Crosslinked gels comprising polyalkyleneimines, and their uses as medical devices

US 20070196454A1
Filed: 01/11/2007
Published: 08/23/2007
Est. Priority Date: 01/11/2006
Status: Active Grant

First Claim

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1. A method of sealing a wound of a patient, comprising the steps of:

exposing an effective amount of a polymerization agent to a compound of formula III to form an adhesive composition, and applying said adhesive composition to a wound of a patient, wherein said polymerization agent is a compound of formula Ia or formula Ib; and

formula Ia is represented by;

wherein, R⁵⁰independently for each occurrence is an electron pair or a substitutent selected from the group consisting of H, alkyl, and aralkyl;

when an instance of R⁵⁰represents a substitutent a pharmaceutically acceptable counterion is present;

R¹and R²represent independently for each occurrence A¹, alkyl, alkenyl, alkynyl, —

C(O)-alkyl, —

C(O)O[C(R⁴)₂]_dN(R⁵)₂, —

C(O)N(R⁵) [C(R⁴)₂]_dN(R⁵)₂, —

C(O)N(R⁵)₂, —

X¹—

[C(R⁴)₂]_dN(R⁵)C(O)N(R⁵)₂, —

X¹—

[C(R⁴)₂]_dN(R⁵)C(O)N(R⁵)₂, —

X¹—

[C(R⁴)₂]_dOC(O)CH₂C(O)-alkyl, or a carbohydrate radical;

R³represents independently for each occurrence H or R⁴represents independently for each occurrence H, alkyl, alkoxyl, halogen, aryl, or aralkyl;

R⁵represents independently for each occurrence H, alkyl, aryl, or aralkyl;

R⁶represents independently for each occurrence H or R⁷represents independently for each occurrence H or R⁸represents independently for each occurrence H or R⁹represents independently for each occurrence H or R¹⁰represents independently for each occurrence H or (C₁-C₃)alkyl;

X¹represents independently for each occurrence a bond or —

C(O)—

;

A¹represents independently for each occurrence H, —

C(O)NH₂, —

X¹—

[C(R⁴)₂]_dN(R⁵)C(O)NH₂, d represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

n represents independently for each occurrence 1, 2, 3, or 4;

p represents independently for each occurrence 1, 2, 3, 4, or 5;

x represents independently for each occurrence 1, 2, 3, 4, or 5;

y is an integer in the range of 1 to about 40,000;

z represents independently for each occurrence an integer in the range of 0 to about 20,000; and

provided at least about 5% of R¹is A¹, and the sum of y and z is less than about 50,000;

formula Ib is represented by;

wherein Q represents independently for each occurrence R⁵⁰independently for each occurrence is an electron pair or a substitutent selected from the group consisting of H, alkyl, and aralkyl;

when an instance of R⁵⁰represents a substitutent a pharmaceutically acceptable counterion is present;

A¹represents independently for each occurrence —

CO₂R⁴;

A²represents independently for each occurrence H or —

CO₂R⁴;

A³represents independently for each occurrence —

N(R¹)(R⁵⁰)(R³);

A⁴represents independently for each occurrence H, alkyl, aryl, —

CO₂R⁴, or —

OC(O)R⁴;

R¹represents independently for each occurrence H, alkyl or polymerization initiator;

R²represents independently for each occurrence H, alkyl aryl, or aralkyl;

R³represents independently for each occurrence H, alkyl, aryl, aralkyl, acyl, —

C(O)NH₂, —

X¹—

[C(R⁵)₂]_dN(R⁵)C(O)NH₂, R⁴represents independently for each occurrence H, alkyl, aryl, aralkyl, R⁵represents independently for each occurrence H or alkyl;

X¹represents independently for each occurrence a bond or —

C(O)—

;

d represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

p represents independently for each occurrence 1, 2, 3, 4, or 5; and

q is an integer from about 50 to about 100,000; and

formula III is represented by;

wherein R^1-IIIrepresents independently for each occurrence —

(C(R^2-III)₂)_fC(O)R^3-III, —

C(O)(C(R^2-III)₂)_kC(O)R^3-III, —

(C(R^2-III)₂)_fR^4-III, —

C(O)(C(R^2-III)₂)_kR^4-III, —

(C(R^2-III)₂)_fC(O)N(R^5-III)-[A^4-III]_t—

C(O)—

R^3-III, —

(C(R^2-III)₂)_fCO₂-[A^4-III]_t—

C(O)—

R^3-III, R^2-IIIrepresents independently for each occurrence H, alkyl, or halogen;

R^3-IIIrepresents independently for each occurrence H, alkyl, fluoroalkyl, chloroalkyl, —

CH₂NO₂, R^4-IIIrepresents independently for each occurrence —

N═

C═

O, —

N═

C═

S, R^5-IIIrepresents independently for each occurrence H, alkyl, or aralkyl;

R^6-IIIrepresents independently for each occurrence H or (C₁-C₆)alkyl;

R^7-IIIrepresents independently for each occurrence —

CO₂H, —

(C(R^6-III)₂)_pN═

C═

O, R^8-IIIrepresents independently for each occurrence A^1-IIIand A^3-IIIrepresent independently for each occurrence alkyl diradical, heteroalkyl diradical, cycloalkyl diradical, heterocycloalkyl diradical, alkenyl diradical, alkynyl diradical, aryl diradical, heteroaryl diradical, aralkyl diradical, or heteroaralkyl diradical;

A^2-IIIrepresents independently for each occurrence a bond, alkyl diradical, heteroalkyl diradical, cycloalkyl diradical, heterocycloalkyl diradical, alkenyl diradical, alkynyl diradical, aryl diradical, heteroaryl diradical, aralkyl diradical, or heteroaralkyl diradical;

A^4-IIIrepresents independently for each occurrence an alkyl diradical, cycloalkyl diradical, aryl diradical, or aralkyl diradical;

B represents independently for each occurrence alkyl diradical, heteroalkyl diradical, or X^1-IIIrepresents independently for each occurrence O or —

N(R^5-III)—

;

m represents independently for each occurrence 1, 2, 3, 4, or 5 in accordance with the rules of valence;

p represents independently for each occurrence 0, 1, 2, 3, 4, or 5;

t represents independently for each occurrence 1, 2, 3 or 4;

v represents independently for each occurrence 2, 3, or 4;

w is independently for each occurrence an integer in the range of about 5 to 1000, inclusive; and

f and k each are independently selected for each occurrence from the group consisting of 1-25 inclusive.

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Abstract

One aspect of the present invention generally relates to methods of sealing a wound or tissue plane or filling a void splace. In a preferred embodiment, the wound is an ophthalmic, pleural or dural wound. In certain instances, the compositions used to seal the wound or tissue plane comprises a polyalkyleneamine. In a preferred embodiment, the polyalkyleneamine is polyethyleneimine. Treatment of the polyethyleneimine with a cross-linking reagent causes the polyethyleneimine polymers to polymerize forming a seal. In certain instances, the cross-linking reagent is a polyethylene glycol having reactive terminal groups. In certain instances, the reactive terminal groups are activated esters, such as N-hydroxy succinimide ester. In certain instances, the reactive terminal groups are isocyanates. In certain instances, the polyethyleneimine has a lysine, cysteine, isocysteine or other nucleophilic group attached to the periphery of the polymer. In certain instances, the polyethyleneimine is mixed with a second polymer, such as a polyethylene glycol containing nucleophilic groups. In certain instances, the compositions used to seal the wound or tissue plane are formed by reacting a polyalkyleneamine bearing electrophilic groups with a cross-linking reagent containing nucleophilic groups. In certain instances, the electrophilic groups on the polyalkyleneamine are activated esters, such as N-hydroxy succinimide ester. In certain instances, the compositions used to seal the wound or tissue plane are formed by reacting a polyalkyleneamine bearing photopolymerizable groups with ultraviolet or visibile light. Compositions used to seal the wound which contain PEI or a derivative of PEI are found to adhere tightly to the tissue. Other aspects of the present invention relate to methods of filling a void of a patient or adhering tissue. In certain instances, the methods use a polyalkyleneamine. In a preferred embodiment, the polyalkyleneamine is polyethyleneimine. Another aspect of the present invention relates to a polymeric composition formed by exposing a polyalkyleneamine to an activated polyalkylene glycol. In certain instances, the composition is attached to mammalian tissue.

Citations

18 Claims

1. A method of sealing a wound of a patient, comprising the steps of:
- exposing an effective amount of a polymerization agent to a compound of formula III to form an adhesive composition, and applying said adhesive composition to a wound of a patient, wherein said polymerization agent is a compound of formula Ia or formula Ib; and
  
  formula Ia is represented by;
  
  wherein, R⁵⁰independently for each occurrence is an electron pair or a substitutent selected from the group consisting of H, alkyl, and aralkyl;
  
  when an instance of R⁵⁰represents a substitutent a pharmaceutically acceptable counterion is present;
  
  R¹and R²represent independently for each occurrence A¹, alkyl, alkenyl, alkynyl, —
  
  C(O)-alkyl, —
  
  C(O)O[C(R⁴)₂]_dN(R⁵)₂, —
  
  C(O)N(R⁵) [C(R⁴)₂]_dN(R⁵)₂, —
  
  C(O)N(R⁵)₂, —
  
  X¹—
  
  [C(R⁴)₂]_dN(R⁵)C(O)N(R⁵)₂, —
  
  X¹—
  
  [C(R⁴)₂]_dN(R⁵)C(O)N(R⁵)₂, —
  
  X¹—
  
  [C(R⁴)₂]_dOC(O)CH₂C(O)-alkyl, or a carbohydrate radical;
  
  R³represents independently for each occurrence H or R⁴represents independently for each occurrence H, alkyl, alkoxyl, halogen, aryl, or aralkyl;
  
  R⁵represents independently for each occurrence H, alkyl, aryl, or aralkyl;
  
  R⁶represents independently for each occurrence H or R⁷represents independently for each occurrence H or R⁸represents independently for each occurrence H or R⁹represents independently for each occurrence H or R¹⁰represents independently for each occurrence H or (C₁-C₃)alkyl;
  
  X¹represents independently for each occurrence a bond or —
  
  C(O)—
  
  ;
  
  A¹represents independently for each occurrence H, —
  
  C(O)NH₂, —
  
  X¹—
  
  [C(R⁴)₂]_dN(R⁵)C(O)NH₂, d represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  
  n represents independently for each occurrence 1, 2, 3, or 4;
  
  p represents independently for each occurrence 1, 2, 3, 4, or 5;
  
  x represents independently for each occurrence 1, 2, 3, 4, or 5;
  
  y is an integer in the range of 1 to about 40,000;
  
  z represents independently for each occurrence an integer in the range of 0 to about 20,000; and
  
  provided at least about 5% of R¹is A¹, and the sum of y and z is less than about 50,000;
  
  formula Ib is represented by;
  
  wherein Q represents independently for each occurrence R⁵⁰independently for each occurrence is an electron pair or a substitutent selected from the group consisting of H, alkyl, and aralkyl;
  
  when an instance of R⁵⁰represents a substitutent a pharmaceutically acceptable counterion is present;
  
  A¹represents independently for each occurrence —
  
  CO₂R⁴;
  
  A²represents independently for each occurrence H or —
  
  CO₂R⁴;
  
  A³represents independently for each occurrence —
  
  N(R¹)(R⁵⁰)(R³);
  
  A⁴represents independently for each occurrence H, alkyl, aryl, —
  
  CO₂R⁴, or —
  
  OC(O)R⁴;
  
  R¹represents independently for each occurrence H, alkyl or polymerization initiator;
  
  R²represents independently for each occurrence H, alkyl aryl, or aralkyl;
  
  R³represents independently for each occurrence H, alkyl, aryl, aralkyl, acyl, —
  
  C(O)NH₂, —
  
  X¹—
  
  [C(R⁵)₂]_dN(R⁵)C(O)NH₂, R⁴represents independently for each occurrence H, alkyl, aryl, aralkyl, R⁵represents independently for each occurrence H or alkyl;
  
  X¹represents independently for each occurrence a bond or —
  
  C(O)—
  
  ;
  
  d represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  
  p represents independently for each occurrence 1, 2, 3, 4, or 5; and
  
  q is an integer from about 50 to about 100,000; and
  
  formula III is represented by;
  
  wherein R^1-IIIrepresents independently for each occurrence —
  
  (C(R^2-III)₂)_fC(O)R^3-III, —
  
  C(O)(C(R^2-III)₂)_kC(O)R^3-III, —
  
  (C(R^2-III)₂)_fR^4-III, —
  
  C(O)(C(R^2-III)₂)_kR^4-III, —
  
  (C(R^2-III)₂)_fC(O)N(R^5-III)-[A^4-III]_t—
  
  C(O)—
  
  R^3-III, —
  
  (C(R^2-III)₂)_fCO₂-[A^4-III]_t—
  
  C(O)—
  
  R^3-III, R^2-IIIrepresents independently for each occurrence H, alkyl, or halogen;
  
  R^3-IIIrepresents independently for each occurrence H, alkyl, fluoroalkyl, chloroalkyl, —
  
  CH₂NO₂, R^4-IIIrepresents independently for each occurrence —
  
  N═
  
  C═
  
  O, —
  
  N═
  
  C═
  
  S, R^5-IIIrepresents independently for each occurrence H, alkyl, or aralkyl;
  
  R^6-IIIrepresents independently for each occurrence H or (C₁-C₆)alkyl;
  
  R^7-IIIrepresents independently for each occurrence —
  
  CO₂H, —
  
  (C(R^6-III)₂)_pN═
  
  C═
  
  O, R^8-IIIrepresents independently for each occurrence A^1-IIIand A^3-IIIrepresent independently for each occurrence alkyl diradical, heteroalkyl diradical, cycloalkyl diradical, heterocycloalkyl diradical, alkenyl diradical, alkynyl diradical, aryl diradical, heteroaryl diradical, aralkyl diradical, or heteroaralkyl diradical;
  
  A^2-IIIrepresents independently for each occurrence a bond, alkyl diradical, heteroalkyl diradical, cycloalkyl diradical, heterocycloalkyl diradical, alkenyl diradical, alkynyl diradical, aryl diradical, heteroaryl diradical, aralkyl diradical, or heteroaralkyl diradical;
  
  A^4-IIIrepresents independently for each occurrence an alkyl diradical, cycloalkyl diradical, aryl diradical, or aralkyl diradical;
  
  B represents independently for each occurrence alkyl diradical, heteroalkyl diradical, or X^1-IIIrepresents independently for each occurrence O or —
  
  N(R^5-III)—
  
  ;
  
  m represents independently for each occurrence 1, 2, 3, 4, or 5 in accordance with the rules of valence;
  
  p represents independently for each occurrence 0, 1, 2, 3, 4, or 5;
  
  t represents independently for each occurrence 1, 2, 3 or 4;
  
  v represents independently for each occurrence 2, 3, or 4;
  
  w is independently for each occurrence an integer in the range of about 5 to 1000, inclusive; and
  
  f and k each are independently selected for each occurrence from the group consisting of 1-25 inclusive.
- View Dependent Claims (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)
- - 4. The method according to any one of claims 1-3, wherein f and k each represent independently for each occurrence 1, 2, 3, 4, 5, 6, 7, 8, or 9.
  - 5. The method according to any one of claims 1-3, wherein said polymerization agent is a compound of formula Ia.
  - 6. The method according to any one of claims 1-3, wherein said polymerization agent is a compound of formula Ia, R¹and R²represent independently for each occurrence A¹, alkyl, alkenyl, alkynyl, —
    - C(O)-alkyl, —
      
      C(O)N(R⁵)₂, —
      
      X¹—
      
      [C(R⁴)₂]_dN(R⁵)C(O)N(R⁵)₂, —
      
      X¹—
      
      [C(R⁴)₂]_dOC(O)CH₂C(O)-alkyl,
  - 7. The method according to any one of claims 1-3, wherein said polymerization agent is a compound of formula Ia, d represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8.
  - 8. The method according to any one of claims 1-3, wherein said polymerization agent is a compound of formula Ib.
  - 9. The method according to any one of claims 1-3, wherein said polymerization agent is a compound of formula Ib, d represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8.
  - 10. The method according to any one of claims 1-3, wherein x is 2, 3 or 4.
  - 11. The method according to any one of claims 1-3, wherein y is an integer in the range of about 2 to about 100.
  - 12. The method according to any one of claims 1-3, wherein said wound is in the eye, liver, lung, heart, pancreas, dura matter, dura mater of the nervous system, an artery, a cardiac artery, a cardiac vein, cartilage, a vertebral disk, or breast.
  - 13. The method according to any one of claims 1-3, further comprising the step of applying a polymer or hydrogel to the wound, void, or tissue of a patient;
    - wherein said polymer or hydrogel is poly(lactic acid), poly(glycolic acid), a copolymer of poly(lactic acid) and poly(glycolic acid), collagen, hyaluronic acid, albumin, cellulose, elastin, fibrin, fibronectin, gelatine, heparin, heparin sulfate, polylysine, poly(vinyl acetate), polyvinylpyrrolidone, poly(acrylic acid), poly(ethylene glycol), poly(propylene glycol)-poly(ethylene glycol) copolymer, trimethylene carbonate, a polypeptide comprising the tripeptide Arg-Gly-Asp, or a polyalkyleneamine hydrogel.
  - 14. The method according to any one of claims 1-3, further comprising the step of applying a mesh to the wound, void, or tissue of a patient.
  - 15. The method according to any one of claims 1-3, further comprising applying a medicament, colorant, flavoring, scent, fibrous additive, thickener or plasticizer.
  - 16. The method of according to any one of claims 1-3, wherein the compound of formula Ia, or Ib and the compound of formula III are combined in an aqueous solution;
    - and wherein subsequent to mixing and crosslinking the aqueous solution has an osmolality of 100-700 mOs/kg.
  - 17. The method of according to any one of claims 1-3, wherein the hydrogel formed has pores in the range of about 1 microns to about 100 microns in diameter.
  - 18. The method according to any one of claims 1-3, further comprising the step of sterilizing a compound of formula Ia, Ib or III to provide a Sterility Assurance Level (SAL) of at least about 10⁻
    - 3.

2. A method of augmenting soft tissue or filling a void of a patient, comprising the steps of:
- exposing an effective amount of a polymerization agent to a compound of formula III to form an adhesive composition, and applying said adhesive composition to soft tissue or a void of a patient, wherein said polymerization agent is a compound of formula Ia or formula Ib; and
  
  formula Ia is represented by;
  
  wherein, R⁵⁰independently for each occurrence is an electron pair or a substitutent selected from the group consisting of H, alkyl, and aralkyl;
  
  when an instance of R⁵⁰represents a substitutent a pharmaceutically acceptable counterion is present;
  
  R¹and R²represent independently for each occurrence A¹, alkyl, alkenyl, alkynyl, —
  
  C(O)-alkyl, —
  
  C(O)O[C(R⁴)₂]_dN(R⁵)₂, —
  
  C(O)N(R⁵)[C(R⁴)₂]_dN(R⁵)₂, —
  
  C(O)N(R⁵)₂, —
  
  X¹—
  
  [C(R⁴)₂]_dN(R⁵)C(O)N(R⁵)₂, —
  
  X¹—
  
  [C(R⁴)₂]_dN(R⁵)C(O)N(R⁵)₂, —
  
  X¹—
  
  [C(R⁴)₂]_dOC(O)CH₂C(O)-alkyl, or a carbohydrate radical;
  
  R³represents independently for each occurrence H or R⁴represents independently for each occurrence H, alkyl, alkoxyl, halogen, aryl, or aralkyl;
  
  R⁵represents independently for each occurrence H, alkyl, aryl, or aralkyl;
  
  R⁶represents independently for each occurrence H or R⁷represents independently for each occurrence H or R⁸represents independently for each occurrence H or R⁹represents independently for each occurrence H or R¹⁰represents independently for each occurrence H or (C₁-C₃)alkyl;
  
  X¹represents independently for each occurrence a bond or —
  
  C(O)—
  
  ;
  
  A¹represents independently for each occurrence H, —
  
  C(O)NH₂, —
  
  X¹—
  
  [C(R⁴)₂]_dN(R⁵)C(O)NH₂, d represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  
  n represents independently for each occurrence 1, 2, 3, or 4;
  
  p represents independently for each occurrence 1, 2, 3, 4, or 5;
  
  x represents independently for each occurrence 1, 2, 3, 4, or 5;
  
  y is an integer in the range of 1 to about 40,000;
  
  z represents independently for each occurrence an integer in the range of 0 to about 20,000; and
  
  provided at least about 5% of R¹is A¹, and the sum of y and z is less than about 50,000;
  
  formula Ib is represented by;
  
  wherein Q represents independently for each occurrence R⁵⁰independently for each occurrence is an electron pair or a substitutent selected from the group consisting of H, alkyl, and aralkyl;
  
  when an instance of R⁵⁰represents a substitutent a pharmaceutically acceptable counterion is present;
  
  A¹represents independently for each occurrence —
  
  CO₂R⁴;
  
  A²represents independently for each occurrence H or —
  
  CO₂R⁴;
  
  A³represents independently for each occurrence —
  
  N(R¹)(R⁵⁰)(R³);
  
  A⁴represents independently for each occurrence H, alkyl, aryl, —
  
  CO₂R⁴, or —
  
  OC(O)R⁴;
  
  R¹represents independently for each occurrence H, alkyl or polymerization initiator;
  
  R²represents independently for each occurrence H, alkyd aryl, or aralkyl;
  
  R³represents independently for each occurrence H, alkyl, aryl, aralkyl, acyl, —
  
  C(O)NH₂, —
  
  X¹—
  
  [C(R⁵)₂]_dN(R⁵)C(O)NH₂, R⁴represents independently for each occurrence H, alkyl, aryl, aralkyl, R⁵represents independently for each occurrence H or alkyl;
  
  X¹represents independently for each occurrence a bond or —
  
  C(O)—
  
  ;
  
  d represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  
  p represents independently for each occurrence 1, 2, 3, 4, or 5; and
  
  q is an integer from about 50 to about 100,000; and
  
  formula III is represented by;
  
  wherein R^1-IIIrepresents independently for each occurrence —
  
  (C(R^2-III)₂)_fC(O)R^3-III, —
  
  C(O)(C(R^2-III)₂)_kC(O)R^3-III, —
  
  (C(R^2-III)₂)_fR^4-III, —
  
  C(O)(C(R^2-III)₂)_kR^4-III, —
  
  (C(R^2-III)₂)_fC(O)N(R^5-III)-[A^4-III]_t—
  
  C(O)—
  
  R^3-III, —
  
  (C(R^2-III)₂)_fCO₂-[A^4-III]_t—
  
  C(O)—
  
  R^3-III, R^2-IIIrepresents independently for each occurrence H, alkyl, or halogen;
  
  R^3-IIIrepresents independently for each occurrence H, alkyl, fluoroalkyl, chloroalkyl, —
  
  CH₂NO₂, R^4-IIIrepresents independently for each occurrence —
  
  N═
  
  C═
  
  O, —
  
  N═
  
  C═
  
  S, R^5-IIIrepresents independently for each occurrence H, alkyl, or aralkyl;
  
  R^6-IIIrepresents independently for each occurrence H or (C₁-C₆)alkyl;
  
  R^7-IIIrepresents independently for each occurrence —
  
  CO₂H, -(C(R^6-III)₂)_pN═
  
  C═
  
  O, R^8-IIIrepresents independently for each occurrence A^1-IIIand A^3-IIIrepresent independently for each occurrence alkyl diradical, heteroalkyl diradical, cycloalkyl diradical, heterocycloalkyl diradical, alkenyl diradical, alkynyl diradical, aryl diradical, heteroaryl diradical, aralkyl diradical, or heteroaralkyl diradical;
  
  A^2-IIIrepresents independently for each occurrence a bond, alkyl diradical, heteroalkyl diradical, cycloalkyl diradical, heterocycloalkyl diradical, alkenyl diradical, alkynyl diradical, aryl diradical, heteroaryl diradical, aralkyl diradical, or heteroaralkyl diradical;
  
  A^4-IIIrepresents independently for each occurrence an alkyl diradical, cycloalkyl diradical, aryl diradical, or aralkyl diradical;
  
  B represents independently for each occurrence alkyl diradical, heteroalkyl diradical, or X^1-IIIrepresents independently for each occurrence O or —
  
  N(R^5-III)—
  
  ;
  
  m represents independently for each occurrence 1, 2, 3, 4, or 5 in accordance with the rules of valence;
  
  p represents independently for each occurrence 0, 1, 2, 3, 4, or 5;
  
  t represents independently for each occurrence 1, 2, 3 or 4;
  
  v represents independently for each occurrence 2, 3, or 4;
  
  w is independently for each occurrence an integer in the range of about 5 to 1000, inclusive; and
  
  f and k each are independently selected for each occurrence from the group consisting of 1-25 inclusive.

3. Another aspect of the present invention relates to a method of adhering tissue of a patient, comprising the steps of:
- exposing an effective amount of a polymerization agent to a compound of formula III to form an adhesive composition, applying said adhesive composition to a first tissue of a patient to form an adhesive tissue, and contacting said adhesive tissue with a second tissue of a patient, wherein said polymerization agent is a compound of formula Ia or formula Ib; and
  
  formula Ia is represented by;
  
  wherein, R⁵⁰independently for each occurrence is an electron pair or a substitutent selected from the group consisting of H, alkyl, and aralkyl;
  
  when an instance of R⁵⁰represents a substitutent a pharmaceutically acceptable counterion is present;
  
  R¹and R²represent independently for each occurrence A¹, alkyl, alkenyl, alkynyl, —
  
  C(O)-alkyl, —
  
  C(O)O[C(R⁴)₂]_dN(R⁵)₂, —
  
  C(O)N(R⁵)[C(R⁴)₂]_dN(R⁵)₂, —
  
  C(O)N(R⁵)₂, —
  
  X¹—
  
  [C(R⁴)₂]_dN(R⁵)C(O)N(R⁵)₂, —
  
  X¹—
  
  [C(R⁴)₂]_dN(R⁵)C(O)N(R⁵)₂, —
  
  X¹—
  
  [C(R⁴)₂]_dOC(O)CH₂C(O)-alkyl, or a carbohydrate radical;
  
  R³represents independently for each occurrence H or R⁴represents independently for each occurrence H, alkyl, alkoxyl, halogen, aryl, or aralkyl;
  
  R⁵represents independently for each occurrence H, alkyl, aryl, or aralkyl;
  
  R⁶represents independently for each occurrence H or R⁷represents independently for each occurrence H or R⁸represents independently for each occurrence H or R⁹represents independently for each occurrence H or R¹⁰represents independently for each occurrence H or (C₁-C₃)alkyl;
  
  X¹represents independently for each occurrence a bond or —
  
  C(O)—
  
  ;
  
  A¹represents independently for each occurrence H, —
  
  C(O)NH₂, —
  
  X¹—
  
  [C(R⁴)₂]_dN(R⁵)C(O)NH₂, d represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  
  n represents independently for each occurrence 1, 2, 3, or 4;
  
  p represents independently for each occurrence 1, 2, 3, 4, or 5;
  
  x represents independently for each occurrence 1, 2, 3, 4, or 5;
  
  y is an integer in the range of 1 to about 40,000;
  
  z represents independently for each occurrence an integer in the range of 0 to about 20,000; and
  
  provided at least about 5% of R¹is A¹, and the sum of y and z is less than about 50,000;
  
  formula Ib is represented by;
  
  wherein Q represents independently for each occurrence R⁵⁰independently for each occurrence is an electron pair or a substitutent selected from the group consisting of H, alkyl, and aralkyl;
  
  when an instance of R⁵⁰represents a substitutent a pharmaceutically acceptable counterion is present;
  
  A¹represents independently for each occurrence —
  
  CO₂R⁴;
  
  A²represents independently for each occurrence H or —
  
  CO₂R⁴;
  
  A³represents independently for each occurrence —
  
  N(R¹)(R⁵⁰)(R³);
  
  A⁴represents independently for each occurrence H, alkyl, aryl, —
  
  CO₂R⁴, or —
  
  OC(O)R⁴;
  
  R¹represents independently for each occurrence H, alkyl or polymerization initiator;
  
  R²represents independently for each occurrence H, alkyl aryl, or aralkyl;
  
  R³represents independently for each occurrence H, alkyl, aryl, aralkyl, acyl, —
  
  C(O)NH₂, —
  
  X¹—
  
  [C(R⁵)₂]_dN(R⁵)C(O)NH₂, R⁴represents independently for each occurrence H, alkyl, aryl, aralkyl, R⁵represents independently for each occurrence H or alkyl;
  
  X¹represents independently for each occurrence a bond or —
  
  C(O)—
  
  ;
  
  d represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  
  p represents independently for each occurrence 1, 2, 3, 4, or 5; and
  
  q is an integer from about 50 to about 100,000; and
  
  formula III is represented by;
  
  wherein R^1-IIIrepresents independently for each occurrence —
  
  (C(R^2-III)₂)_fC(O)R^3-III, —
  
  C(O)(C(R^2-III)₂)_kC(O)R^3-III, —
  
  (C(R^2-III)₂)_fR^4-III, —
  
  C(O)(C(R^2-III)₂)_kR^4-III, —
  
  (C(R^2-III)₂)_fC(O)N(R^5-III)-[A^4-III]_t—
  
  C(O)—
  
  R^3-III, —
  
  (C(R^2-III)₂)_fCO₂-[A^4-III]_t—
  
  C(O)—
  
  R^3-III, R^2-IIIrepresents independently for each occurrence H, alkyl, or halogen;
  
  R^3-IIIrepresents independently for each occurrence H, alkyl, fluoroalkyl, chloroalkyl, —
  
  CH₂NO₂, R^4-IIIrepresents independently for each occurrence —
  
  N═
  
  C═
  
  O, —
  
  N═
  
  C═
  
  S, R^5-IIIrepresents independently for each occurrence H, alkyl, or aralkyl;
  
  R^6-IIIrepresents independently for each occurrence H or (C₁-C₆)alkyl;
  
  R^7-IIIrepresents independently for each occurrence —
  
  CO₂H, —
  
  (C(R^6-III)₂)_pN═
  
  C═
  
  O, R^8-IIIrepresents independently for each occurrence A^1-IIIand A^3-IIIrepresent independently for each occurrence alkyl diradical, heteroalkyl diradical, cycloalkyl diradical, heterocycloalkyl diradical, alkenyl diradical, alkynyl diradical, aryl diradical, heteroaryl diradical, aralkyl diradical, or heteroaralkyl diradical;
  
  A^2-IIIrepresents independently for each occurrence a bond, alkyl diradical, heteroalkyl diradical, cycloalkyl diradical, heterocycloalkyl diradical, alkenyl diradical, alkynyl diradical, aryl diradical, heteroaryl diradical, aralkyl diradical, or heteroaralkyl diradical;
  
  A^4-IIIrepresents independently for each occurrence an alkyl diradical, cycloalkyl diradical, aryl diradical, or aralkyl diradical;
  
  B represents independently for each occurrence alkyl diradical, heteroalkyl diradical, or X^1-IIIrepresents independently for each occurrence O or —
  
  N(R^5-III)—
  
  ;
  
  m represents independently for each occurrence 1, 2, 3, 4, or 5 in accordance with the rules of valence;
  
  p represents independently for each occurrence 0, 1, 2, 3, 4, or 5;
  
  t represents independently for each occurrence 1, 2, 3 or 4;
  
  v represents independently for each occurrence 2, 3, or 4;
  
  w is independently for each occurrence an integer in the range of about 5 to 1000, inclusive; and
  
  f and k each are independently selected for each occurrence from the group consisting of 1-25 inclusive.

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Current Assignee
SQUARE 1 BANK
Original Assignee
HyperBranch Medical Technology, Inc. (Stryker Corporation)
Inventors
Grinstaff, Mark, Stockman, Kenneth, D'Alessio, Keith, Carnahan, Michael

Granted Patent

US 9,393,344 B2
Time in Patent Office

Days
Field of Search
US Class Current

424/445
CPC Class Codes

A61B 2017/0065   the implement being an adhe...

A61B 2017/00951   adhesive

A61K 31/785   Polymers containing nitrogen

A61K 31/787   containing heterocyclic rin...

A61K 51/1279   Plasters, bandages, dressin...

A61L 24/00   Surgical adhesives or cemen...

A61L 24/0031   Hydrogels or hydrocolloids

A61L 24/0036   Porous materials, e.g. foam...

A61L 24/043   Mixtures of macromolecular ...

A61L 24/046   obtained otherwise than by ...

A61L 26/0019   obtained otherwise than by ...

A61L 26/0052   Mixtures of macromolecular ...

A61L 26/008   Hydrogels or hydrocolloids

A61L 26/0085   Porous materials, e.g. foam...

A61L 27/18   obtained otherwise than by ...

A61L 27/26   Mixtures of macromolecular ...

A61L 27/52   Hydrogels or hydrocolloids

A61L 27/56   Porous materials, e.g. foam...

C08L 79/02   Polyamines

Crosslinked gels comprising polyalkyleneimines, and their uses as medical devices

First Claim

3 Assignments

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Abstract

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18 Claims

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Crosslinked gels comprising polyalkyleneimines, and their uses as medical devices

First Claim

3 Assignments

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0 Petitions

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Accused Products

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Abstract

Citations

18 Claims

Specification

Subscription Required

Solutions

Use Cases

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