BIODEGRADABLE MEDICAL ADHESIVE AND PREPARATION METHOD AND USE THEREOF

• US 20140369952A1
• Filed: 10/31/2012
• Published: 12/18/2014
• Est. Priority Date: 11/02/2011
• Status: Active Grant

• Current Assignee: Chengdu Jiaoda Medical Science And Technology Company Limited, Institute of Pharmacology and Toxicology Academy of Military Medical Sciences PLA China
• Original Assignee: Chengdu Jiaoda Medical Science And Technology Company Limited, Institute of Pharmacology and Toxicology Academy of Military Medical Sciences PLA China
• Inventors: Liu, Keliang, Meng, Qingbin, Xu, Liang, Zhang, Qingsong, Cai, Dazhen
• Granted Patent: US 9,750,841 B2
• Time in Patent Office: Days
• US Class Current: 424/78.06
• CPC Class Codes: A61L 24/0015 Medicaments; Biocides
• CPC Class Codes: A61L 24/0042 Materials resorbable by the body
• CPC Class Codes: A61L 24/043 Mixtures of macromolecular materials
• CPC Class Codes: A61L 24/06 obtained by reactions only involving carbon-to-carbon unsaturated bonds A61L24/043, A61L24/046 take precedence
• CPC Class Codes: C08F 220/286 and containing polyethylene oxide in the alcohol moiety, e.g. methoxy polyethylene glycol (meth)acrylate
• CPC Class Codes: C08F 222/322 Alpha-cyano-acrylic acid ethyl ester, e.g. ethyl-2-cyanoacrylate
• CPC Class Codes: C08F 222/324 Alpha-cyano-acrylic acid butyl ester
• CPC Class Codes: C08F 222/326 Alpha-cyano-acrylic acid longer chain ester
• CPC Class Codes: C08F 222/328 Alpha-cyano-acrylic acid with more than one oxygen in the ester moiety
• CPC Class Codes: C08F 283/02 on to polycarbonates or saturated polyesters C08F283/004 takes precedence
• CPC Class Codes: C08L 2312/00 Crosslinking
• CPC Class Codes: C08L 35/04 Homopolymers or copolymers of nitriles C08L35/06, C08L35/08 take precedence
• CPC Class Codes: C09J 133/14 of esters containing halogen, nitrogen, sulfur or oxygen atoms in addition to the carboxy oxygen
• CPC Class Codes: C09J 133/20 Homopolymers or copolymers of acrylonitrile C09J155/02 takes precedence
• CPC Class Codes: C09J 4/00 Adhesives based on organic non-macromolecular compounds having at least one polymerisable carbon-to-carbon unsaturated bond ; adhesives, based on monomers of macromolecular compounds of groups C09J183/00 - C09J183/16

Abstract

A medical adhesive with good biodegradable performance capable of undergoing crosslinking copolymerization, comprising a mono-alpha-cyanoacrylate and a bis-alpha-cyanoacrylic acid diol ester monomer molecule. The olefinic bonds in the mono-alpha-cyanoacrylate structure are polymerized in the presence of infinitesimal anions to form a solid 3D high polymer; the 3D high polymer is provided with degradation sites on the web-like backbone chain, with clear degradation path and absorbable degradation products. The medical adhesive can be used for wound adhesive, large area wound hemostasia, and visceral and soft tissue wound closure.

Claims

1. A medical adhesive, comprising:

a mono-α

-cyanoacrylate and a bis-α

-cyanoacrylic acid diol ester,

wherein the structure of the mono-α

-cyanoacrylate is represented by Formula I;

2. The medical adhesive according to claim 1, wherein,

in X—

R₂—

X,

X is an oxygen atom, and

R₂ is

a straight hydrocarbyl group having 1-30 carbon atoms;

a branched hydrocarbyl group having 1-30 carbon atoms;

a straight hydrocarbyl group having 1-30 carbon atoms substituted with an acyloxy group, a haloalkyl group, an alkoxy group, a halogen atom, a cyano group or a combination thereof;

a branched hydrocarbyl group having 1-30 carbon atoms substituted with an acyloxy group, a haloalkyl group, an alkoxy group, a halogen atom, a cyano group or a combination thereof;

a straight alkenyl group having 1-30 carbon atoms;

a branched alkenyl group having 1-30 carbon atoms;

a straight alkynyl group having 1-30 carbon atoms;

a branched alkynyl group having 1-30 carbon atoms;

a cycloalkyl group;

an aralkyl group;

an alkylaryl group;

an aryl group; and

wherein X—

R₂—

X is a hydrocarbyl diol or a substituted hydrocarbyl diol.

3. The medical adhesive according to claim 1, wherein,

in X—

R₂—

X, X is an oxygen atom or a nitrogen atom; and

R₂ is represented by Formula III;

4. The medical adhesive according to claim 1, wherein,

in X—

R₂—

X, R₂ is represented by Formula IV;

5. The medical adhesive according to claim 1, wherein,

in X—

R₂—

X, R₂ is represented by Formula V;

6. The medical adhesive according to claim 1, wherein the medical adhesive comprises the mono-α

-cyanoacrylate and the bis-α

-cyanoacrylic acid diol ester according to a formulation selected from the group consisting of;

1) bis-α

-cyanoacrylic acid PEG2000 ester and n-butyl α

-cyanoacrylate in a bis-α

-cyanoacrylic acid PEG2000 ester;

n-butyl α

-cyanoacrylate weight ratio of 1;

1;

2)bis-α

-cyanoacrylic acid PEG2000 ester and n-butyl α

-cyanoacrylate in a bis-α

-cyanoacrylic acid PEG2000 ester;

n-butyl α

-cyanoacrylate weight ratio of 1;

5;

3) bis-α

-cyanoacrylic acid PEG2000 ester and n-butyl α

-cyanoacrylate in a bis-α

-cyanoacrylic acid PEG2000 ester;

n-butyl α

-cyanoacrylate weight ratio of 9;

9.9;

4) bis-α

-cyanoacrylic acid PEG2000 ester and n-octyl α

-cyanoacrylate in a bis-α

-cyanoacrylic acid PEG2000 ester;

n-octyl α

-cyanoacrylate weight ratio of 1;

1;

5) bis-α

-cyanoacrylic acid PEG2000 ester and n-octyl α

-cyanoacrylate in a bis-α

-cyanoacrylic acid PEG2000 ester;

n-octyl α

-cyanoacrylate weight ratio of 1;

5;

6) bis-α

-cyanoacrylic acid PEG2000 ester and n-octyl α

-cyanoacrylate in a bis-α

-cyanoacrylic acid PEG2000 ester;

n-octyl α

-cyanoacrylate weight ratio of 9;

9.9;

7) bis-α

-cyanoacrylic acid butanediol ester and n-butyl α

-cyanoacrylate in a bis-α

-cyanoacrylic acid butanediol ester;

n-butyl α

-cyanoacrylate weight ratio of 1;

5;

8)bis-α

-cyanoacrylic acid octanediol ester and n-butyl α

-cyanoacrylate in a bis-α

-cyanoacrylic acid octanediol ester;

n-butyl α

-cyanoacrylate weight ratio of 1;

5;

9) bis-α

-cyanoacrylic acid butanediol ester and n-octyl α

-cyanoacrylate in a bis-α

-cyanoacrylic acid butanediol ester;

n-octyl α

-cyanoacrylate weight ratio of 1;

5;

10) bis-α

-cyanoacrylic acid octanediol ester and n-octyl α

-cyanoacrylate in a bis-α

-cyanoacrylic acid octanediol ester;

n-octyl α

-cyanoacrylate weight ratio of 1;

5;

11) bis-α

-cyanoacrylic acid (PLA-PEG-PLA) ester and n-octyl α

-cyanoacrylate in a bis-α

-cyanoacrylic acid (PLA-PEG-PLA) ester;

n-octyl α

-cyanoacrylate weight ratio of 1;

1;

12) bis-α

-cyanoacrylic acid diethylene glycol ester and n-butyl α

-cyanoacrylate in a bis-α

-cyanoacrylic acid diethylene glycol ester;

n-butyl α

-cyanoacrylate weight ratio of 1;

1;

13) bis-α

-cyanoacrylic acid tetraethylene glycol ester and n-octyl α

-cyanoacrylate in a bis-α

-cyanoacrylic acid tetraethylene glycol ester;

n-octyl α

-cyanoacrylate weight ratio of 1;

1;

14) bis-α

-cyanoacrylic acid PEG600 ester and n-butyl α

-cyanoacrylate in a bis-α

-cyanoacrylic acid PEG600 ester;

n-butyl α

-cyanoacrylate weight ratio of 1;

1;

15) bis-α

-cyanoacrylic acid PEG1000 ester and n-octyl α

-cyanoacrylate in a bis-α

-cyanoacrylic acid PEG 1000 ester;

n-octyl α

-cyanoacrylate weight ratio of 1;

1;

16) bis-α

-cyanoacrylic acid PEG ester and n-octyl α

-cyanoacrylate in a bis-α

-cyanoacrylic acid PEG ester;

n-octyl α

-cyanoacrylate weight ratio of 1;

1; and

17) bis-α

-cyanoacrylic acid PEG2000 ester and n-butyl α

-cyanoacrylate in a bis-α

-cyanoacrylic acid PEG2000 ester;

n-butyl α

-cyanoacrylate weight ratio of 5;

1.

7. The medical adhesive according to claim 1, wherein the mono-α

-cyanoacrylate is n-butyl α

-cyanoacrylate;

the bis-α

-cyanoacrylic acid diol ester is bis-α

-cyanoacrylic acid PEG2000 ester, and the weight ratio of n-butyl α

-cyanoacrylate to bis-α

-cyanoacrylic acid PEG2000 ester is 1;

1.

8. The medical adhesive according to claim 1, further comprising one or more adjuvants selected from the group consisting of

a) a plasticizer selected from the group consisting of polyethylene glycol ester, end-capped polyester, butyl stearate, lauric acid, dioctyl glutarate, triglyceride, dioctyl oxalate, triethyl phosphate, acetyl tributyl citrate, and combinations thereof;

b) a thickener selected from the group consisting of polycyanoacrylate, polylactic acid, polyglycolic acid, polycaprolactone, polyacrylic acid alkyl ester, polymethacrylic acid alkyl ester, and combinations thereof;

c) a preservative selected from the group consisting of potassium sorbate, sodium benzoate, sorbic acid, chlorocresol, and combinations thereof;

d) a coolant;

e) a fiber reinforced material selected from the group consisting of natural rubber and synthetic rubber;

f) a stabilizer including an anionic stabilizer and a free radical stabilizer, wherein the anionic stabilizer is at least one selected from the group consisting of metaphosphoric acid, maleic acid, maleic anhydride, alkyl sulfonic acid, phosphorus pentoxide, iron (III) chloride-, antimony oxide, 2,4,6-trinitrophenol, thiol, alkyl sulfonyl, alkyl sulfone, alkyl sulfoxide, alkyl sulfite, sultone, sulfur dioxide, and sulfur trioxide; and

the free radical stabilizer is at least one selected from the group consisting of hydroquinone, catechol and derivatives thereof;

g) a colorant selected from the group consisting of dyes and pigments, and including at least one selected from the group consisting of PGA microfibrils, collagen microfibrils, cellulose microfibrils, and olefinic microfibrils;

h) a biocompatible agent including sodium bisulfate; and

i) a polymerization or crosslinking initiator or accelerator comprising molecules including at least one selected from nucleophilic functional groups, organics and inorganics.

14. The medical adhesive according to claim 1, wherein,

in the Formula I,

(1) X is an oxygen atom or a nitrogen atom, and R₁ is n-butyl, n-octyl, iso-butyl, or iso-octyl;

(2) X is an oxygen atom, and R₁ is (CH₂CH₂O)_nCH₃, wherein n is an integer from 1 to 100;

or

(3) X is a nitrogen atom, and R₁ is (CH₂CH₂O)_nCH₂CH₂NH₂, wherein n is an integer from 1 to 100; and

wherein, in the Formula II,

X—

R₂—

X represents a middle molecular fragment sandwiched between two α

-cyano acryloyl moieties, and is selected from small molecule diols, polyethylene glycol (PEG), amino PEG, polylactic acid (PLA), polyglycolic acid (PGA), lactic acid-glycolic acid copolymer (PLGA), PLA-PEG-PLA block copolymers, and PGA-PEG-PGA block copolymers.

15. The medical adhesive according to claim 1, wherein, in the medical adhesive, the weight ratio of the mono-α

-cyanoacrylate to the bis-α

-cyanoacrylic acid diol ester is 3-7;

3-7.

17. The medical adhesive according to claim 1, wherein the alkyl mono-α

-cyanoacrylate is at least one selected from the group consisting of n-butyl α

-cyanoacrylate and n-octyl α

-cyanoacrylate, and the bis-α

-cyanoacrylic acid diol ester is bis-α

-cyanoacrylic acid PEG2000 ester.

18. The medical adhesive according to claim 2, wherein X—

R₂—

X is ethylene glycol, butanediol or octanediol.

19. The medical adhesive according to claim 1, wherein, in X—

R₂—

X,

a) R₂ is represented by Formula III;

20. The medical adhesive according to claim 1, further comprising one or more biological agents or therapeutic agents selected from the group consisting of anti-inflammatory analgesics, sedatives, local anesthetics, non-steroidal anti-inflammatory agents, antiallergic agents, anti-ulcer agents, antibiotics, antimicrobial agents, antiviral agents, antifungal agents, immunity inhibitors, naturally derived proteins, genetically engineered proteins, polysaccharides, glycoproteins, lipoproteins, oligonucleotides, polypeptide drugs, antibodies, antigens, chemotherapeutics, coagulant agents, hemostatic agents, coagulation factors, tissue factors, collagen, gelatin, vasopressin, plasminogen activator inhibitors, platelet activators and synthetic peptides having hemostatic activity.

21. The medical adhesive according to claim 1, further comprising a pharmaceutically acceptable excipient.

9. A method comprising the steps of:

uniformly mixing a mono-α

-cyanoacrylate and a bis-α

-cyanoacrylic acid diol ester to form a medical adhesive;

wherein the structure of the mono-α

-cyanoacrylate is represented by Formula I;

10. A method according to claim 9, further comprising placing the medical adhesive in an environment having a temperature of 4°

C. or lower, and storing the medical adhesive in insulation from moisture.

11. A method according to claim 9, further comprising contacting the medical adhesive with a wound site to be treated by smearing, spraying, or dropping the medical adhesive on the wound site.

12. (canceled)

13. A medical adhesive polymer, said medical adhesive polymer being obtained by crosslinking copolymerization of a medical adhesive under the action of anions,

wherein the medical adhesive comprises a mono-α

-cyanoacrylate and a bis-α

-cyanoacrylic acid diol ester,

wherein the structure of the mono-α

-cyanoacrylate is represented by Formula I;

16. The medical adhesive according to claim 16, wherein, in the medical adhesive, the weight ratio of the mono-α

-cyanoacrylate to the bis-α

-cyanoacrylic acid diol ester is 1;

1.