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JP-7854781-B2 - Functionalized and crosslinked polymers

JP7854781B2JP 7854781 B2JP7854781 B2JP 7854781B2JP-7854781-B2

Inventors

  • デビッド・グラベット
  • カラ・バサニー・アカンポラ
  • プラビヨ・サイニ

Assignees

  • ピーエムアイディージー・エルエルシー

Dates

Publication Date
20260507
Application Date
20180901
Priority Date
20170901

Claims (18)

  1. A hyaluronic acid polymer derivative comprising one or more modified hydroxyl groups, wherein the hyaluronic acid polymer derivative has the formula: A) HA-( OCH2CH2SO2CH2CH2 - X - R1 - Y) n , where HA is hyaluronic acid, X is sulfur, R1 is an aromatic moiety, the aromatic moiety is a substituted or unsubstituted carbocyclic aromatic moiety or a heteroaromatic moiety, the carbocyclic aromatic moiety and the heteroaromatic moiety each have 1 to 20 carbon atoms, and Y is one or more of H, a carboxylic acid group or its salt or ester, a hydroxyl group, a sulfonic acid group or its salt, or an amine group, and n is the number of modified hydroxyl groups, provided n≧1; or B) (Y- R2 - X - CH2CH2SO2CH2CH2O ) m -HA-( OCH2CH2SO2CH2CH2 - X - R1 - Y ) n In the formula, HA is hyaluronic acid, X is sulfur, R1 and R2 are each a substituted or unsubstituted C1 - C20 aliphatic or aromatic moiety, the aromatic moiety being a substituted or unsubstituted carbocyclic aromatic moiety or a heteroaromatic moiety, the carbocyclic aromatic moiety and the heteroaromatic moiety each having 1 to 20 carbon atoms, where R1 and R2 are different from each other, Y may be the same or different, and Y is one or more of H, a carboxylic acid group or its salt or ester, a hydroxyl group, a sulfonic acid group or its salt, or an amine group, n≧1 and m≧1, and the sum of n and m is the number of modified hydroxyl groups; or C)( CH2 = CH - SO2CH2CH2O ) m -HA-( OCH2CH2SO2CH2CH2 - X - R1 - Y) n In the formula, HA is hyaluronic acid, X is S, R1 is a substituted or unsubstituted C1 - C20 aliphatic or aromatic moiety, the aromatic moiety is a substituted or unsubstituted carbocyclic aromatic moiety or heteroaromatic moiety, the carbocyclic aromatic moiety and the heteroaromatic moiety each have 1 to 20 carbon atoms, Y is one or more of H, a carboxylic acid group or its salt or ester, a hydroxyl group, a sulfonic acid group or its salt, or an amine group, n≧1 and m≧1, and the sum of n and m is the number of modified hydroxyl groups. It has, A hyaluronic acid polymer derivative wherein 0.25 to 50% of the hydroxyl groups of hyaluronic acid constituting the hyaluronic acid polymer derivative are modified hydroxyl groups.
  2. A crosslinked polymer synthesized from one or more hyaluronic acid polymer derivatives described in claim 1, A crosslinked polymer in which the hydroxyl group, vinyl group, or ionic group of the hyaluronic acid polymer derivative was crosslinked at the site of the hyaluronic acid polymer derivative.
  3. A crosslinked polymer synthesized from one or more hyaluronic acid polymer derivatives described in claim 1, A crosslinked polymer, including photocrosslinking.
  4. formula: C) (CH 2 = CH-SO 2 CH 2 CH 2 O) m -HA-(OCH 2 CH 2 SO 2 CH 2 CH 2 -X-R 1 -Y) n A process for producing a hyaluronic acid polymer derivative according to claim 1, comprising: a) To provide a first HA derivative by reacting a hydroxyl group of a hyaluronic acid (HA) polymer with divinyl sulfone (DVS); and b) To provide a second HA derivative by reacting the first HA derivative with i) a nucleophile of formula X'- R1 -Y; where i) R1 is a substituted or unsubstituted C1 - C20 aliphatic or aromatic moiety, X' is a nucleophile of SH, Y is the same or different, and Y is one or more of H, a carboxylic acid group or its salt or ester, a hydroxyl group, a sulfonic acid group or its salt, or an amine group. Includes, The process involves converting 0.25 to 50% of the hydroxyl groups present on the HA polymer to oxyethylethenylsulfone groups of the formulas -OCH₂CH₂ - SO₂CH = CH₂ and -OCH₂CH₂SO₂CH₂CH₂ - X - R₁ -Y, where R₁ is a substituted or unsubstituted C₁ - C₂0 aliphatic or aromatic moiety, X is S, and Y is the same or different, and Y is one or more of H, a carboxylic acid group or its salt or ester, a hydroxyl group, a sulfonic acid group or its salt, or an amine group, and the first HA derivative being an oxyethylethenylsulfone derivative of hyaluronic acid having the formula: HA- ( OCH₂CH₂SO₂CH = CH₂ )n(HA-DVS), n≧ 2 .
  5. formula: A) HA-(OCH 2 CH 2 SO 2 CH 2 CH 2 -X-R 1 -Y) n A process for producing a hyaluronic acid polymer derivative according to claim 1, comprising: a) To provide a first HA derivative by reacting a hydroxyl group of a hyaluronic acid (HA) polymer with divinyl sulfone (DVS); and b) To provide a second HA derivative by reacting the first HA derivative with a nucleophile of formula X'- R1 -Y; where R1 is an aromatic moiety, X' is a nucleophile of SH, Y is the same or different, and Y is one or more of H, a carboxylic acid group or its salt or ester, a hydroxyl group, a sulfonic acid group or its salt, or an amine group. Includes, The second HA derivative is HA-( OCH2CH2SO2CH2CH2 - X - R1 - Y )n, where HA is hyaluronic acid, X is sulfur, R1 is an aromatic moiety; Y is one or more of H, a carboxylic acid group or its salt or ester, a hydroxyl group, a sulfonic acid group or its salt, or an amine group, and n≧1, and 0.25-50% of the hydroxyl groups present on the HA polymer are derivatized to the -OCH2CH2SO2CH2CH2 - X - R1 - Y group, where X is sulfur, R1 is an aromatic moiety; and Y is one or more of H, a carboxylic acid group or its salt or ester, a hydroxyl group, a sulfonic acid group or its salt, or an amine group, and the first HA derivative is formula :HA-( OCH2CH2SO2 A process for hyaluronic acid oxyethyl ethenyl sulfone derivatives having CH= CH2 )n(HA-DVS), n≧1.
  6. formula: B) (Y-R 2 -X-CH 2 CH 2 SO 2 CH 2 CH 2 O) m -HA-(OCH 2 CH 2 SO 2 CH 2 CH 2 -X-R 1 -Y) n A process for producing a hyaluronic acid polymer derivative according to claim 1, comprising: a) To provide a first HA derivative by reacting the hydroxyl group of a hyaluronic acid (HA) polymer with divinyl sulfone (DVS); and b) To provide a second HA derivative by reacting the first HA derivative with i) nucleophiles of formula X'- R1 -Y and ii) X'- R2 -Y; where R2 is different from R1 , R1 and R2 are each a substituted or unsubstituted C1 - C20 aliphatic or aromatic moiety, X' is a nucleophile of SH, Y is the same or different, and Y is one or more of H, a carboxylic acid group or its salt or ester, a hydroxyl group, a sulfonic acid group or its salt, or an amine group. Includes, The process involves derivatizing 0.25 to 50% of the hydroxyl groups present on the HA polymer into -OCH₂CH₂SO₂CH₂CH₂ - X - R₁ - Y and -OCH₂CH₂SO₂CH₂CH₂ - X - R₂ - Y groups, where R₁ and R₂ are different and are substituted or unsubstituted C₁ - C₂0 aliphatic or aromatic moieties, X is S, and Y is the same or different and is one or more of H, a carboxylic acid group or its salt or ester, a hydroxyl group, a sulfonic acid group or its salt, or an amine group, and the first HA derivative being an oxyethyl ethenyl sulfone derivative of hyaluronic acid having the formula: HA- ( OCH₂CH₂SO₂CH = CH₂ )n(HA-DVS), n≧ 2 .
  7. formula: C) (CH 2 = CH-SO 2 CH 2 CH 2 O) m -HA-(OCH 2 CH 2 SO 2 CH 2 CH 2 -X-R 1 -Y) n A process for producing a hyaluronic acid polymer derivative according to claim 1, comprising: a) To provide a first HA derivative by reacting a hydroxyl group of a hyaluronic acid (HA) polymer with divinyl sulfone (DVS); and b) To provide a second HA derivative by reacting the first HA derivative with a nucleophile of formula X'- R1 -Y; where R1 is a substituted or unsubstituted C1 - C20 aliphatic or aromatic moiety, X' is a nucleophile of SH, and Y is the same or different, and Y is one or more of H, a carboxylic acid group or its salt or ester, a hydroxyl group, a sulfonic acid group or its salt, or an amine group. Includes, The process further includes step c) derivatizing a second HA derivative polymer by repeating step a) one or more times, 0.25 to 50% of the hydroxyl groups present on the HA polymer are converted to oxyethylethenylsulfone groups of the formulas -OCH₂CH₂ - SO₂CH = CH₂ and -OCH₂CH₂SO₂CH₂CH₂ - X - R₁ -Y, where R₁ is a substituted or unsubstituted C₁ - C₂0 aliphatic or aromatic moiety, X is S, and Y is the same or different, and Y is one or more of H, a carboxylic acid group or its salt or ester, a hydroxyl group, a sulfonic acid group or its salt, or an amine group, and The process is such that the first HA derivative is an oxyethyl ethenyl sulfone derivative of hyaluronic acid having the formula: HA-( OCH₂CH₂SO₂CH = CH₂ )n(HA-DVS), n≧ 2 .
  8. formula: B) (Y-R 2 -X-CH 2 CH 2 SO 2 CH 2 CH 2 O) m -HA-(OCH 2 CH 2 SO 2 CH 2 CH 2 -X-R 1 -Y) n A process for producing a hyaluronic acid polymer derivative according to claim 1, comprising: a) To provide a first HA derivative by reacting a hydroxyl group of a hyaluronic acid (HA) polymer with divinyl sulfone (DVS); and b) To provide a second HA derivative by reacting the first HA derivative with i) a nucleophile of formula X'- R1 -Y, or ii) a nucleophile of formula X'- R2 -Y; where R2 is different from R1 , R1 and R2 are each a substituted or unsubstituted C1 - C20 aliphatic or aromatic moiety, X' is a nucleophile of SH, Y is the same or different, and Y is one or more of H, a carboxylic acid group or its salt or ester, a hydroxyl group, a sulfonic acid group or its salt, or an amine group. Includes, The process further includes step c) derivatizing a second HA derivative polymer by repeating steps a) and b) one or more times, The process involves derivatizing 0.25 to 50% of the hydroxyl groups present on the HA polymer into -OCH₂CH₂SO₂CH₂CH₂ - X - R₁ - Y and -OCH₂CH₂SO₂CH₂CH₂ - X - R₂ - Y groups, where R₁ and R₂ are different and are substituted or unsubstituted C₁ - C₂0 aliphatic or aromatic moieties, X is S, and Y is the same or different and is one or more of H, a carboxylic acid group or its salt or ester, a hydroxyl group, a sulfonic acid group or its salt, or an amine group, and the first HA derivative being an oxyethyl ethenyl sulfone derivative of hyaluronic acid having the formula: HA- ( OCH₂CH₂SO₂CH = CH₂ )n(HA-DVS), n≧ 2 .
  9. formula: A) HA-(OCH 2 CH 2 SO 2 CH 2 CH 2 -X-R 1 -Y) n A process for producing a hyaluronic acid polymer derivative according to claim 1, comprising: a) To provide a first HA derivative by reacting a hydroxyl group of a hyaluronic acid (HA) polymer with divinyl sulfone (DVS); and b) To provide a second HA derivative by reacting the first HA derivative with a nucleophile of formula X'- R1 -Y; where R1 is an aromatic moiety, X' is a nucleophile of SH, Y is the same or different, and Y is one or more of H, a carboxylic acid group or its salt or ester, a hydroxyl group, a sulfonic acid group or its salt, or an amine group. Includes, The process further includes step c) derivatizing a second HA derivative polymer by repeating steps a) and b) one or more times, The second HA derivative is HA-( OCH2CH2SO2CH2CH2 - X - R1 - Y )n, where HA is hyaluronic acid, X is sulfur, R1 is an aromatic moiety; Y is one or more of H, a carboxylic acid group or its salt or ester, a hydroxyl group, a sulfonic acid group or its salt, or an amine group, and n≧1, and 0.25-50% of the hydroxyl groups present on the HA polymer are derivatized to the -OCH2CH2SO2CH2CH2 - X - R1 - Y group, where X is sulfur, R1 is an aromatic moiety; and Y is one or more of H, a carboxylic acid group or its salt or ester, a hydroxyl group, a sulfonic acid group or its salt, or an amine group, and the first HA derivative is formula :HA-( OCH2CH2SO2 A process for hyaluronic acid oxyethyl ethenyl sulfone derivatives having CH= CH2 )n(HA-DVS), n≧1.
  10. A process for producing a crosslinked polymer, comprising reacting a hyaluronic acid polymer derivative produced by the process described in any one of claims 4 to 9 with a crosslinking agent to provide a crosslinked polymer.
  11. A composition comprising the hyaluronic acid polymer derivative described in claim 1, or the crosslinked polymer described in claim 2 or 3.
  12. The composition according to claim 11, further comprising a pharmaceutically acceptable excipient, a synthetic polymer, a thermoreversible polymer, a biodegradable polymer, a buffer, a complexing agent, a tonicity modifier, an ionic strength modifier, a solvent, an antioxidant, a preservative, a viscosity modifier, a pH modifier, a surfactant, an emulsifier, a phospholipid, a stabilizer, or a pologen.
  13. The composition according to claim 11 or 12, further comprising a bioactive agent.
  14. A composition according to any one of claims 11 to 13, for use as a wound healing matrix, nasal stent, adhesion prevention barrier, hemostatic agent, filler, skin filler, intra-articular grafting agent, tissue sealant, eye drop, punctal plug, antimicrobial composition, biopsy plug, female contraceptive plug, tissue scaffold, burr hole plug, nerve guide, vaginal lubricant, or coating agent for a device.
  15. A composition according to any one of claims 11 to 13, for use in treating wounds, filling cavities, reducing joint pain, preventing postoperative adhesions, sealing tissue, treating bacterial vaginosis, treating ocular conditions, treating mucositis, treating ear conditions, or assisting tissue growth in a subject.
  16. A medical device comprising the hyaluronic acid polymer derivative according to claim 1, the crosslinked polymer according to claim 2 or 3, and/or the composition according to claim 11.
  17. An additive manufacturing method comprising producing an article containing a hyaluronic acid polymer derivative according to claim 1, or a crosslinked polymer according to claim 2 or 3, or a hyaluronic acid polymer derivative produced by the process described in any one of claims 4 to 9, or a crosslinked polymer produced by the process described in claim 10, using an additive manufacturing machine.
  18. A method for producing electrospun materials or electrospun articles, comprising producing an electrospun material or electrospun article containing a hyaluronic acid polymer derivative according to claim 1, or a crosslinked polymer according to claim 2 or 3, or a hyaluronic acid polymer derivative produced by a process according to any one of claims 4 to 9, or a crosslinked polymer produced by a process according to claim 10, using an electrospinning apparatus.

Description

Cross-reference of related applications This application claims the interests of U.S. Provisional Patent Application No. 62/553,371, filed on September 1, 2017, under Section 119 of the U.S. Patent Act, and this application, without purpose, is incorporated herein by reference in its entirety as part of this specification. Field of Disclosure: This disclosure generally relates to functionalized polymers, including crosslinked polymers, and methods for producing and using them. The polymers of this disclosure offer useful properties that cannot be obtained from currently available polymers. Background: The use of polymer materials as biomaterials has increased in recent years, forming an ever-expanding polymer toolbox. Both synthetic and natural polymers are used as components of biomaterials, and their unique chemical structures can provide specific functions for desired applications. The use of polymers as biomaterials has expanded due to advances in polymer synthesis with controlled functional design, thereby improving the range of possible materials and their biocompatibility. While these biocompatible polymers are useful because they do not specifically interact with biological systems, this hinders their use in applications where natural physiological interactions are desired to manipulate biological responses such as wound healing, binding of cellular or growth factors, or enzymatic degradation. Therefore, there is interest in the use of polymers that are found in living organisms, or polymers that have been modified to provide properties improved from or different from those of unmodified polymers. Examples of such polymers include those containing polyhydric alcohols. A not limited example of such polymers is hyaluronic acid (HA) polymers. HA is a non-sulfated glycosaminoglycan (GAG) composed of repeating high molecular weight disaccharides of D-glucuronic acid and N-acetyl-D-glucosamine linked by glucuronide β(1→3) bonds. In aqueous solution, HA forms a specific stable three-dimensional structure. Despite its simple composition, unchanging sugar composition, and lack of branching points, HA possesses a variety of physicochemical properties. HA polymers exist in several configurations and shapes depending on their size, salt concentration, pH, and the cations they are bound to. Unlike other GAGs, in living organisms, HA does not covalently bond to protein cores but can form aggregates with proteoglycans. HA can encapsulate large volumes of water, making solutions highly viscous even at low concentrations. HA is involved in several physiological processes, such as skin. A key molecule involved in skin hydration is hyaluronan or hyaluronic acid (HA), a glycosaminoglycan (GAG) with the unique ability to bind to and retain water molecules. HA belongs to the extracellular matrix (ECM) molecules. ECM molecules present between cells provide a structural framework and exert major effects on cellular function. While these ECM molecules appear amorphous under a light microscope, they form highly organized structures primarily consisting of GAGs, proteoglycans, growth factors, and structural proteins such as collagen; HA is the major component of the cutaneous ECM. Figure 1 shows the 1H NMR spectrum of divinyl sulfone-modified hyaluronic acid according to this disclosure.Figure 2 shows an exemplary response of the present disclosure.Figure 3 shows an exemplary response of the present disclosure.Figure 4 shows the 1H -NMR spectrum of 2-mercaptobenzoic acid (MBA)-modified hyaluronic acid according to this disclosure.Figure 5 is a graph illustrating the characteristics of exemplary derivatized polymers disclosed herein.Figure 6 is a graph illustrating the characteristics of exemplary derivatized polymers disclosed herein.Figure 7 is a graph illustrating the characteristics of exemplary derivatized polymers disclosed herein.Figure 8 is a graph illustrating the characteristics of exemplary derivatized polymers disclosed herein.Figure 9 is a graph illustrating the characteristics of exemplary derivatized polymers disclosed herein.Figure 10 is a graph illustrating the characteristics of exemplary derivatized polymers disclosed herein.Figure 11 is a graph illustrating the characteristics of exemplary derivatized polymers disclosed herein.Figure 12 is a graph illustrating the characteristics of exemplary derivatized polymers disclosed herein.Figure 13 is a graph showing cell proliferation on exemplary derivatized polymers disclosed herein.Figure 14 is a graph showing cell proliferation on electrospun products containing exemplary derivatized polymers disclosed herein. Detailed Description of the Disclosure This disclosure can be more readily understood by referring to the detailed description of preferred embodiments of the Disclosure below and the examples contained herein. In one embodiment, this disclosure provides a functionalized polymer, including a crosslinked type. A functionalized polymer refers to an organic