Polymeric coupling agents and pharmaceutically-active polymers made therefrom

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...

AI Technical Summary

Benefits of technology

[0039] It is a further object of the present invention to provide said polymer compounds alone as a coating or in admixture with either a base polyurethane, polysilicone, polyester, polyethersulfone, polycarbonate, polyolefin or polyamide for use as said medical devices in the biomedical sector, for improving anti-infection, anti-inflammatory, antimicrobials, anti-coagulation, anti-oxidation, anti-proliferation function.

[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 hydrolysis in vivo to release the biologically-active ingredient. LINK A offers a range of hydrolysis rates by reason of chain length variation and possibly, also, due to steric and conformational variations resulting from the variations in chain length.

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, longterm studies have failed to demonstrate a significant reduction in the number or severity of exit site infections.

In addition, bacterial resistance to silver can develop over time and carries with it the risk of multiple antibiotic resistances (8).

Since bacteria adhesion is a very complex process, complete prevention of bacteria adhesion is difficult to achieve with only a passive approach.

These approaches have the benefit of localized delivery at high drug concentration, but are unable to keep a sustained and controlled release of drug for long periods.

Since the drug release mechanism is totally controlled by porous sizes, making a suitable porous size distribution in the second layer in order to satisfy the required release model is often a technical challenge.

As well, this type of system requires multiple processing steps which increases production cost and adds to the need for QA / QC steps.

However, having such pendant groups will dramatically alter the physical structure of the polymer.

These materials can deliver a large array of drugs, including anti-microbials, anti-coagulants and anti-inflammatory agents, to the surface, however modification is limited to the surface.

This becomes a limitation in a biodegradable polymer which may require sustained activity throughout the bio-erosion process of the polymer.

However, since the reactivities of the carboxylic acid group and the secondary amine group of ciprofloxacin with the isocyanate groups are different, the reaction kinetics become challenging.

As well, formulations must be selective in order to minimize strong van der Waals interactions between the drug components and hydrogen bonding moieties of the polymer chains since this can delay the effective release of drug.

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