim 12, the weight average molecular weight of wherein said 3-hydroxybutyric acid-4 hydroxybutyric acid copolymer is 550,000-700,000.
14. each compositions according to claim 1-13, wherein said hydrophilic organic solvent is selected from the group that is made of following member: N-Methyl pyrrolidone, N-ethyl pyrrolidone, ketopyrrolidine, N, N-dimethyl acetylamide, N, dinethylformamide, 1,4-dioxane, 1,4-butyrolactone, ethylene carbonate, methyl ethyl ketone, dimethyl sulfoxide, butanone, caprolactam and two or more mixture in them.
15. according to each the compositions of claim 1-14, the weight ratio of wherein said formula (I) chemical compound and described hydrophilic organic solvent is in 1: 5～1: 20 scope.
16. according to the compositions of claim 15, the weight ratio of wherein said formula (I) chemical compound and described hydrophilic organic solvent is in 1: 10～1: 15 scope.
17. formula (I) chemical compound is used for preventing the purposes of the medicament of postoperative intestinal adhesion in preparation,
Wherein:
In the bracket is construction unit, and each construction unit can be identical or different;
N represents the sum of construction unit;
The m of each construction unit is independently selected from 1～3 integer;
The R of each construction unit
1Be independently selected from by H, C
1-C
9The group that constitutes of alkyl.
18. according to the purposes of claim 17, wherein R
1Be selected from by H, C
1-C
5The group that constitutes of alkyl.
19. according to the purposes of claim 17, wherein said formula (I) chemical compound is 3-hydroxybutyric acid-3-hydroxycaproic acid copolymer.
20. according to the purposes of claim 19, wherein the monomeric molar percentage of 3-hydroxycaproic acid is 5-15%.
21. according to each the purposes of claim 19-20, the weight average molecular weight of wherein said 3-hydroxybutyric acid-3-hydroxycaproic acid copolymer is 80,000-700,000.
22. according to the purposes of claim 17, wherein said formula (I) chemical compound is 3-hydroxybutyric acid-4 hydroxybutyric acid copolymer.
23. according to the purposes of claim 22, wherein the monomeric molar percentage of 4 hydroxybutyric acid is 10-40%.
24. according to each the purposes of claim 22-23, the weight average molecular weight of wherein said 3-hydroxybutyric acid-4 hydroxybutyric acid copolymer is 550,000-700,000.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102657546A (en) * | 2012-05-16 | 2012-09-12 | 段华 | Carrier barrier system applied to prevention and treatment of metrosynizesis |
| CN103906537A (en) * | 2011-06-20 | 2014-07-02 | 格拉茨科技大学 | Hybrid polymeric materials for medical applications and preparation thereof |
| CN105497991A (en) * | 2016-01-07 | 2016-04-20 | 北京大学第三医院 | Application of polyhydroxyalkanoate (PHA) to preparation of product for treating glaucoma |
| CN109517156A (en) * | 2019-01-02 | 2019-03-26 | 清华大学 | A kind of purification process of polyhydroxyalkanoate |
| CN112608463A (en) * | 2020-11-25 | 2021-04-06 | 珠海麦得发生物科技股份有限公司 | Method for regulating and controlling molecular weight of aliphatic polyester |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1446544A (en) * | 2002-03-27 | 2003-10-08 | 成都航利生物材料研究所 | Anti blocking new mateial used after surgical operation |
| CN1569253A (en) * | 2004-04-23 | 2005-01-26 | 清华大学 | Preparation method of hematopoietic tissue repairing material |
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2008
- 2008-07-03 CN CN 200810127297 patent/CN101618045B/en not_active Expired - Fee Related
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103906537A (en) * | 2011-06-20 | 2014-07-02 | 格拉茨科技大学 | Hybrid polymeric materials for medical applications and preparation thereof |
| CN103906537B (en) * | 2011-06-20 | 2016-04-13 | 格拉茨科技大学 | The polymeric material of the hydridization of medical applications and preparation thereof |
| CN102657546A (en) * | 2012-05-16 | 2012-09-12 | 段华 | Carrier barrier system applied to prevention and treatment of metrosynizesis |
| CN102657546B (en) * | 2012-05-16 | 2014-05-28 | 段华 | Carrier barrier system applied to prevention and treatment of metrosynizesis |
| CN105497991A (en) * | 2016-01-07 | 2016-04-20 | 北京大学第三医院 | Application of polyhydroxyalkanoate (PHA) to preparation of product for treating glaucoma |
| CN105497991B (en) * | 2016-01-07 | 2018-08-31 | 北京大学第三医院 | Application of the polyhydroxyalkanoates in the product for preparing treatment glaucoma |
| CN109517156A (en) * | 2019-01-02 | 2019-03-26 | 清华大学 | A kind of purification process of polyhydroxyalkanoate |
| CN112608463A (en) * | 2020-11-25 | 2021-04-06 | 珠海麦得发生物科技股份有限公司 | Method for regulating and controlling molecular weight of aliphatic polyester |
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| CN101618045B (en) | 2013-08-07 |
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