Polymeric coupling agents and pharmaceutically-active polymers made therefrom

Inactive Publication Date: 2005-11-17
INTERFACE BIOLOGICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0060] Without being bound by theory, it is believed that the presence of LINK A as hereindefined, allows of a satisfactory “inter-bio distance” in the biologically-active polymer according to the invention, which inter-bio distance facilitates hydr

Problems solved by technology

However, medical device implantation often comes along with the risk of infections (1), inflammation (2), hyperplasia (3), coagulation (4).
Despite the unique biomedical related benefits that any particular group of polymers may possess, the materials themselves, once incorporated into the biomedical device, may be inherently limited in their performance because of their inability to satisfy all the critical biocompatibility issues associated with the specific application intended.
For instance while one material may have certain anti-coagulant features related to platelets it may not address key features of the coagulation cascade, nor be able to resist the colonization of bacteria.
Another material may exhibit anti-microbial function but may not be biostable for longterm applications.
The incorporation of multi-functional character in a biomedical device is often a complicated and costly process which almost always compromises one polymer property or biological function over another, yet all blood and tissue contacting devices can benefit from improved biocompatibility character.
Clotting, toxicity, inflammation, infection, immune response in even the simplest devices can result in death or irreversible damage to the patient.
This is a particularly challenging problem for biodegradable polymer systems when a continuous exposure of new surfaces through erosion of the bulk polymer requires a continuous renewal of biocompatible moieties at the surface.
Unfortunately, such a material would only be applicable for substrates which were not intended to under go biodegradation and exchange with new tissue integration since the heparin in limited to surface and does not form the bulk structure of the polymer chains.
However, longte

Method used

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  • Polymeric coupling agents and pharmaceutically-active polymers made therefrom
  • Polymeric coupling agents and pharmaceutically-active polymers made therefrom
  • Polymeric coupling agents and pharmaceutically-active polymers made therefrom

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0143] NORF-TEG-NORF and CIPRO-TEG-NORF are examples of antimicrobial drug containing biomonomers according to the invention. The example shows the use of a single drug or combination of drugs. The conditions of synthesis for this reaction are as follows.

[0144] In step A, of NORF (1.3 g, 4 mmol) / or CIPRO hydrochloride salt (4 mmol) were reacted with trityl chloride (2.7 g, 8.8 mmol) and TEA (0.6 ml, 8 mmol) (Aldrich, 99%) / or 12 mmol of TEA in the case of CIPRO in 40 ml of CHCl3 for four hours at room temperature. A clear solution was obtained.

[0145] In step B, 40 ml of methanol was added into the above clear solution. The mixture was heated to 50° C. and stirred for one hour, a precipitate appeared in the solution. After the reaction mixture was cooled down to room temperature, precipitates were collected by filtration. The precipitate was further purified from CHCl3 / methanol. 3.4 mmol of Product B were obtained. Yield was usually greater than 85%.

[0146] In step C, Product B (20 ...

example 2

[0152] CIPRO-HDL-CIPRO is an example of biomonomer according to the invention and different from example 1 by the introduction of a hydrophobic link A molecule rather than hydrophilic link A molecule. The conditions of synthesis for this reaction are as follows.

[0153] The reaction conditions for selectively protecting amine groups of CIPRO are the same as the step A and B in Example 1.

[0154] In step C, Product B (20 mmol), HDL (9.5 mmol), DMAP (1.24 g, 10 mmol) are dissolved in 100 ml DCM. EDAC (31 g, 160 mmol) is then added into reaction system. The reaction mixture is stirred at room temperature under a nitrogen atmosphere for one week. After the reaction is finished, DCM is removed by rotary evaporatior. The residues are washed with de-ionized water several times to remove soluble reagents such as the by-product of urea. The solids are then dissolved in chloroform and washed with de-ionized water again. The crude product of the reaction is recovered from the solution by extract...

example 3

[0156] NORF-HDA-NORF is example of biomonomer according to the invention and different from example 1 in that a diamine is used to generate an amide rather than ester linkage in the biomonomer. The conditions of synthesis for this reaction are as follows.

[0157] The reaction conditions for selectively protecting the amine groups of NORF are the same as the step A and B in Example 1.

[0158] In step C, Product B (20 mmol), HDA (9.5 mmol), DMAP (1.24 g, 10 mmol) are dissolved in 100 ml DCM. EDAC (31 g, 160 mmol) is then added into reaction system. The reaction mixture is stirred at room temperature under a nitrogen atmosphere for one week. After the reaction is finished, DCM is removed by rotary evaporatior. The residues are washed with de-ionized water several times to remove soluble reagents such as the by-product of urea. The solids are then dissolved in chloroform and washed with de-ionized water again. The crude product of the reaction is recovered from the solution by extraction....

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Abstract

A pharmaceutically-active polymeric compound of the general formula (I),
Y−[Yn−LINK B−X]m−LINK B  (I)
wherein (i) X is a coupled biological coupling agent of the general formula (II)
Bio−LINK A−Bio  (II)
wherein Bio is a biologically active agent fragment or precursor thereof linked to LINK A through a hydrolysable covalent bond; and LINK A is a coupled central flexible linear first segment of <2000 theoretical molecular weight linked to each of said Bio fragments; (ii) Y is LINK B-OLIGO; wherein (a) LINK B is a coupled second segment linking one OLIGO to another OLIGO and an OLIGO to X or precursor thereof; and (b) OLIGO is a short length of polymer segment having a molecular weight of less than 5,000 and comprising less than 100 monomeric repeating units; (iii) m is 1-40; and (iv) n is selected from 2-50. The compounds are useful as biomaterials, particularly, providing antibacterial a.i. in vivo. Also provided are biological coupling agents useful as intermediates in the preparation of the pharmaceutically-active polymeric compounds.

Description

FIELD OF THE INVENTION [0001] This invention relates to polymeric coupling agents as intermediates, pharmaceutically-active polymers made therefrom, composition comprising said polymers and shaped articles made therefrom. BACKGROUND TO THE INVENTION [0002] It has become common to utilize implantable medical devices for a wide variety of medical conditions, e.g., drug infusion and hemodialysis access. However, medical device implantation often comes along with the risk of infections (1), inflammation (2), hyperplasia (3), coagulation (4). It is therefore important to design such materials to provide enhanced biocompatibility. Biocompatibility is defined as the ability of a material to perform with an appropriate host response in a specific application. The host relates to the environment in which the biomaterial is placed and will vary from being blood, bone, cartilage, heart, brain, etc. Despite the unique biomedical related benefits that any particular group of polymers may possess...

Claims

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Application Information

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IPC IPC(8): A61K31/785A61K47/30A61K47/48A61L27/14A61L27/54H05H1/00
CPCA61K9/0024A61K47/48169A61K47/48215C08G18/73A61K47/48192C08G18/4277A61L27/54A61L2300/406A61L2300/41A61L2300/416A61L2300/42A61L2300/45A61L2300/604A61K47/60A61K47/55A61K47/56A61K47/59A61K47/50A61K47/30A61L27/14
Inventor SANTERRE, PAUL J.LI, MEI
Owner INTERFACE BIOLOGICS INC
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